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| Mendeliome v1.1859 | SERPINA11 |
Ain Roesley gene: SERPINA11 was added gene: SERPINA11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SERPINA11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SERPINA11 were set to 38831697 Review for gene: SERPINA11 was set to RED gene: SERPINA11 was marked as current diagnostic Added comment: 1 family with 2 fetuses. 1st fetus presented with isolated pericardial effusion and a TOP was opted. post mortem: mild subcutaneous edema with subtle facial dysmorphic features small gelatinous glistening cyst on the right pericardium. Bilateral pleural effusion and multiple similar cysts were noted on the lung surfaces 2nd fetus also presented with pleural and pericardial effusion and a TOP was opted post mortem findings were similar to fetus#1 homozygous nonsense variant in SERPINA11 was found p.(Tyr224*) Immunofluorescence of lung sections from fetus#1 and a gestation-matched fetus as a control demonstrated undetectable levels of SERPINA11 in the bronchiolar epithelium Sources: Literature |
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| Mendeliome v1.1857 | PSMD11 |
Bryony Thompson gene: PSMD11 was added gene: PSMD11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PSMD11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PSMD11 were set to 38866022; 30733659 Phenotypes for gene: PSMD11 were set to Neurodevelopmental disorder, MONDO:0700092, PSMD11-related Review for gene: PSMD11 was set to GREEN Added comment: PMID: 38866022 - 10 unrelated children with early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity. Cognitive impairment is recapitulated in a drosophila model. Loss of function is the mechanism of disease PMID: 30733659 - 4 probands with ID and different 17q11.2 deletions spanning PSMD11 Sources: Literature |
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| Mendeliome v1.1855 | VPS50 | Ain Roesley reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis MIM#619685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1853 | PAK2 | Ain Roesley reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38894571, 38712026; Phenotypes: Knobloch syndrome 2 MIM#618458; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1847 | GRXCR2 | Zornitza Stark edited their review of gene: GRXCR2: Added comment: PMID:33528103 reported another family and an unrelated individual from Cameroon with a different homozygous variant (c.251delC/ p.Ile85SerfsTer33).; Changed rating: GREEN; Changed publications: 24619944, 33528103 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1840 | PRRX1 |
Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2. > PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures. ; to: Craniosynostosis (MONDO:0015469), PRRX1-related > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) Agnathia-otocephaly complex, MIM# 202650 >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2. > PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures. |
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| Mendeliome v1.1840 | PRRX1 |
Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.; to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2. > PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures. |
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| Mendeliome v1.1840 | PRRX1 |
Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708).; to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2. |
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| Mendeliome v1.1840 | PRRX1 |
Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doen't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708).; to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). |
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| Mendeliome v1.1840 | PRRX1 |
Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly don't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651); to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly doen't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) >Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). |
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| Mendeliome v1.1840 | PRRX1 |
Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651); to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain. > These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. > These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149) > Authors discuss how the previous reports of agnathia-otocephaly don't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import. Supporting evidence: > Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454) >Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651) |
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| Mendeliome v1.1819 | FLT3LG |
Ain Roesley gene: FLT3LG was added gene: FLT3LG was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FLT3LG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FLT3LG were set to 38701783 Phenotypes for gene: FLT3LG were set to Increased susceptibility to infections Review for gene: FLT3LG was set to RED gene: FLT3LG was marked as current diagnostic Added comment: 3x sibs from a consanguineous family with a homozygous frameshift variant p.(Ser118Alafs*23) recurrent infections and hypoplastic bone marrow with marked reduction in HPSCs KO mice recapitulated BM findings over a period of 5 (P1), 9 (P2), and 19 (P3) years of follow-up, all 3 were found to have moderate anaemia. Total platelet counts and morphology decreased in 2 siblings. Total WBC oscillated between low and normal Eosinophils, basophils were in normal range Neutrophils were in the lower part of the control range, ocassiannly lower total lymphocyte counts were normal Sources: Literature |
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| Mendeliome v1.1817 | TIE1 | Ain Roesley reviewed gene: TIE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38820174; Phenotypes: Lymphatic malformation 11, MIM# 619401; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1816 | ATXN7L3 |
Chirag Patel gene: ATXN7L3 was added gene: ATXN7L3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATXN7L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATXN7L3 were set to PMID: 38753057 Phenotypes for gene: ATXN7L3 were set to Neurodevelopmental disorder, MONDO_0100500 Review for gene: ATXN7L3 was set to GREEN gene: ATXN7L3 was marked as current diagnostic Added comment: This study reports 9 unrelated individuals with de novo heterozygous variants in ATXN7L3 identified through WES testing and GeneMatcher. Core clinical features included: global motor and language developmental delay, hypotonia, and dysmorphic features (hypertelorism, epicanthal folds, blepharoptosis, small nose, small mouth, and low-set posteriorly rotated ears). Variable features included: feeding difficulties, seizures, mild periventricular leukomalacia, and structural cardiac abnormalities. A recurrent nonsense variant [p.(Arg114Ter)] was found in 5/9 individuals. The other variants were 1 frameshift [p.(Ser112LysfsTer12)] and 3 missense variants [p.(Ile71Thr), p.(Ser92Arg), and p.(Leu106Pro)]. They investigated the effects of the recurrent nonsense variant [p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired (as indicated by an increase in histone H2Bub1 levels). This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. Pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Sources: Literature |
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| Mendeliome v1.1814 | FAM177A1 |
Chirag Patel gene: FAM177A1 was added gene: FAM177A1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAM177A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM177A1 were set to PMID: 38767059, 25558065 Phenotypes for gene: FAM177A1 were set to Neurodevelopmental disorder, MONDO_0100500 Review for gene: FAM177A1 was set to GREEN gene: FAM177A1 was marked as current diagnostic Added comment: PMID: 38767059 5 individuals from 3 unrelated families reported with with biallelic loss of function variants in FAM177A1. Clinical features included: global developmental delay, intellectual disability, seizures, behavioural abnormalities, hypotonia, gait disturbance, and macrocephaly. They showed that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA-seq and metabolomic datasets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation. PMID: 25558065 A study of 143 multiplex consanguineous families identified a homozygous frameshift variant in FAM177A1 in 1 family with 4 affected siblings with intellectual disability, dolicocephaly, obesity, and macrocephaly. The variant segregated with all 4 affected siblings and parents were confirmed heterozygous carriers. Sources: Literature |
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| Mendeliome v1.1813 | ERF | Chirag Patel reviewed gene: ERF: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38824261; Phenotypes: Noonan syndrome-like with or without craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1811 | FUZ | Chirag Patel reviewed gene: FUZ: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38702430, 29068549, 34719684; Phenotypes: Ciliopathy_MONDO_0005308, skeletal ciliopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1810 | ANO4 |
Ain Roesley gene: ANO4 was added gene: ANO4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ANO4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ANO4 were set to 38744284 Phenotypes for gene: ANO4 were set to neurodevelopmental disorder MONDO:0700092, ANO4-related Review for gene: ANO4 was set to GREEN gene: ANO4 was marked as current diagnostic Added comment: aka TMEM16D 5x de novo + 2x inherited missense (73% penetrance + asymptomatic) the ones with de novo variants: all had ID, hypotonia 4x skeletal features (scoliosis, funnel chest, pet plants, hyper extensible joints) all had epilepsy all had abnormal MRI Sources: Literature |
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| Mendeliome v1.1808 | KCND1 |
Ain Roesley gene: KCND1 was added gene: KCND1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KCND1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: KCND1 were set to 38772379 Phenotypes for gene: KCND1 were set to neurodevelopmental disorder MONDO:0700092, KCND1-related Review for gene: KCND1 was set to GREEN gene: KCND1 was marked as current diagnostic Added comment: 18 males from 17 families 2x de novo missense + 3x maternal NMDs + 12x maternal missense Some functional studies were done 14x ID 4x delayed motor dev 7x muscular hypotonia 6x epilepsy Sources: Literature |
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| Mendeliome v1.1802 | ICOSLG | Zornitza Stark Phenotypes for gene: ICOSLG were changed from Combined immunodeficiency; recurrent bacterial and viral infections; neutropaenia to Immunodeficiency 119, MIM# 620825; Combined immunodeficiency; recurrent bacterial and viral infections; neutropaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1801 | ICOSLG | Zornitza Stark edited their review of gene: ICOSLG: Changed phenotypes: Immunodeficiency 119, MIM# 620825, Combined immunodeficiency, recurrent bacterial and viral infections, neutropaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1795 | TAP2 | Zornitza Stark Phenotypes for gene: TAP2 were changed from Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis to MHC class I deficiency 2, MIM# 620813; Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1794 | LYZ | Zornitza Stark Phenotypes for gene: LYZ were changed from Amyloidosis, renal, MIM# 105200 to Amyloidosis, renal, MIM# 105200; Amyloidosis, hereditary systemic 5, MIM# 620658 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1787 | AGTR2 |
Zornitza Stark changed review comment from: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267). Sources: Expert Review; to: DISPUTED by ClinGen: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267). Sources: Expert Review |
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| Mendeliome v1.1787 | AGTR2 |
Zornitza Stark gene: AGTR2 was added gene: AGTR2 was added to Mendeliome. Sources: Expert Review disputed tags were added to gene: AGTR2. Mode of inheritance for gene: AGTR2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: AGTR2 were set to X-linked complex neurodevelopmental disorder MONDO:0100148 Review for gene: AGTR2 was set to RED Added comment: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267). Sources: Expert Review |
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| Mendeliome v1.1786 | AVPR1A |
Zornitza Stark gene: AVPR1A was added gene: AVPR1A was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: AVPR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AVPR1A were set to 24924430 Phenotypes for gene: AVPR1A were set to Autism spectrum disorder MONDO:0005258 Review for gene: AVPR1A was set to RED Added comment: DISPUTED by ClinGen: The Arginine Vasopressin Receptor 1A (AVPR1A) was considered a candidate gene in autism spectrum disorder (ASD) based on reports focused on linkage intervals and animal models. Additionally, experimental evidence showed that AVPR1A is possibly involved in social behaviors, including affiliation and attachment (PMID: 24924430). However, these association studies were underpowered—sequencing more individuals may have identified variants of functional significance. In two studies, transmission disequilibrium between AVPR1A microsatellites and autism were found but most were not statistically significant (PMID: 12082568, 16520824). In another study, investigators screened AVPR1A exons in 125 independent autistic probands (PMID: 15098001). However, the study did not demonstrate a disease-causing variant in the coding sequence, and the authors noted that differences in AVPR1A at the amino-acid level are unlikely to confer genetic vulnerability to autism. Experimental evidence is available, but, in the absence of human genetic evidence, such data were not utilized in the scoring. In summary, there is no valid genetic evidence to support an association between AVPR1A and autism spectrum disorder. Sources: Expert list |
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| Mendeliome v1.1783 | LCP1 |
Zornitza Stark gene: LCP1 was added gene: LCP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LCP1 were set to 38710235 Phenotypes for gene: LCP1 were set to Bone marrow failure syndrome, MONDO:0000159, LCP1-related Review for gene: LCP1 was set to AMBER Added comment: 3 individuals from single kindred presenting with fevers, recurrent infections ,lymphopenia, neutropenia and thrombocytopenia. Murine model with similar phenotype. heterozygous LCP1c.740 -1G>A splice site variant hypothesized to cause dominant negative mode of inheritance Sources: Literature |
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| Mendeliome v1.1778 | KCNIP4 |
Ain Roesley gene: KCNIP4 was added gene: KCNIP4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KCNIP4 was set to Unknown Publications for gene: KCNIP4 were set to 33826137 Phenotypes for gene: KCNIP4 were set to seizures; epilepsy Review for gene: KCNIP4 was set to RED gene: KCNIP4 was marked as current diagnostic Added comment: single paper describing insertions of L1 retrotransposons in KCNIP4 samples were post-mortem of resected temporal cortex from individuals with idiopathic temporal lobe epilepsy 1x de novo insertion of L1 in KCNIP4 however ddPCR revealed that this did NOT alter KCNIP4 mRNA expression Sources: Literature |
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| Mendeliome v1.1777 | CHRNA7 |
Ain Roesley gene: CHRNA7 was added gene: CHRNA7 was added to Mendeliome. Sources: Literature cnv tags were added to gene: CHRNA7. Mode of inheritance for gene: CHRNA7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHRNA7 were set to 20979196; 21596161; 21290787 Phenotypes for gene: CHRNA7 were set to intellectual disability; seizures; hypotonia Review for gene: CHRNA7 was set to RED gene: CHRNA7 was marked as current diagnostic Added comment: Homozygous deletion of 15q13.3, which includes CHRNA7, causes ID, hypotonia, seizures, encephalopathy Sources: Literature |
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| Mendeliome v1.1763 | DAGLA |
Zornitza Stark gene: DAGLA was added gene: DAGLA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DAGLA were set to 35737950 Phenotypes for gene: DAGLA were set to Neuroocular syndrome 2, paroxysmal type, MIM# 168885 Review for gene: DAGLA was set to GREEN Added comment: 9 individuals from 8 families reported with daily paroxysmal spells characterized by eye deviation or nystagmus with abnormal head posturing apparent from birth or early infancy. The episodes tend to be triggered after sleeping, and most patients show improvement of the ocular symptoms over time. Affected individuals also have hypotonia, mild developmental delay, dysarthria, and gait ataxia; most have mildly impaired intellectual development. Seizures are not observed. Sources: Literature |
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| Mendeliome v1.1758 | PKHD1L1 |
Sangavi Sivagnanasundram gene: PKHD1L1 was added gene: PKHD1L1 was added to Mendeliome. Sources: Other Mode of inheritance for gene: PKHD1L1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PKHD1L1 were set to non syndromic hearing loss (MONDO:0020678) Review for gene: PKHD1L1 was set to GREEN Added comment: At least 4 individuals from unrelated families with sensorineural hearing loss (SNHL) (2 of the reported probands were from consanguineous parents). The individuals are either homozygous or compound heterozygous for mutations in PKHD1L1 (missense, frameshift and nonsense mutations have been reported). In vitro functional assessment as well as a mini-gene assay of Gly605Arg was conducted. The mini-gene assay on Gly605Arg showed that exon skipping occurs resulting in an in-frame deletion of 48 aa. Both studies didn't use a positive control however loss of function or disruption to protein stability is the speculated mechanism of disease. Sources: Other |
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| Mendeliome v1.1749 | IL27RA |
Ain Roesley gene: IL27RA was added gene: IL27RA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: IL27RA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL27RA were set to 38509369 Phenotypes for gene: IL27RA were set to Epstein-Barr virus infection MONDO:0005111 , IL27RA-related Review for gene: IL27RA was set to AMBER gene: IL27RA was marked as current diagnostic Added comment: 3 children from 2 families with severe acute EBV infection. fam1: homozygous for p.(Gln96*) (NMD-pred) fam2: chet for p.(Arg446Gly) and c.1142-2A>C the splice variant in fam2 was found to to result in an in-frame deletion p.(Gln381_Ala395del) the missense in fam2 is hypothesised to be a hypomorphic allele: - out of 15 Homs in the Finnish database, 2 had hospital diagnoses of EBV IM - expression of this variant on its own results in a weak but detectable IL-27RA expression associated with significant increase in STAT1/3 phosphorus in response to IL-27 stimulation borderline amber/green due to functional studies performed Sources: Literature |
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| Mendeliome v1.1744 | SHH | Ain Roesley reviewed gene: SHH: Rating: GREEN; Mode of pathogenicity: None; Publications: 38562108, 29321670, 32703609; Phenotypes: Hypertelorism, ACC, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1734 | PQLC2 |
Chirag Patel gene: PQLC2 was added gene: PQLC2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PQLC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PQLC2 were set to PMID: 35486108; and online publication GiM Feb 2024 Phenotypes for gene: PQLC2 were set to Retinitis pigmentosa, MONDO:0019200 Review for gene: PQLC2 was set to GREEN gene: PQLC2 was marked as current diagnostic Added comment: HGNC Gene Symbol: SLC66A1 Total 8 individuals from 6 families. Millo et al. (2022)(PMID: 35486108) - WES (with targeted analysis of SLC genes) in 913 cases from 785 families with inherited retinal dystrophy. They identified 2 different homozygous variants in SLC66A1 in 3 individuals from 2 families with adult-onset retinal dystrophy. No functional data. Olinger et al. (2024)(https://www.sciencedirect.com/science/article/pii/S2949774424009804) - CNV analysis of trio and non-trio WGS data from Genomics England 100K genomes project. They identified homozygous 21kb deletion spanning nearly entire SLC66A1 gene in 2 siblings with adult-onset rod-cone dystrophy (parents HTZ carriers). Review of cohort data then identified homozygous LOF variants (1 nonsense, 2 frameshift) in another 3 individuals with rod-cone dystrophy. Sources: Literature |
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| Mendeliome v1.1715 | KIAA1024L |
Achchuthan Shanmugasundram gene: KIAA1024L was added gene: KIAA1024L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KIAA1024L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA1024L were set to 35727972 Phenotypes for gene: KIAA1024L were set to Deafness, autosomal recessive 120, OMIM:620238 Review for gene: KIAA1024L was set to GREEN Added comment: New gene name - MINAR2 PMID:35727972 reported 13 patients from four unrelated families with non-syndromic sensorineural hearing loss. Four of these patients had prelingual onset of severe to profound, progressive bilateral hearing loss. The other nine patients had congenital onset of severe to profound bilateral hearing loss, which was not progressive on one patient, while data was not available for the other. Three different homozygous variants (c.144G > A/ p.Trp48Ter, c.412_419delCGGTTTTG/ p.Arg138Valfs*10 and c.393G > T/ p.Lys131Asn) were identified in MINAR2/ KIAA1024L gene in these patients. There is some functional evidence available for the p.Lys131Asn variant. In addition, mice with loss of function of the Minar2 protein present with rapidly progressive sensorineural hearing loss. This gene has also been associated with relevant phenotype in OMIM (MIM #620238). Sources: Literature |
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| Mendeliome v1.1707 | SHARPIN |
Zornitza Stark gene: SHARPIN was added gene: SHARPIN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SHARPIN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHARPIN were set to 38609546 Phenotypes for gene: SHARPIN were set to Autoinflammatory syndrome, MONDO:0019751, SHARPIN-related Review for gene: SHARPIN was set to GREEN Added comment: Two unrelated patients with homozygous frameshift variants presenting with: P1 - recurrent fever, parotitis, joint inflammation, colitis and chronic otitis media necessitating tympanoplasty P2 - recurrent fever episodes with lymphadenopathy and vomiting every 2–3 weeks. Extensive functional data and mouse model. Sources: Literature |
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| Mendeliome v1.1698 | CADM3 | Zornitza Stark edited their review of gene: CADM3: Added comment: Two additional families reported with a different variant, de novo in one family.; Changed rating: GREEN; Changed publications: 38074074 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1696 | PTCRA |
Achchuthan Shanmugasundram gene: PTCRA was added gene: PTCRA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTCRA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTCRA were set to 38422122 Phenotypes for gene: PTCRA were set to Autoimmunity, HP:0002960; lymphopenia, MONDO:0003783 Review for gene: PTCRA was set to GREEN Added comment: PMID:38422122 reported the identification of 10 individuals from seven kindreds from four different ethnicities with biallelic PTCRA variants (homozygous in five kindreds and compound heterozygous in two kindreds). Six of these 10 patients were clinically asymptomatic at their most recent evaluation, while other four patients displayed infection, lymphoproliferation, and/or autoimmunity with an onset during their teens or in adulthood. One of these patients died from SARS-CoV-2 pneumonia at the age of 24 years. Patient 9 had a small thymus on MRI at the age of 2 years, whereas P5 and P6 had no visible thymus at the ages of 13 and 8 years, respectively. Three of the nine patients with pLOF PTCRA variants tested were found to produce autoantibodies, several of which were associated with clinical manifestations. Anti-thyroid autoantibodies and/or clinically overt thyroiditis were found in three of the nine patients. P7, who suffered from recurrent herpes infections, had autoantibodies against type I interferons. Two of those identified variants are hypomorphic and are associated with autoimmunity. In addition, there is extensive functional and epidemiological data available. Sources: Literature |
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| Mendeliome v1.1695 | RTN2 |
Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy. All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences. Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy. All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain, and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences. Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM. |
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| Mendeliome v1.1695 | RTN2 |
Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences. Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy. All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences. Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM. |
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| Mendeliome v1.1676 | YKT6 |
Zornitza Stark gene: YKT6 was added gene: YKT6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: YKT6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: YKT6 were set to 38522068 Phenotypes for gene: YKT6 were set to Syndromic disease, MONDO:0002254, YKT6-related Review for gene: YKT6 was set to AMBER Added comment: Two individuals homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] exhibited normal prenatal course followed by failure to thrive, developmental delay and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] exhibited neurodevelopmental disorders and optic atrophy. Supportive functional data in Drosophila. Amber rating due to homozygous missense variants and founder effect in two of the families. Sources: Literature |
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| Mendeliome v1.1674 | SEPHS1 |
Zornitza Stark gene: SEPHS1 was added gene: SEPHS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEPHS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SEPHS1 were set to 38531365 Phenotypes for gene: SEPHS1 were set to Neurodevelopmental disorder, MONDO:0700092, SEPHS1-related Review for gene: SEPHS1 was set to GREEN Added comment: Nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Sources: Literature |
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| Mendeliome v1.1664 | MCOLN1 | Zornitza Stark edited their review of gene: MCOLN1: Added comment: PMID 37972748: 23 affected individuals from 13 families with Lisch epithelial corneal dystrophy. WGS in 2 families and then targeted Sanger sequencing in the other families identified 9 rare heterozygous loss of function variants in MCOLN1. Homozygous and compound-heterozygous state of 4 of 9 LECD-associated variants cause Mucolipidosis IV (MLIV), which comprises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. Six parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype. Heterozygous MCOLN1 variants can be associated with incomplete penetrance and variable expressivity of LECD with an estimated penetrance of 0.2% for MCOLN1 loss-of-function variants based on gnomAD.; Changed publications: 37972748; Changed phenotypes: Mucolipidosis IV, MIM# 252650, MONDO:0009653, Lisch epithelial corneal dystrophy, OMIM# 620763; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1660 | DOCK4 |
Sangavi Sivagnanasundram gene: DOCK4 was added gene: DOCK4 was added to Mendeliome. Sources: Other Mode of inheritance for gene: DOCK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DOCK4 were set to PMID: 38526744 Phenotypes for gene: DOCK4 were set to DOCK4-related neurodevelopmental disorder (MONDO:0060490) Review for gene: DOCK4 was set to GREEN Added comment: 7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities. Two of the individuals are reportedly compound heterozygous. Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS). Sources: Other |
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| Mendeliome v1.1657 | DISP1 |
Sangavi Sivagnanasundram changed review comment from: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant. Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well. PMID: 38529886 25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE). A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense). 14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families). HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP. ; to: Gene disease association with differing mechanism of disease depending on the type of causative variant. Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well. PMID: 38529886 25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE). A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense). 14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families). HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP. |
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| Mendeliome v1.1657 | DISP1 |
Sangavi Sivagnanasundram changed review comment from: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant. PMID: 38529886 25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE). A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense). Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function f DISP1 cause HPE as well.; to: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant. Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well. PMID: 38529886 25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE). A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense). 14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families). HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP. |
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| Mendeliome v1.1656 | FRYL |
Ain Roesley gene: FRYL was added gene: FRYL was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FRYL were set to 38479391 Phenotypes for gene: FRYL were set to neurodevelopmental disorder MONDO:0700092, FRYL-related Review for gene: FRYL was set to GREEN gene: FRYL was marked as current diagnostic Added comment: 14 individuals, all de novo except 1x duo testing (not present in tested father) 5x missense + 8x fs/stopgain + 1x canonical splice 13/13 with ID/DD (1x deceased) 4/14 seizures 7/14 with cardiac anomalies such as PDA, TOF, VSD, dextrocardia 1x also has a de novo fs variant in SF3B4 1x also has a de novo stop gain variant in SDHA functional studies using flies were performed Sources: Literature |
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| Mendeliome v1.1654 | KCNB2 |
Ain Roesley gene: KCNB2 was added gene: KCNB2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KCNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNB2 were set to 38503299 Phenotypes for gene: KCNB2 were set to neurodevelopmental disorder MONDO:0700092, KCNB2-related Review for gene: KCNB2 was set to GREEN gene: KCNB2 was marked as current diagnostic Added comment: 7 individuals, all missense 1x from asymptomatic father 2/5 MRI anomalies 2/5 cardiac anomalies 2/7 urogenital anomalies 7/7 with ID 2/7 epilepsy 2/7 hypotonia Sources: Literature |
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| Mendeliome v1.1649 | PLXNB2 |
Chirag Patel gene: PLXNB2 was added gene: PLXNB2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLXNB2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLXNB2 were set to PMID: 38458752 Phenotypes for gene: PLXNB2 were set to Amelogenesis imperfecta MONDO:0019507, PLXNB2 -related; Sensorineural hearing loss disorder MONDO:0020678, PLXNB2 -related Review for gene: PLXNB2 was set to GREEN gene: PLXNB2 was marked as current diagnostic Added comment: 8 individuals from 6 families with core features of amelogenesis imperfecta and sensorineural hearing loss. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. WES and WGS identified biallelic pathogenic variants in PLXNB2 (missense, nonsense, splice and a multiexon deletion variants). Variants segregated with disease. PLXNB2 is a large transmembrane semaphorin receptor protein, and semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Plxnb2 expression was detected in differentiating ameloblasts in mice. Human phenotype overlaps with that seen in Plxnb2 knockout mice. Sources: Literature |
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| Mendeliome v1.1648 | CEP295 |
Chirag Patel gene: CEP295 was added gene: CEP295 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CEP295 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP295 were set to PMID: 38154379 Phenotypes for gene: CEP295 were set to Seckel syndrome 11, OMIM # 620767 Review for gene: CEP295 was set to GREEN gene: CEP295 was marked as current diagnostic Added comment: 4 children from 2 unrelated families with Seckel-like syndrome - severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes. WES identified biallelic pathogenic variants in CEP295 gene (p(Q544∗) and p(R1520∗); p(R55Efs∗49) and p(P562L)). Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying mechanisms. Depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest. Loss of CEP295 caused extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts. Sources: Literature |
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| Mendeliome v1.1646 | SASS6 | Ain Roesley reviewed gene: SASS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 38501757, 36739862; Phenotypes: Microcephaly 14, primary, autosomal recessive, MIM# 616402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1645 | FANCI | Ain Roesley reviewed gene: FANCI: Rating: AMBER; Mode of pathogenicity: None; Publications: 38483614; Phenotypes: primary ovarian failure MONDO:0005387, FANCI-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1634 | FEM1B | Zornitza Stark edited their review of gene: FEM1B: Added comment: Five individuals reported now with same recurrent missense variant, NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells.; Changed rating: GREEN; Changed publications: 31036916, 38465576; Changed phenotypes: Syndromic disease MONDO:0002254, FEM1B-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1633 | USP14 |
Zornitza Stark gene: USP14 was added gene: USP14 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: USP14 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: USP14 were set to 38469793; 35066879 Phenotypes for gene: USP14 were set to Syndromic disease MONDO:0002254, USP14-related Review for gene: USP14 was set to GREEN Added comment: PMID 35066879: 3 fetuses from 2 different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11) in USP14, and sequencing of family members showed segregation with the phenotype. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human multiple congenital contractures phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. PMID 38469793: biallelic USP14 variants in four individuals from three unrelated families: one fetus, a newborn with a syndromic NDD, and two siblings affected by a progressive neurological disease. Specifically, the two siblings from the latter family carried two compound heterozygous variants c.8T>C p.(Leu3Pro) and c.988C>T p.(Arg330*), while the fetus had a homozygous frameshift c.899_902del p.(Lys300Serfs*24) variant and the newborn patient harbored a homozygous frameshift c.233_236del p.(Leu78Glnfs*11) variant. The fetus and the newborn had extensive brain malformations. Sources: Literature |
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| Mendeliome v1.1621 | EHHADH | Bryony Thompson reviewed gene: EHHADH: Rating: GREEN; Mode of pathogenicity: None; Publications: 35738466, 38310177, 24401050; Phenotypes: Fanconi renotubular syndrome 3 MONDO:0014275; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1616 | FHL2 |
Zornitza Stark gene: FHL2 was added gene: FHL2 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: FHL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FHL2 were set to 36854411; 25358972 Phenotypes for gene: FHL2 were set to Cardiomyopathy, MONDO:0004994, FHL2-related Review for gene: FHL2 was set to AMBER Added comment: Emerging evidence that variants in this gene may be associated with cardiomyopathy. Reports of HCM and DCM. c.391C>T (p.Arg131Cys) may be recurrent in early-onset DCM. Sources: Expert Review |
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| Mendeliome v1.1596 | CIAO1 |
Paul De Fazio changed review comment from: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence. PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out. All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1. Sources: Literature; to: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence. Muscle biopsy showed variation in fiber size and an increase in internalized nuclei, as well as scattered degenerating/regenerating fibers and a mild to minimal increase in endomysial fibrosis. Electron microscopy revealed morphologically abnormal mitochondria. PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out. All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1. |
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| Mendeliome v1.1596 | MMS19 |
Paul De Fazio gene: MMS19 was added gene: MMS19 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MMS19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MMS19 were set to 38411040 Phenotypes for gene: MMS19 were set to Neuromuscular disease, MMS19-related (MONDO:0019056) Penetrance for gene: MMS19 were set to unknown Review for gene: MMS19 was set to RED gene: MMS19 was marked as current diagnostic Added comment: Single patient reported with postnatal microcephaly, bilateral cataracts, failure to thrive, progressive spastic tetraparesis, scoliosis, myoclonic epilepsy and precocious puberty. Cerebral MRI at age 4 years showed pontocerebellar atrophy and white matter abnormalities. Patient died age 13 after recurrent respiratory tract infections. A homozygous in-frame deletion p.(Glu213del) was identified. Cell line studies supported pathogenicity of the variant. A zebrafish knockout model also showed a detrimental effect of Mms19 deficincy. Sources: Literature |
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| Mendeliome v1.1596 | CIAO1 |
Paul De Fazio gene: CIAO1 was added gene: CIAO1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CIAO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CIAO1 were set to 38411040; 38196629 Phenotypes for gene: CIAO1 were set to Neuromuscular disease, CIAO1-related (MONDO:0019056) Penetrance for gene: CIAO1 were set to unknown Review for gene: CIAO1 was set to GREEN gene: CIAO1 was marked as current diagnostic Added comment: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence. PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out. All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1. Sources: Literature |
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| Mendeliome v1.1588 | UBAP1L |
Ee Ming Wong gene: UBAP1L was added gene: UBAP1L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UBAP1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UBAP1L were set to PMID: 38293907; 38420906 Phenotypes for gene: UBAP1L were set to Cone-rod dystrophy (MONDO:0015993), UBAP1L-related Review for gene: UBAP1L was set to GREEN gene: UBAP1L was marked as current diagnostic Added comment: - Twelve unrelated families with Hungary, the United States, Israel, Tunisia and the Netherlands with members presenting with autosomal recessive rod-cone or cone-rod dystrophy - Reported variants included splice, nonsense, frameshift and in-frame del variants - Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later. Sources: Literature |
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| Mendeliome v1.1585 | SNF8 |
Chern Lim gene: SNF8 was added gene: SNF8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNF8 were set to 38423010 Phenotypes for gene: SNF8 were set to Neurodevelopmental disorder (MONDO:0700092), SNF8-related Review for gene: SNF8 was set to GREEN gene: SNF8 was marked as current diagnostic Added comment: PMID: 38423010 - Nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8. In total, three putative LoF variants and four missense variants were identified. - The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. - Functional studies using fibroblasts derived from patients and zebrafish model showed LoF is the disease mech. Sources: Literature |
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| Mendeliome v1.1584 | SNUPN |
Suliman Khan gene: SNUPN was added gene: SNUPN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SNUPN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNUPN were set to PMID: 38413582; PMID: 38366623 Phenotypes for gene: SNUPN were set to autosomal recessive limb-girdle muscular dystrophy MONDO:0015152 Review for gene: SNUPN was set to GREEN Added comment: PMID: 38413582: reported 18 children from 15 unrelated families with muscular phenotypes, including proximal upper limb weakness, distal upper and lower limb weakness, and myopathy (EMG) with elevated serum creatinine kinase level. Exome sequencing revealed nine hypomorphic biallelic variants in the SNUPN gene, predominantly clustered in the last coding exon. Functional studies showed that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients’ primary fibroblasts. PMID: 38366623: reported five individuals from two unrelated families with limb-girdle muscular dystrophy. Sources: Literature |
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| Mendeliome v1.1583 | DIP2C |
Melanie Marty gene: DIP2C was added gene: DIP2C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DIP2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DIP2C were set to PMID: 38421105 Phenotypes for gene: DIP2C were set to Neurodevelopmental disorder (MONDO#0700092), DIP2C-related Review for gene: DIP2C was set to GREEN Added comment: PMID: 38421105 - Twenty three patients with het DIP2C variants (10 de novo). All patients had developmental delays affecting expressive language and speech, most had mild dev delay and ID. Four patients had seizures. Additional phenotypic findings were non-specific but recurrent anomalies did include a high anterior hair-line, prominent forehead, and a broad nasal tip. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects,and bicuspid aortic valve) Sources: Literature |
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| Mendeliome v1.1580 | NIT1 |
Paul De Fazio gene: NIT1 was added gene: NIT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NIT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NIT1 were set to 38430071 Phenotypes for gene: NIT1 were set to Cerebrovascular disorder, NIT1-related (MONDO:0011057) Penetrance for gene: NIT1 were set to unknown gene: NIT1 was marked as current diagnostic Added comment: 5 unrelated families reported with recessively inherited cerebral small vessel disease had compound hetereozygous or homozygous variants in NIT1. 1 family (3 siblings) had p.(Ala68*) in trans with p.(Arg243Trp), the remaining 4 families (1 individual each) were all homozygous for p.(Arg243Trp). Patients presented in mid-adulthood with progressive movement disorders (e.g. dystonia, chorea, bradykinesia and tremor, gait disturbance, dysarthria) and had abnormal brain MRI findings (honeycomb appearance of the basal ganglia-thalamus complex, due to numerous strongly dilated PVS). 3 patients had non-lobar intracerebral hemorrhage. Slowly progressive cognitive decline was also a key feature. Metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Note p.(Arg243Trp) has 1 homozygote in gnomAD v4, but permitted due to later presentation in reported patients. Sources: Literature |
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| Mendeliome v1.1578 | FEZF2 |
Ain Roesley gene: FEZF2 was added gene: FEZF2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FEZF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FEZF2 were set to 38425142 Phenotypes for gene: FEZF2 were set to neurodevelopmental disorder MONDO:0700092, FEZF2-related Review for gene: FEZF2 was set to GREEN gene: FEZF2 was marked as current diagnostic Added comment: - 7 indiv but 1 has whole gene deletion and 6x SNV (4x PTCs and 2x same missense Arg344Cys) - of the 6x SNV, 4x de novo + 1x from affected father - all have ID/ASD - 1x seizures - 1x hypotonia - 1x motor coordination disorder - 2x enuresis after 7yo Sources: Literature |
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| Mendeliome v1.1576 | ZFX |
Zornitza Stark gene: ZFX was added gene: ZFX was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZFX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: ZFX were set to 26350204; 26740508; 38325380 Phenotypes for gene: ZFX were set to Neurodevelopmental disorder, MONDO:0700092, ZFX-related Review for gene: ZFX was set to GREEN Added comment: A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508). PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model. Sources: Literature |
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| Mendeliome v1.1543 | ONECUT1 |
Bryony Thompson gene: ONECUT1 was added gene: ONECUT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ONECUT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ONECUT1 were set to 37639628; 34663987; 10825208 Phenotypes for gene: ONECUT1 were set to Neonatal diabetes mellitus MONDO:0016391 Review for gene: ONECUT1 was set to GREEN Added comment: 3 unrelated neonatal diabetes cases with homozygous variants & supporting iPSC/mouse models PMID: 37639628 - UK biobank study of ONECUT1 variants in neonatal diabetes mellitus (NDM), MODY, and type 2 diabetes. Identified a case with syndromic NDM with a homozygous frameshift (p.Met289Argfs*8). Rare heterozygous variants were not enriched in individuals with suspected MODY (n=484). Heterozygous null variants were significantly associated with type 2 diabetes (p=0.006) as a potential susceptibility gene. PMID: 34663987 - 2 consanguineous families with homozygous variants (Glu231Ter or Glu231Asp) in cases with syndromic ND. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation. PMID: 10825208 - Hnf6 (old gene name) null mice have diabetes Sources: Literature |
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| Mendeliome v1.1537 | PRDM8 |
Zornitza Stark gene: PRDM8 was added gene: PRDM8 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PRDM8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRDM8 were set to 2296154; 35034233 Phenotypes for gene: PRDM8 were set to Epilepsy, progressive myoclonic, 10 MIM#616640 Review for gene: PRDM8 was set to RED Added comment: - PMID:22961547, 3 individuals from one family, all with myoclonic epilepsy, all had the Phe261Leu variant. This variant is absent from gnomAD V4. - PMID: 35034233, Two individuals from one family, no clinical seizures but presented with myoclonus and abnormal EEG (generalised epileptiform charges), these individuals had the Ala230Gly missense change, which has currently been reported as a VUS. Sources: Expert list |
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| Mendeliome v1.1536 | PRIMA1 |
Zornitza Stark gene: PRIMA1 was added gene: PRIMA1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PRIMA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRIMA1 were set to 26339676 Phenotypes for gene: PRIMA1 were set to Frontal Lobe Epilepsy MONDO:0002612 Review for gene: PRIMA1 was set to RED Added comment: - 2/3 siblings from unaffected parents in PMID: 26339676 were diagnosed with nocturnal frontal lobe epilepsy, which was confirmed by EEG. The affected siblings were homozygous for the c.93+2T>C variant canonical splice site variant. This variant was demonstrated by mini-gene assay to skip exon 2 of PRIMA1. Overall 1 family, 2 individuals with epilepsy and high impact variants in PRIMA1. Sources: Expert list |
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| Mendeliome v1.1534 | PLXNC1 |
Zornitza Stark gene: PLXNC1 was added gene: PLXNC1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PLXNC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLXNC1 were set to 36808730 Phenotypes for gene: PLXNC1 were set to Malformations of cortical development Review for gene: PLXNC1 was set to RED Added comment: This gene was included in the genes4epilepsy resource (PMID:36808730) and was reported as being associated with the clinical phenotype "malformations of cortical development". There are no current PubMed articles linking this gene with epilepsy however Sources: Expert list |
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| Mendeliome v1.1532 | CASZ1 |
Zornitza Stark gene: CASZ1 was added gene: CASZ1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CASZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CASZ1 were set to 28099117; 36293425; 31268246 Phenotypes for gene: CASZ1 were set to Dilated cardiomyopathy, MONDO:0005021, CASZ1-related; left ventricular non compaction Review for gene: CASZ1 was set to GREEN Added comment: Rare cause of paeditric onsent DCM. at least 3 papers report LoF variants, 2 of which each report a novel de novo frameshift variant in children diagnosed with DCM less than 1 and who died at 11 mths ( PMID: 31268246; Guo 2019) and 22mths (PMID: 36293425, Orlova 2022). Another paper (PMID: 28099117, Qiu 2017) reported a nonsense variant that segregated with DCM in a family in an AD fashion (full text not available). Sources: Expert list |
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| Mendeliome v1.1529 | NDUFB9 |
Zornitza Stark edited their review of gene: NDUFB9: Added comment: PMID: 38129218: Thr144Met, listed as ACMG-P, hom in 1x pt with mito complex I deficiency and leukodystrophy, no functional studies, both parents are het. However, this variant has 2 homozygotes in gnomADv4 so unlikely pathogenic.; Changed publications: 22200994, 38129218 |
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| Mendeliome v1.1528 | SMC3 | Bryony Thompson reviewed gene: SMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38297832; Phenotypes: Cornelia de Lange syndrome MONDO:0016033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1513 | NUP160 |
Melanie Marty changed review comment from: PMID: 30910934 1 x patient with familial steroid-resistant nephrotic syndrome (SRNS) and FSGS carried novel compound-heterozygous variants in NUP160 (R1173X and E803K). Silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by the expression of the wild-type human NUP160 gene in nephrocytes. PMID: 30179222 1 x family (2 sibs) with compound het variants E803K and Arg910X. 1 Sib had SRNS and FSGS, the other had proteinuria. PMID: 33456446 1 x family (2 sibs) with steroid-resistant nephrotic syndrome and chronic kidney disease. Homozygous for NUP160 c.1179+5G>A, confirmed by RT-PCR to cause abnormal splicing [r.1102_1179del;p.(Phe368_Gln393del)]. These individuals also had additional neurological features of intellectual disability and epilepsy. PMID: 38224683 Generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse mode using CRISPR/Cas9 and Cre/loxP technologies. They showed that Nup160podKO mice develop typical signs of NS.; to: PMID: 30910934 1 x patient with familial steroid-resistant nephrotic syndrome (SRNS) and FSGS carried novel compound-heterozygous variants in NUP160 (R1173X and E803K). Silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by the expression of the wild-type human NUP160 gene in nephrocytes. PMID: 30179222 1 x family (2 sibs) with compound het variants E803K and Arg910X. 1 Sib had SRNS and FSGS, the other had proteinuria. PMID: 33456446 1 x family (2 sibs) with SRNS and chronic kidney disease. Homozygous for NUP160 c.1179+5G>A, confirmed by RT-PCR to cause abnormal splicing [r.1102_1179del;p.(Phe368_Gln393del)]. These individuals also had additional neurological features of intellectual disability and epilepsy. PMID: 38224683 Generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. They showed that Nup160podKO mice develop typical signs of NS. |
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| Mendeliome v1.1511 | MEI4 |
Lisa Norbart changed review comment from: PMID: 38252283 - 5x compound heterozygous missense variants and 1x homozygous missense variant seen in five individuals across 4 unrelated families affected with female infertility characterised by preimplantation embryonic arrest. Includes one family with two affected sisters with the same compound heterozygous variants. 2/4 families showed inheritance, parental data not available for other two families. Homozygous variant in the consanguineous family appears with a more severe phenotype. In vitro evidence shows variants reduced the interactions between MEI4 and DNA, but no effects on protein levels. In vivo knock-out mouse model showed female mice were infertile, characterised by developmental defects during oogenesis. Sources: Literature; to: PMID: 38252283 - 5x compound heterozygous missense variants and 1x homozygous missense variant seen in five individuals across 4 unrelated families affected with female infertility characterised by preimplantation embryonic arrest. Includes one family with two affected sisters with the same compound heterozygous variants. 2/4 families showed inheritance, parental data not available for other two families. Homozygous variant in the consanguineous family appears with a more severe phenotype. In vitro evidence shows variants reduced the interactions between MEI4 and DNA, but no effects on protein levels. In vivo knock-out mouse model showed female mice were infertile, characterised by developmental defects during oogenesis. Sources: Literature |
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| Mendeliome v1.1507 | MEI4 |
Lisa Norbart gene: MEI4 was added gene: MEI4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MEI4 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: MEI4 were set to 38252283 Phenotypes for gene: MEI4 were set to Infertility disorder, MONDO:0005047, MEI4-related Review for gene: MEI4 was set to GREEN Added comment: PMID: 38252283 - 5x compound heterozygous missense variants and 1x homozygous missense variant seen in five individuals across 4 unrelated families affected with female infertility characterised by preimplantation embryonic arrest. Includes one family with two affected sisters with the same compound heterozygous variants. 2/4 families showed inheritance, parental data not available for other two families. Homozygous variant in the consanguineous family appears with a more severe phenotype. In vitro evidence shows variants reduced the interactions between MEI4 and DNA, but no effects on protein levels. In vivo knock-out mouse model showed female mice were infertile, characterised by developmental defects during oogenesis. Sources: Literature |
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| Mendeliome v1.1506 | WDR44 |
Andrew Fennell gene: WDR44 was added gene: WDR44 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: WDR44 were set to PMID: 38191484 Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308, WDR44-related Review for gene: WDR44 was set to GREEN Added comment: 11 male patients with 6 missense and 1 nonsense variant in WDR44 displaying a wide range of cognitive impairment and variable congenital anomalies associated with primary cilium dysfunction. All patients had learning difficulties with 8 labelled as intellectually disabled (mild-moderate). Other clinical features included anomalies of craniofacial, musculoskeletal, brain, renal and cardiac development. WDR44 is a negative regulator of ciliogenesis. Increased binding is hypothesised to underlie the pathogenicity of WDR44 variants identified in this cohort. Functional data supported impaired ciliogenesis initiation in patient fibroblasts and a zebrafish model. A zebrafish model recapitulated the human phenotype when morphants expressed WDR44 L668S, D669N, S764F, G782C, H839R, and R733* variants. Of note, D648G or N840S did not recapitulate the phenotype in the zebrafish model. The studies supported a GoF mechanism, but the authors could not rule out that LoF of WDR44 contributes to the ciliopathy-like phenotype observed, because protein expression data was only available for a limited number of patients. Sources: Literature |
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| Mendeliome v1.1502 | SH2B3 | Ain Roesley reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37206266, 23908464, 38152053; Phenotypes: Myeloproliferation and multi-organ autoimmunity, juvenile myelomonocytic leukemia MONDO:001190, SH2B3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1502 | SAMD7 |
Paul De Fazio gene: SAMD7 was added gene: SAMD7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SAMD7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SAMD7 were set to 38272031 Phenotypes for gene: SAMD7 were set to Macular dystrophy, retinal, SAMD7-related MONDO:0031166 Review for gene: SAMD7 was set to GREEN gene: SAMD7 was marked as current diagnostic Added comment: Five biallelic variants were identified in eight individuals from six families with macular dystrophy with or without cone dysfunction. Three families were consanguineous. Mean age at first presentation was 34.8 years, range 14 to 51. Four variants affected splicing, while one missense variant impaired the repressive activity of SAMD7. All functional work was performed using in vitro assays. Sources: Literature |
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| Mendeliome v1.1457 | SPIN4 |
Belinda Chong gene: SPIN4 was added gene: SPIN4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SPIN4 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: SPIN4 were set to 36927955 Phenotypes for gene: SPIN4 were set to Lui-Jee-Baron syndrome MIM#301114 Review for gene: SPIN4 was set to AMBER Added comment: PMID 36927955 * Single family, hemizygous frameshift variant (NM_001012968.3, c.312_313AGdel) identified in a male individual with generalized overgrowth of prenatal onset, variant also present in the mother and grandmother (both had adult heights 2 SDS greater than their midparental heights). * In vitro shows loss of function and mice studies recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Sources: Literature Sources: Literature |
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| Mendeliome v1.1457 | SOX8 |
Paul De Fazio gene: SOX8 was added gene: SOX8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SOX8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SOX8 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200088 Phenotypes for gene: SOX8 were set to Neurodevelopmental disorder (MONDO:0700092), SOX8-related Review for gene: SOX8 was set to RED gene: SOX8 was marked as current diagnostic Added comment: Proband presented to genetics clinic at 27 years of age with BMI -3.4SD, height -2.7SD, head circumference -1.8SD. She had mild intellectual delay and clinical features of a congenital, nonprogressive myopathy with moderate proximal and distal weakness. X-rays showed skeletal dysplasia, including cervical thoracic scoliosis and lumbar scoliosis. She was reported as having had weakness at birth with poor suck, micrognathia, hypotonia, and talipes. She was documented to have significant motor delay as a child. MRI of the brain demonstrated large posterior fossa CSF spaces. Biallelic SOX8 variants biallelic (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)) were identified by WGS. The +5 variant was shown to affect splicing, while the frameshift variant resulted in production of low-level truncated protein (not NMD predicted). Functional studies on patient fibroblasts showed misregulation of downstream SOX8 targets. Sources: Literature |
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| Mendeliome v1.1457 | BORCS8 |
Lauren Rogers changed review comment from: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. Sources: Literature; to: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. 5/5 hypotonia, failure to thrive, global developmental delay, profound intellectual disability, muscle weakness and atrophy, dysmorphic features. 3/5 with microcephaly, 3/5 with seizures, 4/5 with spasticity, 3/5 with scoliosis, 4/4 with optic atrophy. HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. Sources: Literature |
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| Mendeliome v1.1457 | BORCS8 |
Lauren Rogers gene: BORCS8 was added gene: BORCS8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BORCS8 were set to 38128568 Phenotypes for gene: BORCS8 were set to Neurodevelopmental disorder (MONDO#0700092), BORCS8-related Review for gene: BORCS8 was set to GREEN Added comment: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. Sources: Literature |
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| Mendeliome v1.1457 | GTPBP1 |
Lucy Spencer gene: GTPBP1 was added gene: GTPBP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTPBP1 were set to 38118446 Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder (MONDO#0700092), GTPBP1-related Review for gene: GTPBP1 was set to GREEN Added comment: PMID: 38118446- Cohort of individuals with variants in GTPBP2 (which has been previously described) and GTPBP1 (new) who have an identical neurodevelopmental syndrome. 4 homozygous individuals from 3 consanguineous families. 2 families have different NMD-predicted nonsense variants and the third has a missense, all are absent from gnomad v4. The shared cardinal features of GTPBP1 and 2 related disease are microcephaly, profound neurodevelopmental impairment, and distinctive craniofacial features. Epilepsy was present in 10 of 20 individuals but its not clear if those individuals had GTPBP1 or 2 variants. Sources: Literature |
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| Mendeliome v1.1442 | LCK |
Zornitza Stark edited their review of gene: LCK: Added comment: Additional cases: PMID 38100037: Description of a second unrelated patient with novel biallelic missense LCK c.1393T>C, p.C465R variant in a patient from a consanguineous Syrian family with profound T-cell immune deficiency characterized by complete LCK protein expression deficiency and ensuing proximal TCR signaling-and CD4 and CD8-co-receptor-mediated functional and phenotypical defects. PMID: 27087313 reported 3 siblings of a consanguineous family presenting with recurrent pneumonia and severe viral skin disease leading to malignant transformation. The patients had an intronic LCK c.188-2A>G splice site variant resulting in skipping of exon 3 and mRNA decay. Clinical data alongside with CD4+ T-cell lymphocytopenia suggested a hypomorphic LCK deficiency.; Changed rating: GREEN; Changed publications: 22985903, 1579166, 11021796, 27087313, 38100037 |
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| Mendeliome v1.1436 | MAP1LC3B2 |
Zornitza Stark gene: MAP1LC3B2 was added gene: MAP1LC3B2 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: MAP1LC3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAP1LC3B2 were set to 35748970; 33310865 Phenotypes for gene: MAP1LC3B2 were set to Hereditary susceptibility to infection, MONDO:0015979, MAP1LC3B2 -related; Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2 Review for gene: MAP1LC3B2 was set to RED Added comment: PMID: 35748970 Affects CNS (resident cells and fibroblasts) Impaired autophagy induction after HSV2 infection - increased viral replication and apoptosis of patient fibroblasts. PMID: 33310865 one affected individual with heterozygous variant in MAP1LC3B2 (p.L109M) Sources: Expert Review |
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| Mendeliome v1.1415 | RAB1A |
Zornitza Stark gene: RAB1A was added gene: RAB1A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RAB1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAB1A were set to 37924809 Phenotypes for gene: RAB1A were set to neurodevelopmental disorder MONDO:0700092, RAB1A-related Review for gene: RAB1A was set to AMBER Added comment: Four families and 5 individuals, 2/5 have speech delay and 4/5 have motor delay. Anxiety in 3/5 and autism in 2/5. Microcephaly in only one individual, spastic paraplegia observed in 2 individuals from one family. In 2 families variants were inherited from an affected parent. Sources: Literature |
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| Mendeliome v1.1408 | CEP192 |
Chern Lim gene: CEP192 was added gene: CEP192 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CEP192 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CEP192 were set to 37981762 Phenotypes for gene: CEP192 were set to microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size Review for gene: CEP192 was set to RED gene: CEP192 was marked as current diagnostic Added comment: PMID: 37981762: - In one family, chet missense p.His638Tyr and p.Asn1917Ser segregated with microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size in two affected siblings. Both sibs also fulfilled dx for mosaic variegated aneuploidy (MVA) syndrome and have tetraploidy. - A lower but substantial proportion of MVA/tetraploidy cells was observed in II-1, II-2, and II-4 (who are het for one of the variants). - In the same family, each variants in heterozygous state segregated with infertility and/or reduced testicular size in the proband’s father and maternal uncle. - Variant screening of CEP192 coding regions performed for 1264 unrelated males with idiopathic infertility. - Asn1917Ser was also detected in three additional unrelated infertile males with reduced testicular volumes. - Two other missense and two synonymous variants were repeatedly detected in infertile males. - qPCR showed CEP192 expression was decreased in individuals with c.1912C>T His638Tyr, mini-gene assay showed that c.1912C>T His638Tyr led to the skipping of exon 14, predicted to result in NMD. - Epithelial cells cultured in vitro from patients with biallelic variants showed the number of cells arrested during the prophase increased because of the failure of spindle formation. - Embyronic mouse lethality in Cep192-/- (hom for His638Tyr), Cep192M/M (hom for Asn1917Ser) and Cep192-/M (chet). - Embryos of Cep192M/M mice had significant increase of MVA and tetraploidy cells. - Number of apoptotic cells increased in Cep192M/M embryos compared with that of Cep192+/+, similar result in Cep192-/- embryos. - Male mice with Cep192 heterozygous variants replicated infertility Conclusions: - Association of this gene with autosomal recessive disease has not been established. - Association of monoallelic variants in this gene with infertility is not well established: - Two variants with some supportive evidence from mouse model. Sources: Literature |
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| Mendeliome v1.1408 | SV2A |
Karina Sandoval changed review comment from: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous. This paper references 5 other families with both AR & AD Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother (in gnomAD v2 1 het, absent from gnomAD v3) Family #3 – p.Gly660Arg, AD, de novo Family #4 – p.Gly660Arg, AD, segregated in 11 family members Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers Sources: Literature; to: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo with p.Arg289Ter and another 5yo from another paper with homozygous p.Arg383Gln, reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. This paper references 5 other families with both AR & AD Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother (in gnomAD v2 1 het, absent from gnomAD v3) Family #3 – p.Gly660Arg, AD, de novo Family #4 – p.Gly660Arg, AD, segregated in 11 family members Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers Sources: Literature |
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| Mendeliome v1.1408 | SV2A |
Karina Sandoval changed review comment from: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous. This paper references 5 other families with both AR & AD Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother Family #3 – p.Gly660Arg, AD, de novo Family #4 – p.Gly660Arg, AD, segregated in 11 family members Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers Sources: Literature; to: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous. This paper references 5 other families with both AR & AD Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother (in gnomAD v2 1 het, absent from gnomAD v3) Family #3 – p.Gly660Arg, AD, de novo Family #4 – p.Gly660Arg, AD, segregated in 11 family members Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers Sources: Literature |
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| Mendeliome v1.1405 | SV2A |
Karina Sandoval gene: SV2A was added gene: SV2A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SV2A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: SV2A were set to PMID: 37985816 Phenotypes for gene: SV2A were set to Epilepsy, MONDO:0005027 Review for gene: SV2A was set to GREEN Added comment: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous. This paper references 5 other families with both AR & AD Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother Family #3 – p.Gly660Arg, AD, de novo Family #4 – p.Gly660Arg, AD, segregated in 11 family members Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers Sources: Literature |
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| Mendeliome v1.1402 | SLC19A1 | Paul De Fazio reviewed gene: SLC19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36517554, 36745868; Phenotypes: Combined immunodeficiency, SLC19A1-related MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1402 | KCNJ3 |
Daniel Flanagan gene: KCNJ3 was added gene: KCNJ3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: KCNJ3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNJ3 were set to PMID: 37963718 Phenotypes for gene: KCNJ3 were set to Epilepsy (MONDO#0005027), KCNJ3-related Review for gene: KCNJ3 was set to AMBER Added comment: Two de novo missense variants, p.(Leu333Ser) and p.(Arg313Gln), were identified in two unrelated probands with epilepsy. 1/2 had developmental delay. Whole-cell patch-clamp functional studies showed a significantly reduction in current amplitude and density. Kcnj3-knockout mice display hyperactivity and decreased anxiety, while a knock-in mouse line displays spontaneous seizure-like activity. Sources: Expert list |
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| Mendeliome v1.1401 | PLA2G16 |
Lauren Rogers changed review comment from: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy. Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte diferentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. Sources: Literature; to: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy. Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. Sources: Literature |
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| Mendeliome v1.1401 | PLA2G16 |
Lauren Rogers gene: PLA2G16 was added gene: PLA2G16 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLA2G16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PLA2G16 were set to PMID: 37919452 Phenotypes for gene: PLA2G16 were set to Lipodystrophy (MONDO:0006573) Review for gene: PLA2G16 was set to GREEN Added comment: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy. Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte diferentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. Sources: Literature |
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| Mendeliome v1.1401 | MARK4 |
Rylee Peters gene: MARK4 was added gene: MARK4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MARK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MARK4 were set to PMID: 38041405 Phenotypes for gene: MARK4 were set to neurodevelopmental disorder (MONDO:0700092), MARK4-related Mode of pathogenicity for gene: MARK4 was set to Other Review for gene: MARK4 was set to AMBER gene: MARK4 was marked as current diagnostic Added comment: Missense variant, c.604T>C; p.Phe202Leu, identified in two siblings with childhood-onset neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and dysmorphic features. The variant is located in the catalytic domain of the kinase, and is inherited from unaffected mosaic mother. Functional investigation revealed that the variant results in a gain-of-function in the ability of MARK4 to phosphorylate tau and leads to up-regulation of the mTORC1 pathway. Sources: Literature |
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| Mendeliome v1.1401 | SEL1L |
Sarah Pantaleo gene: SEL1L was added gene: SEL1L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEL1L were set to PMID: 37943610; PMID: 37943617 Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder, MONDO:0700092, SEL1L-related Penetrance for gene: SEL1L were set to Complete Added comment: Wang paper PMID: 37943610 SEL1L protein is involved in the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation. Report two biallelic missense variants in SEL1L in six children from three independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia and/or ataxia (termed ERAD-associated neurodevelopment disorder with onset in infancy (ENDI). The variants were hypomorphic and impaired ERAD function. Identified by WES. Parents heterozygous and asymptomatic. P.(Gly585Asp) in Patient 1, p.(Met528Arg) in Patients 2 and 3 (siblings). All variants cause substrate accumulation. The extent of substrate accumulation in knockin cells was modest compared to those in knockout cells, pointing to a hypomorphic nature. They also had a variant in HRD1. Weis paper PMID: 37943617 Third variant p.(Cys141Tyr), biallelic, causing premature death in five patients from a consanguineous family with early-onset neurodevelopmental disorders and agammaglobulinaemia due to severe SEL1L-HRD1 ERAD dysfunction. This variant appears to have a more severe outcome, exhibiting B cell depletion and agammaglobulinaemia, causing the most severe dysfunction among all of the variants described by this group so far. They postulate that functionality of SEL1L-HRD1 ERAD is inversely correlated with disease severity in humans. Their symptoms were dev delay, neurological disorder and agammaglobulinaemia in childhood. Along with severe axial hypotonia, short stature and microcephaly. “Not a complete loss-of-function variant”. Sources: Literature |
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| Mendeliome v1.1400 | COL17A1 | Zornitza Stark Phenotypes for gene: COL17A1 were changed from Epidermolysis bullosa, junctional 4, intermediate MIM#619787; Epithelial recurrent erosion dystrophy MIM#122400 to Epidermolysis bullosa, junctional 4, intermediate MIM#619787; Epithelial recurrent erosion dystrophy MIM#122400; Amelogenesis imperfecta MONDO:0019507, COL17A1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1335 | AGPAT3 |
Ee Ming Wong gene: AGPAT3 was added gene: AGPAT3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AGPAT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGPAT3 were set to 37821758 Phenotypes for gene: AGPAT3 were set to Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related Review for gene: AGPAT3 was set to GREEN gene: AGPAT3 was marked as current diagnostic Added comment: - Single consanguineous family with four individuals with severe intellectual disability and retinitis pigmentosa - All affected individuals were homozygous for a nonsense variant in AGPAT3, healthy unaffected individuals who were tested were heterozygous for the variant - Overexpression of mutant transcript revealed absence of AGPAT3 protein compared to WT transcript via Western blot analysis - KO AGPAT3 mouse demonstrated impaired neuronal migration Sources: Literature |
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| Mendeliome v1.1330 | LRRC23 |
Belinda Chong gene: LRRC23 was added gene: LRRC23 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LRRC23 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRRC23 were set to 37804054 Phenotypes for gene: LRRC23 were set to Non-syndromic male infertility due to sperm motility disorder MONDO:0017173 Review for gene: LRRC23 was set to RED Added comment: PMID 37804054: A homozygous nonsense mutation in LRRC23 (c.376C>T: p. Arg126X) in an infertile AZS patient whose parents were consanguineous. We verified the adversity of this novel mutation because of its ability to disrupt LRRC23 synthesis and impair RSs integrity. Furthermore, we demonstrated an interaction between LRRC23 and RSPH3 in vitro, indicating that LCCR23 is associated with RS in humans. Meanwhile, the LRRC23-mutant patient had a good prognosis following intracytoplasmic sperm injection. Sources: Literature |
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| Mendeliome v1.1330 | CASP2 |
Lisa Norbart gene: CASP2 was added gene: CASP2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CASP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CASP2 were set to 37880421 Phenotypes for gene: CASP2 were set to neurodevelopmental disorder MONDO:0700092, CASP2-related Penetrance for gene: CASP2 were set to Complete Review for gene: CASP2 was set to GREEN gene: CASP2 was marked as current diagnostic Added comment: 7 patients from 5 families 4 families hom for PTCs, 1 family Chet for splice+PTC RNA studies done for the splice to indicate usage of two cryptic splice donor sites 5/5 have ID/dev delay 1/5 has seizures 2/5 hypotonia 3/5 lissencephaly (pachygyria and cortical thickening) Sources: Literature |
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| Mendeliome v1.1324 | SAT1 | Chirag Patel reviewed gene: SAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35977808; Phenotypes: Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1318 | ZFHX3 | Zornitza Stark edited their review of gene: ZFHX3: Added comment: 41 individuals with protein truncating variants (PTVs) or (partial) deletions of ZFHX3. Presentations included (mild) ID and/or behavioural problems, postnatal growth retardation, feeding difficulties, dysmorphism (rarely cleft palate). Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation in neural stem cells and SH-SY5Y cells, ZFHX3 interacts with the chromatin remodelling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex. ZFHX3 haploinsufficiency associates with a specific DNA methylation profile in leukocyte-derived DNA, and participates in chromatin remodelling and mRNA processing.; Changed publications: 37292950; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1306 | ZFHX3 | Chirag Patel reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37292950; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1296 | IRF1 | Zornitza Stark edited their review of gene: IRF1: Added comment: PMID 36736301: Two unrelated children with recurrent early-onset life-threatening mycobacterial diseases due to multiple mycobacteria (BCG, M. avium). Homozygous LoF vairiants with extensive supporting functional data.; Changed rating: GREEN; Changed publications: 36736301; Changed phenotypes: Inherited susceptibility to mycobacterial disease, MONDO:0019146, IRF1-related; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1293 | IRF4 | Zornitza Stark edited their review of gene: IRF4: Added comment: PMID 36662884: Seven individuals with profound CID from six kindreds of diverse ethnic origins (Fig. 1A). All affected individuals suffered with early onset (<1 year of age) recurrent sinopulmonary infections, with the opportunistic pathogen Pneumocystis jirovecii causing pneumonia in most individuals. p.T95R variant found in all patients. Extensive functional data including knockout mouse model. The heterozygous IRF4T95R variant found in multiple unrelated families caused a fully penetrant, severe very early-onset immunodeficiency characterized by greatly enhanced susceptibility to opportunistic pathogens such as P. jirovecii and weakly pathogenic mycobacteria.; Changed rating: GREEN; Changed publications: 29537367, 36662884; Changed phenotypes: Combined immunodeficiency, MONDO:0015131, IRF4-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1289 | CR2 | Zornitza Stark edited their review of gene: CR2: Added comment: PMID:28499783 reported two siblings from consanguineous parents, both with a homozygous frameshift variant in CR2 and with recurrent respiratory infections and hypogammaglobulinaemia.; Changed rating: GREEN; Changed publications: 22035880, 26325596, 28499783 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1287 | HMOX1 | Zornitza Stark edited their review of gene: HMOX1: Added comment: PMID:33066778 provides a third case in support of promoting HMOX1 to green rating. This third case is a boy born to nonconsanguineous parents who presented with early onset asplenia, recurrent infections, and associated flares with bone marrow histiocyte activation with worsening interstitial lung disease and joint pain. This boy harboured compound heterozygous variants (p.L89Sfs*24 and p.Ala88Profs*51).; Changed rating: GREEN; Changed publications: 21088618, 9884342, 20844238, 33066778 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1283 | MCM9 | Natalie Tan reviewed gene: MCM9: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26806154, 34556653, 32841224, 32613604, 37378315); Phenotypes: Primary ovarian insufficiency, Lynch-like syndrome/colorectal cancer; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1280 | ERBIN | Zornitza Stark Phenotypes for gene: ERBIN were changed from Recurrent respiratory infections; Susceptibility to S.aureus; Eczema; Hyperextensible joints; Scoliosis; Arterial dilatation in some to Combined immunodeficiency, MONDO:0015131, ERBIN-related; Recurrent respiratory infections; Susceptibility to S.aureus; Eczema; Hyperextensible joints; Scoliosis; Arterial dilatation in some | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1279 | ERBIN | Zornitza Stark edited their review of gene: ERBIN: Changed phenotypes: Combined immunodeficiency, MONDO:0015131, ERBIN-related, Recurrent respiratory infections, Susceptibility to S.aureus, Eczema, Hyperextensible joints, Scoliosis, Arterial dilatation in some | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1267 | SRP68 |
Zornitza Stark gene: SRP68 was added gene: SRP68 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SRP68 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SRP68 were set to 32273475 Phenotypes for gene: SRP68 were set to Neutropenia, severe congenital, 10, autosomal recessive, MIM# 620534 Review for gene: SRP68 was set to AMBER Added comment: Single individual reported with bi-allelic LoF variants and presenting with infantile-onset severe neutropenia and recurrent infections. Multiple lines of functional evidence provided. Sources: Expert list |
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| Mendeliome v1.1251 | GPRASP1 |
Paul De Fazio gene: GPRASP1 was added gene: GPRASP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GPRASP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: GPRASP1 were set to 37787182 Phenotypes for gene: GPRASP1 were set to Arteriovenous hemangioma/malformation, GPRASP1-related, MONDO:0001256 Penetrance for gene: GPRASP1 were set to unknown Review for gene: GPRASP1 was set to AMBER gene: GPRASP1 was marked as current diagnostic Added comment: Two hemizygous germline missense variants, p.Arg1167Trp and p.Trp553Cys, were identified in three male patients presenting with spinal AVM, Cobb syndrome, or scalp AVM. The variants were inherited from unaffected heterozygous mothers. Note that p.Arg1167Trp has hemizygous (>70) and homozygous individuals reported in gnomAD. The variants were found to result in LoF in endothelial cells. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral hemorrhage, AVMs, and exhibited vascular anomalies in multiple organs. Sources: Literature |
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| Mendeliome v1.1249 | MAST4 |
Ain Roesley gene: MAST4 was added gene: MAST4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAST4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAST4 were set to 36910266; 33057194 Phenotypes for gene: MAST4 were set to neurodevelopmental disorder MONDO:0700092, MAST4-related Penetrance for gene: MAST4 were set to Complete Review for gene: MAST4 was set to GREEN gene: MAST4 was marked as current diagnostic Added comment: PMID: 36910266 - 4 families with 4 affecteds, all de novo missense 2x borderline microcephaly (-2SD) 2x gross motor delay 2x dysmorphism 4x ID + seizures 3x abnormal brain MRI findings PMID: 33057194 - 5x de novos, 4x missense + 1x PTC Cohort of individuals with severe developmental disorder individual phenotypic information not provided Recurrent variants are Thr1471Ile (3x) and Ser1181Phe) Sources: Literature |
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| Mendeliome v1.1229 | CASP4 |
Zornitza Stark gene: CASP4 was added gene: CASP4 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CASP4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CASP4 were set to 37647624 Phenotypes for gene: CASP4 were set to Hereditary susceptibility to infection, MONDO:0015979, CASP4-related; Susceptibility to meliodiosis Review for gene: CASP4 was set to RED Added comment: Single patient with severe disease secondary to B. pseudomallei requiring ECMO. Adjunctive IFN-γ administration as replacement for its failed induction by IL-18 promptly led to clearance of B. pseudomallei and subsequent weaning of support. Novel homozygous missense mutation in CASP4, at exon 7 c.1030C > T. Peripheral blood mononuclear cells (PBMC) of the patient and her parents showed reduced IFN-γ production, notably to IL-12 stimulation, and decreased IL-18 in response to LPS and increased IL-1B. Cloned cells show impacts on CASP4 activation and pyroptosis. Sources: Expert Review |
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| Mendeliome v1.1222 | CNTN6 | Zornitza Stark Phenotypes for gene: CNTN6 were changed from Intellectual disability; autism; Tourette syndrome; schizophrenia to Neurodevelopmental disorder, MONDO:0700092, CNTN6-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1172 | NR2F2 | Zornitza Stark Phenotypes for gene: NR2F2 were changed from 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 to Krithika Murali (Victorian Clinical Genetics Services) 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Current 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Edit; 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1163 | GJA4 |
Zornitza Stark gene: GJA4 was added gene: GJA4 was added to Mendeliome. Sources: Expert Review somatic tags were added to gene: GJA4. Mode of inheritance for gene: GJA4 was set to Other Publications for gene: GJA4 were set to 33912852 Phenotypes for gene: GJA4 were set to Cavernous hemangioma, MONDO:0003155, GJA4-related Review for gene: GJA4 was set to GREEN Added comment: Recurrent somatic GJA4 c.121G>T (p.Gly41Cys) mutation as a driver of hepatic (n=12) and cutaneous (n=3) vascular malformations. Induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation, in lentiviral transduction of primary human endothelial cells. Sources: Expert Review |
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| Mendeliome v1.1158 | DBR1 |
Zornitza Stark edited their review of gene: DBR1: Added comment: PMID: 37656279: - A homozygous missense as a founder recessive DBR1 variant in four consanguineous families. - Total of 7 affected children. WES done for one proband from each family. - Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. - RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample. - Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant. - Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency.; Changed publications: 29474921, 37656279; Changed phenotypes: {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441, Viral infections of the brainstem, Ichthyosis (MONDO#0019269), DBR1-related |
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| Mendeliome v1.1156 | RAB5C |
Rylee Peters changed review comment from: 12 individuals with nine different heterozygous de novo variants in RAB5C. 9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe). All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD). Sources: Literature; to: 12 individuals with nine different heterozygous de novo variants in RAB5C. 9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe). All have mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD). Sources: Literature |
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| Mendeliome v1.1156 | DBR1 | Chern Lim reviewed gene: DBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37656279; Phenotypes: Ichthyosis (MONDO#0019269), DBR1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1155 | COL4A3BP |
Ee Ming Wong changed review comment from: - Thirty-one unrelated individuals with twenty-two distinct missense variants. The majority of variants were de novo. - Several variants transfected into HeLa cells demonstrated gain of CERT activity - CERT gain of function in Drosophila melanogaster led to head and brain size defects and impaired locomotor activity, which was corrected by pharmacological inhibition of CERT; to: - current HGNC symbol: CERT1 - Thirty-one unrelated individuals with twenty-two distinct missense variants. The majority of variants were de novo. - Several variants transfected into HeLa cells demonstrated gain of CERT activity - CERT gain of function in Drosophila melanogaster led to head and brain size defects and impaired locomotor activity, which was corrected by pharmacological inhibition of CERT |
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| Mendeliome v1.1153 | COL4A3BP | Ee Ming Wong reviewed gene: COL4A3BP: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36976648; Phenotypes: Intellectual developmental disorder 34 (MIM#616351); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1152 | RAB5C |
Rylee Peters gene: RAB5C was added gene: RAB5C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAB5C were set to PMID: 37552066 Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related Penetrance for gene: RAB5C were set to Complete Review for gene: RAB5C was set to GREEN gene: RAB5C was marked as current diagnostic Added comment: 12 individuals with nine different heterozygous de novo variants in RAB5C. 9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe). All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD). Sources: Literature |
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| Mendeliome v1.1117 | APOL1 |
Zornitza Stark edited their review of gene: APOL1: Added comment: Assigned Definitive gene-disease validity by the ClinGen Glomerulopathy GCEP - Classification - 09/28/2021 Increased risk of kidney and glomerular diseases in persons carrying two of the risk alleles in this gene: G1/G1, G2/G2 and compound heterozygous G1/G2. PMID: 20647424 - first study to identify G1 & G2 alleles associated with risk of renal disease. Comparing participants with zero or 1 risk allele of APOL1 to participants with 2 risk alleles provided an odds ratio for FSGS of 10.5 (CI, 6.0-18.4). This analysis supported a completely recessive pattern of inheritance. PMID: 25993319 - only G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN rs73885319 (G1) OR 9.66, p=9.97E-25 rs60910145 (G1) OR 9.75, p=9.04E-24 rs71785313 (G2) OR 5.69, p=3.39E-06 2 APOL1 risk alleles OR 18.31, p=3.31E-58 PMID: 34350953 - recessive gain-of-function toxicity mouse model recapitulates human kidney disease G1: p.Ser342Gly, AFR/AA gnomAD v2.1 AF 0.2276 (5,671/24,920 alleles, 687 homozygotes) p.Ile384Met, AFR/AA gnomAD v2.1 AF 0.2278 (5,487/24,082 alleles, 662 homozygotes) G2: p.Asn388_Tyr389del, AFR/AA gnomAD v2.1 AF 0.1402(3,402/24,268 alleles, 224 homozygotes AMBER status due to these being susceptibility alleles, and evidence being limited to these specific variants.; Changed rating: AMBER |
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| Mendeliome v1.1117 | GOSR2 |
Achchuthan Shanmugasundram changed review comment from: Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry. All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134).; to: This gene should be added in 'Deafness_IsolatedAndComplex' panel with red rating. Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry. All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134). |
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| Mendeliome v1.1116 | DDRGK1 |
Ain Roesley gene: DDRGK1 was added gene: DDRGK1 was added to Mendeliome. Sources: Literature founder tags were added to gene: DDRGK1. Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336 Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type (MIM#602557) Review for gene: DDRGK1 was set to GREEN gene: DDRGK1 was marked as current diagnostic Added comment: RNA and protein studies performed for the splice variant. These two variants likely represents founder variants PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development. PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD. In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455). Sources: Literature |
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| Mendeliome v1.1111 | FBXO31 | Ain Roesley reviewed gene: FBXO31: Rating: AMBER; Mode of pathogenicity: None; Publications: 35019165, 24623383; Phenotypes: Intellectual developmental disorder, autosomal recessive 45 (MIM#615979); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1111 | CCT5 | Bryony Thompson edited their review of gene: CCT5: Added comment: Now two families reported with two different missense variants (Leu224Val and His147Arg).; Changed publications: 16399879, 25124038, 25345891, 33076433, 37237456 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1103 | PSMC3 | Zornitza Stark edited their review of gene: PSMC3: Added comment: PMID:37256937 - 23 individuals with neurodevelopmental disorder was identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.; Changed rating: GREEN; Changed publications: 32500975, 37256937; Changed phenotypes: neurodevelopmental disorder, MONDO:0700092, PSMC3-related, Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1101 | EMC1 | Chern Lim reviewed gene: EMC1: Rating: ; Mode of pathogenicity: None; Publications: 35234901, 26942288; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1099 | DPP9 | Zornitza Stark Phenotypes for gene: DPP9 were changed from Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias to Hatipoglu immunodeficiency syndrome MIM#620331; Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1098 | DPP9 | Zornitza Stark Phenotypes for gene: DPP9 were changed from Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias to Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1095 | PDGFD |
Zornitza Stark gene: PDGFD was added gene: PDGFD was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PDGFD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PDGFD were set to 33187088; 33971972 Phenotypes for gene: PDGFD were set to Pulmonary arterial hypertension MONDO:0015924, PDGFD-related Review for gene: PDGFD was set to RED Added comment: Rated as LIMITED by ClinGen. 10 unique variants (all missense) that have been reported in 10 probands in 2 publications (PMIDs: 33187088, 33971972) are included in this curation. 9 of these variants were observed in a cohort of 1647 idiopathic pulmonary arterial hypertension (IPAH) patients of European Ancestry as part of a case-control study. Variant aggregation analysis revealed a significant burden (p=0.0000172) of likely gene damaging PDGFD variants in the IPAH cohort as compared to a group of 18,819 European controls (PMID:33971972). Gelinas et al. also reported a missense PDGFD variant in a proband with IPAH (PMID:33187088). There is currently no functional evidence demonstrating a damaging effect of any of the reported PDGFD variants in humans. Sources: Expert list |
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| Mendeliome v1.1093 | FBLN2 |
Zornitza Stark gene: FBLN2 was added gene: FBLN2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: FBLN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBLN2 were set to 33971972 Phenotypes for gene: FBLN2 were set to Pulmonary arterial hypertension MONDO:0015924, FBLN2-related Review for gene: FBLN2 was set to RED Added comment: LIMITED by ClinGen. Out of a cohort of 1647 idiopathic PAH cases, 3 rare predicted deleterious missense variants were identified in 6 unrelated individuals with one variant recurrent in four individuals. Gene-disease association also supported by tissue expression data. Sources: Expert list |
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| Mendeliome v1.1085 | PRDM10 | Zornitza Stark Phenotypes for gene: PRDM10 were changed from Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086 to Birt-Hogg-Dube syndrome 2, MIM# 620459 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1083 | IL1R1 |
Zornitza Stark gene: IL1R1 was added gene: IL1R1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: IL1R1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IL1R1 were set to 37315560 Phenotypes for gene: IL1R1 were set to Chronic recurrent multifocal osteomyelitis 3, MIM# 259680 Review for gene: IL1R1 was set to RED Added comment: Single individual reported with de novo missense variant in this gene and a phenotype of chronic recurrent multifocal osteomyelitis, auto inflammatory in nature. Some functional data presented. Sources: Literature |
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| Mendeliome v1.1081 | RINT1 | Zornitza Stark Phenotypes for gene: RINT1 were changed from Recurrent acute liver failure to Infantile liver failure syndrome 3, MIM# 618641 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1071 | SMARCA4 |
Paul De Fazio changed review comment from: Additional phenotype reported: A single missense variant E1610K (M_001128849.3) was reported in 7 affected members of a family with progressive hearing loss due to otosclerosis and no other clinical features. Variant is absent from gnomAD. Note that unaffected members of the family were not tested. A mouse CRISPR model with the orthologous variant had a similar phenotype.; to: Additional phenotype reported: A single missense variant E1610K (M_001128849.3) was reported in 7 affected members of a family with progressive hearing loss due to otosclerosis and no other clinical features. Variant is absent from gnomAD. Note that unaffected members of the family were not tested - some obligate carriers were apparently unaffected, reflecting incomplete penetrance. A mouse CRISPR model with the orthologous variant had a similar phenotype. |
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| Mendeliome v1.1071 | PHF5A |
Daniel Flanagan gene: PHF5A was added gene: PHF5A was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PHF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PHF5A were set to PMID: 37422718 Phenotypes for gene: PHF5A were set to Neurodevelopmental disorder (MONDO#0700092), PHF5A-related Review for gene: PHF5A was set to GREEN Added comment: Nine subjects with congenital malformations, including hypospadias, growth abnormalities, and developmental delay who had de novo PHF5A variants. Prenatally, six subjects had intrauterine growth retardation. All subjects had motor and speech delay and developmental delay. Congenital abnormalities comprised hypospadias in three of four male subjects, and heart defects (3/9), inguinal hernia (3/9), and sacral dimple (3/9). Six of the nine subjects had short stature. Craniofacial dysmorphism is variable in the nine subjects, high forehead and preauricular skin tag(s) in five subjects. Sources: Expert list |
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| Mendeliome v1.1071 | AQP4 |
Lucy Spencer gene: AQP4 was added gene: AQP4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AQP4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AQP4 were set to 37143309 Phenotypes for gene: AQP4 were set to ?Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448 Review for gene: AQP4 was set to AMBER Added comment: PMID: 37143309 Cohort of patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). Missense variant in AQP4 seen homozygous in 2 siblings and het in the parents. Patients had macrocephaly, developmental delay, hypotonia, epilepsy, and cognitive deficit. Western blots on generated MDCK cell lines showed no detectable expression of AQP4 protein from the cells with the patients variant. Immunofluorescence also showed no membrane expression. Overexpression studies in HEK293T cells showed WT was seen as mainly monomers or dimers where as variant protein formed large aggregates- likely due to the saturation of protein degradation pathways because of the overexpression. Sources: Literature |
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| Mendeliome v1.1068 | MAMDC2 |
Belinda Chong gene: MAMDC2 was added gene: MAMDC2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAMDC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAMDC2 were set to 37503746 Phenotypes for gene: MAMDC2 were set to Muscular Dystrophy MONDO:0020121, MAMDC2-related Review for gene: MAMDC2 was set to AMBER Added comment: 17 individuals with an autosomal dominant muscular dystrophy belonging to two unrelated families in which different heterozygous truncating variants in the last exon of MAMDC2 co-segregate correctly with the disease. Sources: Literature |
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| Mendeliome v1.1064 | TUFM | Ain Roesley reviewed gene: TUFM: Rating: RED; Mode of pathogenicity: None; Publications: 37461298; Phenotypes: Inherited primary ovarian failure MONDO:0019852, TUFM-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1064 | STAB1 |
Chern Lim gene: STAB1 was added gene: STAB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: STAB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STAB1 were set to 37490907; 28052375 Phenotypes for gene: STAB1 were set to Iron metabolism disease (MONDO:0002279), STAB1-related Review for gene: STAB1 was set to GREEN gene: STAB1 was marked as current diagnostic Added comment: PMID: 37490907 - Biallelic variants identified in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies. - Homozygous/compound heterozygous variants: missense, frameshift, stopgain, inframe del of 3 AAs, one synonymous. - Samples from three of the patients from two families showed no immunoreactivity with anti-stabilin-1 compared to control liver where high signal was detected in the liver sinusoids (immunohistochemistry analysis). - Patients’ peripheral monocytes and monocyte-derived macrophages showed very little expression of stabilin-1 on CD14+ monocytes and macrophages compared to control subjects (flow cytometry analysis). - These families have also been published in PMID: 28052375. Sources: Literature |
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| Mendeliome v1.1063 | PTPA | Ee Ming Wong reviewed gene: PTPA: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37448355; Phenotypes: Intellectual disability, MONDO: 36073231, PTPA-related, Parkisonism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1062 | SMARCA4 | Paul De Fazio reviewed gene: SMARCA4: Rating: AMBER; Mode of pathogenicity: None; Publications: 37399313; Phenotypes: Otosclerosis MONDO:0005349, SMARCA4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1062 | NAA30 |
Sarah Pantaleo gene: NAA30 was added gene: NAA30 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NAA30 was set to Unknown Publications for gene: NAA30 were set to PMID: 37387332 Penetrance for gene: NAA30 were set to unknown Added comment: Report a de novo heterozygous NAA30 nonsense variant c.244C>T, p.(Gln82*) in a 5yo boy with GDD, ASD, hypotonia, seizures, tracheal cleft and recurrent respiratory infections. Seizures resolved after two weeks of life. Family history of ASD in older sister. Epilepsy in mother, childhood onset. Biochemical studies performed to assess the functional impact of the premature stop codon on catalytic activity. The variant was found to completely disrupt N-terminal acetyltransferase activity using an in vitro acetylation assay. Variant de novo, “in a gene sensitive to loss of heterozygosity”. Limitation of study - have not established whether this gene variant acts in a dominant or recessive manner. Sources: Literature |
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| Mendeliome v1.1054 | STX5 |
Ain Roesley gene: STX5 was added gene: STX5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: STX5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: STX5 were set to congenital disorder of glycosylation MONDO#0015286, STX5-related Review for gene: STX5 was set to AMBER gene: STX5 was marked as current diagnostic Added comment: 1x family with 3x deceased shortly after death + 3x spontaneous abortions + 2x abortions due to abnormal fatal ultrasound (US). Hom for NM_003164.4:c.163 A > G p.(Met55Val), which results in complete loss of short isoform (which uses Met55 as the start) phenotype: short long bones on US, dysmorphism, skeletal dysplasia, profound hypotonia, hepatomegaly elevated cholesterol. Post-natally they died of progressive liver failure with cholestasis and hyperinsulinemic hypoglycemias Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking Sources: Literature |
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| Mendeliome v1.1052 | TEP1 |
Zornitza Stark gene: TEP1 was added gene: TEP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TEP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TEP1 were set to 34543729 Phenotypes for gene: TEP1 were set to Cerebral palsy, MONDO:0006497, TEP1-related Review for gene: TEP1 was set to AMBER Added comment: Wang et al. screened a large cohort of more than 600 CP patients from China and found several variants in TEP1, 11 of which were LoF, while no LoF variant was found in the control cohort. These children all had spastic CP. Among these 11 children, 6 children had birth asphyxia and neonatal encephalopathy. Compared to the total group with birth asphyxia (71/667), 6 patients with TEP1 LOF mutations had a significantly greater risk of birth asphyxia. They confirmed TEP1 as a risk factor for CP by cytological and animal models. Uncertain if these are risk alleles vs indicative of a monogenic disorder. Note LoF variants in gnomad. As this was a cohort study, inheritance of these variants is unknown. Sources: Literature |
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| Mendeliome v1.1045 | TMEM63B |
Achchuthan Shanmugasundram changed review comment from: There is sufficient evidence for this gene to be included with green rating in intellectual disability and epilepsy panels. 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment. All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%). Sources: Literature; to: There is sufficient evidence for this gene to be included with green rating in 'Intellectual disability syndromic and non-syndromic' and 'Genetic epilepsy' panels. 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment. All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%). Sources: Literature |
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| Mendeliome v1.1045 | TMEM63B |
Achchuthan Shanmugasundram gene: TMEM63B was added gene: TMEM63B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TMEM63B were set to 37421948 Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062 Review for gene: TMEM63B was set to GREEN Added comment: There is sufficient evidence for this gene to be included with green rating in intellectual disability and epilepsy panels. 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment. All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%). Sources: Literature |
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| Mendeliome v1.1033 | MAP3K14 | Zornitza Stark Phenotypes for gene: MAP3K14 were changed from NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels to Immunodeficiency 112, MIM# 620449; NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1032 | MAP3K14 | Zornitza Stark edited their review of gene: MAP3K14: Changed phenotypes: Immunodeficiency 112, MIM# 620449, NIK deficiency, Poor T cell proliferation to antigen, Low B-cell numbers, Low NK number and function, recurrent bacterial/viral/ cryptosporidium infections, hypogammaglobulinaemia, decreased immunoglobulin levels | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1010 | TBX6 | Chirag Patel reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36112137, 36161696; Phenotypes: Mayer-Rokitansky-Küster-Hauser syndrome, Combined skeletal-kidney dysplasia syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1009 | WBP4 |
Chirag Patel gene: WBP4 was added gene: WBP4 was added to Mendeliome. Sources: Other Mode of inheritance for gene: WBP4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: WBP4 were set to Neurodevelopmental disorder Review for gene: WBP4 was set to GREEN gene: WBP4 was marked as current diagnostic Added comment: ESHG 2023: 11 individuals from 8 families with homozygous LOF variants in WBP4 gene (4 different variants). Presentation of severe DD and ID, hypotonia, abnormal outer ears, and varying congenital anomalies. WBP4 is spliceosome protein which binds/interacts with SNRNP200. In vivo and in vitro studies previously showed WBP4 enhances splicing and regulates alternative splicing. Patient fibroblasts showed loss of expression of WBP4. RNA sequencing analysis showed abnormal splicing patterns. Proposed spliceosomopathy. Sources: Other |
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| Mendeliome v1.1007 | KDM2A |
Chirag Patel gene: KDM2A was added gene: KDM2A was added to Mendeliome. Sources: Other Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: KDM2A were set to Neurodevelopmental disorder Review for gene: KDM2A was set to GREEN gene: KDM2A was marked as current diagnostic Added comment: ESHG 2023: 14 patients with de novo HTZ variants in KDM2A (5 x truncating, 9 x missense) Presentation with DD, ID (mild), seizures, growth retardation, and dysmorphism. Functional studies: -patient blood showed aberrant genome wide methylation profile - potential episignature -HEK293T cells showed altered subcellular localisation of KDM2A -Drosophila models showed variants caused neurotoxicity Sources: Other |
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| Mendeliome v1.1005 | PIP5K1C | Chirag Patel reviewed gene: PIP5K1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder and microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1003 | INTS13 |
Chirag Patel gene: INTS13 was added gene: INTS13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: INTS13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INTS13 were set to PMID: 36229431 Phenotypes for gene: INTS13 were set to Oral-facial-digital syndrome Review for gene: INTS13 was set to GREEN gene: INTS13 was marked as current diagnostic Added comment: 2 families with 4 affected individuals with Oral-facial-digital (OFD) phenotype. Homozygosity mapping and WES found 2 homozygous variants in INTS13 gene. This is a subunit of the Integrator complex, which associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. Variants segregated with disease. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Knockdown in Xenopus embryos leads to motile cilia anomalies. Sources: Literature |
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| Mendeliome v1.1001 | DCAF15 |
Chirag Patel gene: DCAF15 was added gene: DCAF15 was added to Mendeliome. Sources: Other Mode of inheritance for gene: DCAF15 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DCAF15 were set to Cornelia de Lange syndrome Review for gene: DCAF15 was set to AMBER Added comment: ESHG 2023: 3 unrelated cases with CdLS (1 x TOP with MCA, 1 x death @20mths, 1 x living child) Features suggestive of CdLS - DD, microcephaly, CHD, dysmorphism, visual/hearing impairment. WES identified recurrent de novo variant (p.Ser470Phe) in DCAF15 gene. This mediates ubiquitination and degradation of target proteins, and interacts with cohesin complex members (SMC1/SMC3). Protein analysis from individuals showed increased accumulation of ubiquitination-modified proteins and SM3 (GOF mechanism). EpiSign analysis showed same DNA methylation pattern as other CdLS cases/genes. Zebrafish model showed reduced body length, reduced head size, reduced oligodendrocytes, heart defect, aberrant motor neurons, and abnormal response to visual/auditory stimuli. Sources: Other |
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| Mendeliome v1.996 | RIPK3 |
Zornitza Stark gene: RIPK3 was added gene: RIPK3 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: RIPK3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RIPK3 were set to 37083451 Phenotypes for gene: RIPK3 were set to Hereditary susceptibility to infections, MONDO:0015979, RIPK3-related; Recurrent HSV encephalitis Review for gene: RIPK3 was set to AMBER Added comment: Single female patient with independent episodes of HSE at 6 and 17 months of age and with autoimmune encephalitis 1 month after the second episode of HSE with two heterozygous mutations of RIPK3 predicted to be loss of function (pLOF): p. Arg422* (c.1264 C > T, MAF 0.001568, CADD 35) and p. Pro493fs9* (c.1475 C > CC, MAF 0.002611, CADD 24.2). Extensive supportive functional data including RIPK3 knockout human pluripotent stem cell–derived cortical neurons. Sources: Expert Review |
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| Mendeliome v1.989 | NAA60 | Chirag Patel reviewed gene: NAA60: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary familial brain calcification; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.989 | NAA60 |
Chirag Patel gene: NAA60 was added gene: NAA60 was added to Mendeliome. Sources: Other Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: NAA60 were set to Basal ganglia calcification Review for gene: NAA60 was set to GREEN gene: NAA60 was marked as current diagnostic Added comment: ESHG 2023: 10 individuals from 7 families with biallelic variants in NAA60 (missense and framshift). All with primary brain calcification - 4/10 childhood onset (DD, ID), 6/10 adult onset (cerebellar and pyramidal dysfunction, dystonia, parkinsonism, cognitive impairment, psychiatric manifestations). NAA60 catalyses N-terminal acetylation of transmembrane proteins and localises to Golgi apparatus. In vitro assay of variants showed reduced capacity of Nt acetylation. Fibroblast studies showed significantly reduced levels of phosphate importer (SLC20A2). Loss of function variants in SLC20A2 (~50% of PFBC cases) lead to increased extracellular phosphate (which is thought to lead to calcium deposits in brain). Sources: Other |
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| Mendeliome v1.987 | POPDC2 |
Chirag Patel gene: POPDC2 was added gene: POPDC2 was added to Mendeliome. Sources: Other Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POPDC2 were set to Sinus node dysfunction Review for gene: POPDC2 was set to GREEN gene: POPDC2 was marked as current diagnostic Added comment: ESHG 2023: 3 families with 7 affected with sinus node dysfunction (bradycardia) and AV block (2/7 HCM). 3 x HMZ variants found in POPDC2 (2 x missense, 1 x indel). Variants predicted to diminish cAMP binding of POPDC2, and shown to disrupt regulation of TREK1 channels (lowering of outward K+ current). POPDC2 is highly expressed in cardiac myocytes, sinoatrial node, and atrioventricular node. Knockdown in zebrafish leads to AV block, and knockout in mice leads to sinus node dysfunction. Sources: Other Sources: Other |
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| Mendeliome v1.985 | GPATCH11 |
Chirag Patel gene: GPATCH11 was added gene: GPATCH11 was added to Mendeliome. Sources: Other Mode of inheritance for gene: GPATCH11 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GPATCH11 were set to Leber congenital amaurosis and developmental delay Review for gene: GPATCH11 was set to GREEN gene: GPATCH11 was marked as current diagnostic Added comment: ESHG 2023: 3 families with 8 individuals with leber congenital amaurosis, developmental delay, language disorder, and behavioural issues. GPATCH11 localises to nucleus and basal body of primary cilium (similar to other LCA genes). Biallelic variants found in GPATCH11 - 1 splice variant common to all 3 families (1 other variant in 3rd family). Splice variant leads to loss of exon 4 (mRNA studies). Mouse models showed i) abnormal rod/cone responses on ERG; ii) decreased outer nuclear layer in retina, and iii) abnormal associate/episodic memory Sources: Other |
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| Mendeliome v1.982 | KCNA3 |
Chirag Patel gene: KCNA3 was added gene: KCNA3 was added to Mendeliome. Sources: Other Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: KCNA3 were set to Neurodevelopmental disorder Review for gene: KCNA3 was set to GREEN gene: KCNA3 was marked as current diagnostic Added comment: ESHG 2023: 10 individuals with de novo missense variants in KCNA3 (K+ channel) Variable electrophysiology studies of effect of variants (5 x LOF, 4 x GOF, 1 no change) Presentation: abnormal speech development (8/8), ID (6/8), epilepsy (5/8), and ASD (7/8) Sources: Other |
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| Mendeliome v1.980 | FSD1L |
Chirag Patel gene: FSD1L was added gene: FSD1L was added to Mendeliome. Sources: Other Mode of inheritance for gene: FSD1L was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FSD1L were set to Neurodevelopmental disorder Review for gene: FSD1L was set to GREEN gene: FSD1L was marked as current diagnostic Added comment: ESHG 2023: 8 families with biallelic missense/nonsense variants Presentation only described 1 family/2 affecteds with DD, ID, spastic paraparesis, epilepsy, corpus callosum hypoplasia, and optic nerve hypoplasia Functional assays: -reduced expression of FSD1L in mature neurons (RNA studies) -very low % mature neurons (neuronal differentiation) -reduced neuronal migration Sources: Other |
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| Mendeliome v1.978 | DENND5B |
Chirag Patel gene: DENND5B was added gene: DENND5B was added to Mendeliome. Sources: Other Mode of inheritance for gene: DENND5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: DENND5B were set to Neurodevelopmental disorder with white matter anomalies Review for gene: DENND5B was set to GREEN gene: DENND5B was marked as current diagnostic Added comment: ESHG 2023: 7 patients/7 families with de novo DENND5B variants (6 missense, 1 splice) DD/ID (mod/profound)(7/7), white matter anomalies (6/7) hypotonia, epilepsy (3/7) DENND5B acts as: -GEF for activation of RAB proteins which are involved in membrane trafficking and neurotransmitter release -regulator of lipid absorption and homeostasis Functional studies showed loss of expression of DENND5B in fibroblasts, abnormal vesicle trafficking, and impaired lipid uptake and intracellular distribution Sources: Other |
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| Mendeliome v1.976 | DMAP1 |
Chirag Patel gene: DMAP1 was added gene: DMAP1 was added to Mendeliome. Sources: Other Mode of inheritance for gene: DMAP1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DMAP1 were set to Neurodevelopmental disorder Review for gene: DMAP1 was set to GREEN gene: DMAP1 was marked as current diagnostic Added comment: ESHG 2023: 9 patients/8 families with bilallelic variants in DMAP1 (3 missense, 7 LOF) All with DD, speech delay, hypotonia, and ID Some with epilepsy (4/6), FTT (4/5), and brain malformations (3/5) Drosophila showed abnormal behaviour pattern and bang sensitivity Specific methylation episignature also seen Sources: Other |
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| Mendeliome v1.974 | VGLL2 |
Chirag Patel gene: VGLL2 was added gene: VGLL2 was added to Mendeliome. Sources: Other Mode of inheritance for gene: VGLL2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: VGLL2 were set to Syngnathia Review for gene: VGLL2 was set to GREEN gene: VGLL2 was marked as current diagnostic Added comment: ESHG 2023: 4 families/7 affected individuals with isolated unilateral/bilateral syngnathia biallelic truncating variants in VGLL2 But not phenotype in KO mouse or zebrafish models Sources: Other |
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| Mendeliome v1.972 | ITFG2 | Chirag Patel reviewed gene: ITFG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.972 | COL4A6 | Ain Roesley reviewed gene: COL4A6: Rating: AMBER; Mode of pathogenicity: None; Publications: 33840813; Phenotypes: Deafness, X-linked 6 MIM#300914; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.972 | SLC4A3 | Chern Lim reviewed gene: SLC4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36806574; Phenotypes: Short QT syndrome 7, MIM#620231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.969 | NFE2L2 | Zornitza Stark edited their review of gene: NFE2L2: Changed phenotypes: Immunodeficiency, developmental delay, and hypohomocysteinemia, MIM# 617744, Recurrent respiratory and skin infection, Growth retardation, Developmental delay, borderline ID, White matter cerebral lesions; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.966 | ZNF808 |
Hazel Phillimore gene: ZNF808 was added gene: ZNF808 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF808 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF808 were set to PMID: 37308312 Phenotypes for gene: ZNF808 were set to non-syndromic neonatal diabetes; MONDO:0016391 Review for gene: ZNF808 was set to GREEN Added comment: PMID: 37308312; Alqahtani, MA. et al. (2023) Clin Genet. doi: 10.1111/cge.14389. Three siblings in one consanguineous Saudi Arabian family with non-syndromic neonatal diabetes, all with a homozygous frameshift variant, NM_001321425.2:c.1448dupA, p.(Tyr483*), in ZNF808. (Same nucleotide and amino acid numbering as for the MANE SELECT transcript, NM_001039886.4). This variant has been entered as likely pathogenic in ClinVar by this group. This variant occurs in the last exon of the gene and is therefore not NMD-predicted. Instead it is predicted to cause a truncated protein. This paper shows a diagram with several other truncating variants in this exon, which were reported in the paper by De Franco, E. et al. (2021). (These patients also had low vitamin D levels, suggesting an association, and is consistent with other studies looking into loci that are associated with vitamin D). De Franco, E. et al. (2021) medRxiv 08.23.21262262. (Exeter, UK): Firstly, this group found a homozygous variant NM_001039886.3:c.637del, p.(Leu213*) that is predicted to cause a truncated protein, and also a homozygous CNV Chr19(GRCh37):g.53057128_53100968del (predicted to cause a deletion of exons 4 and 5) in two unrelated affected individuals. These patients had pancreatic agenesis, defined as insulin-dependent diabetes in the first 6 months of life (neonatal diabetes) and exocrine pancreatic insufficiency. Both were from consanguineous families. Parents were subsequently tested and shown to be heterozygous carriers. They then investigated 232 additional patients who had been diagnosed with neonatal diabetes before the age of 6 months and found ten more homozygous ZNF808 variants. Six were nonsense: p.(Gln194*), p.(Cys233*), p.(Tyr427*), p.(Lys458*), p.(Tyr528*) and p.(Arg727*), and three were frameshift variants: p.(Ala379Valfs*157), p.(Leu588Profs*118), p.(Asn770Ilefs*98) and one was a whole-gene deletion. All the frameshift and nonsense variants occurred in the last exon of the gene, which contains all 23 zinc finger domains; and therefore all of these variants are predicted to result in truncated proteins, and removal of some, if not all, those domains. This group also carried out functional studies using an in vitro model of pancreas development and showed an aberrant activation of many transposable elements (mostly MER11 elements) that would be normally be repressed during early pancreas development. Sources: Literature |
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| Mendeliome v1.965 | SART3 |
Daniel Flanagan gene: SART3 was added gene: SART3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SART3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SART3 were set to PMID: 37296101 Phenotypes for gene: SART3 were set to Neurodevelopmental disorder (MONDO#0700092), SART3-related; 46,XY disorder of sex development (MONDO:0020040), SART3-related Review for gene: SART3 was set to GREEN Added comment: Nine individuals from six families presenting with intellectual disability, global developmental delay, a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Additionally, two individuals had seizures and two had epileptiform activity reported on EEG. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Sources: Expert list |
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| Mendeliome v1.962 | NUDCD2 |
Ee Ming Wong gene: NUDCD2 was added gene: NUDCD2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NUDCD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUDCD2 were set to 37272762 Phenotypes for gene: NUDCD2 were set to Multiple congenital anomalies (MONDO:0019042), NUDCD2-related Penetrance for gene: NUDCD2 were set to unknown Review for gene: NUDCD2 was set to AMBER gene: NUDCD2 was marked as current diagnostic Added comment: - Two unrelated probands, each biallelic for two variants in NUDCD2 (total 3x LoF variants, 1x missense variant) - Immunoblotting of proteins extracted from the primary fibroblasts of one proband with 2x LoF variants demonstrated markedly reduced NUDCD2 levels compared to healthy individuals Sources: Literature |
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| Mendeliome v1.961 | ARPC5 |
Paul De Fazio gene: ARPC5 was added gene: ARPC5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARPC5 were set to 37349293; 37382373 Phenotypes for gene: ARPC5 were set to Combined immunodeficiency, ARPC5-related MONDO:0015131 Review for gene: ARPC5 was set to GREEN gene: ARPC5 was marked as current diagnostic Added comment: 4 individuals from 3 families reported with homozygous LoF variants. All had recurrent and severe infections. Other developmental anomalies were present but seemed variable. PMID:37349293 reports 2 unrelated patients. Both had scoliosis. One had neurodevelopmental delay and brain atrophy. Patient 1 died at 15yo after a sudden episode of hemoptysis and hematochezia. Patient 2 died at 1yo because of progressive neurologic and respiratory disease; an autopsy was not performed. PMID:37382373 reports 2 patients from the same family. One had multiple congenital anomalies including a congenital heart defect (CHD) (patent foramen ovale), cleft palate, and hypoplastic corpus callosum. The sibling also had CHD (moderate pulmonary stenosis and atrial septal defect). Functional studies and a mouse model were supportive of the disease association. Sources: Literature |
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| Mendeliome v1.956 | RAB34 |
Sarah Pantaleo gene: RAB34 was added gene: RAB34 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RAB34 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAB34 were set to PMID: 37384395 Phenotypes for gene: RAB34 were set to Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies Penetrance for gene: RAB34 were set to Complete Review for gene: RAB34 was set to GREEN Added comment: Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogenous disorders characterised by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in >20 genes encoding ciliary proteins have been found to cause OFDS. Identified by WES biallelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families (aided by GeneMatcher). Affected individuals presented a novel form of OFDS accompanied by cardiac, cerebral, skeletal (eg. Shortening of long bones), and anorectal defects. RAB34 encodes a member of the Lab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Protein products of pathogenic variants clustered near the RAB34 C-terminus exhibit a strong loss of function. Onset is prenatal (multiple developmental defects including short femur, polydactyly, heart malformations, kidney malformations, brain malformations), resulting in medical termination for three probands. In the fourth, the only one alive at birth, proband born at 39+5 weeks, normal growth parameters after pregnancy with polyhydramnios, corpus callosum agenesis and polydactyly. Respiratory distress at birth. All four probands presented typical features of ciliopathy disorders, overlapping with oral, facial and digital abnormalities. All with homozygous missense variants. All absent in gnomAD (in homozygous state). Sanger sequencing confirmed mode of inheritance. Sources: Literature |
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| Mendeliome v1.956 | RPH3A |
Lucy Spencer gene: RPH3A was added gene: RPH3A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RPH3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPH3A were set to 37403762; 29441694 Phenotypes for gene: RPH3A were set to Neurodevelopmental disorder (MONDO#0700092), RPH3A-related Review for gene: RPH3A was set to GREEN Added comment: PMID: 37403762- 6 patients with RPH3A variant. All 6 have ID, 4 have epilepsy, 2 with obesity, 1 with dysmorphic features. All 6 have missense variants, 3 shown to be de novo, the other 3 parents were not available for testing. I patient also had language and motor impairment, breathing issues and mixed hypo/hypertonia- he also had variants in CUL4B, PRKAG2, SCN4A, none of these genes cause seizures (which he had). Patch clamp studies on 2 of the missense showed they increased either the number of NMDA receptors on neuron membrane surface or increased their conductance. Study suggests that the variants interrupt the normal role of RPH3A activity at the synaptic NMDAR complex which is needed for the induction of synaptic plasticity and NMDAR-dependant behaviours Previously this gene was reported in PMID: 29441694- 1 girl with learning disabilities, tremors, ataxia, hyperglycemia and muscle fatigability. Chet for 2 RPH3A missense. Functional analysis showed strong and marginal impairment of protein binding for each variant. this is the only biallelic report currently. Sources: Literature |
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| Mendeliome v1.956 | MIR204 |
Chern Lim gene: MIR204 was added gene: MIR204 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MIR204 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MIR204 were set to 26056285; 37321975 Phenotypes for gene: MIR204 were set to Retinal dystrophy and iris coloboma with or without cataract (MIM#616722) Mode of pathogenicity for gene: MIR204 was set to Other Review for gene: MIR204 was set to GREEN gene: MIR204 was marked as current diagnostic Added comment: PMID: 26056285 - Bilateral coloboma and rod-cone dystrophy with or without cataract in nine individuals of a five-generation family. - Heterozygous n.37C>T segregates with the disease in all affected individuals. - Functional analysis including transcriptome analysis showed this variant resulted in significant alterations of miR-204 targeting capabilities. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family. - Authors suggested gain of function is the likely disease mechanism. PMID: 37321975 - Four members of a three-generation family with early-onset chorioretinal dystrophy, heterozygous for n.37C>T. - Additionally, four family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants. - Haplotype analysis excluded relatedness with the family reported in PMID: 26056285. - In silico analysis of the MIR204 n.37C>T variant reveals profound changes to its target mRNAs and suggests a gain-of-function mechanism of miR 204 variant. Sources: Literature |
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| Mendeliome v1.943 | POGZ |
Achchuthan Shanmugasundram changed review comment from: Although there are more than three unrelated cases reported with either cleft palate or bifid uvula in total, this phenotype is not consistently present in patients with monoallelic variants in POGZ gene. Hence, this gene should only be added with amber rating in 'Clefting disorders panel'. PMID:26739615 - Five unrelated individuals were identified with de novo truncating variants in POGZ gene, of which one individual had cleft palate and another one had bifid uvula. PMID:31782611 - In this cohort of 22 individuals with 21 different loss of function variants in POGZ, two patients were reported with bifid uvula. DECIPHER database - Of 42 patients with heterozygous sequence variants, one had cleft palate and another one had bifid uvula (PMID:37010288). The OMIM entry for White-Sutton syndrome (MIM #616364) does not currently include cleft lip/ palate as one of the clinical manifestations of this syndrome.; to: Although there are more than three unrelated cases reported with either cleft palate or bifid uvula in total, this phenotype is not consistently present in patients with monoallelic variants in POGZ gene. Hence, this gene should only be added with amber rating in 'Clefting disorders' panel. PMID:26739615 - Five unrelated individuals were identified with de novo truncating variants in POGZ gene, of which one individual had cleft palate and another one had bifid uvula. PMID:31782611 - In this cohort of 22 individuals with 21 different loss of function variants in POGZ, two patients were reported with bifid uvula. DECIPHER database - Of 42 patients with heterozygous sequence variants, one had cleft palate and another one had bifid uvula (PMID:37010288). The OMIM entry for White-Sutton syndrome (MIM #616364) does not currently include cleft lip/ palate as one of the clinical manifestations of this syndrome. |
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| Mendeliome v1.927 | NFATC1 |
Zornitza Stark gene: NFATC1 was added gene: NFATC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NFATC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NFATC1 were set to 37249233 Phenotypes for gene: NFATC1 were set to Inborn error of immunity, MONDO:0003778, NFATC1-related; Combined Immune deficiency Review for gene: NFATC1 was set to AMBER Added comment: 3 individuals from a multigenerational consanguineous pedigree with early-onset sinopulmonary infections and bronchiectasis, recurrent viral (warts) and bacterial (folliculitis and abscesses) skin infections, hypogammaglobulinemia, lower CD4+/CD8+ T-cell ratio and lower recent thymic emigrants compared with the age-matched controls. Lymphocyte proliferation responses to PHA and CD3/CD28 stimulations were defective. Single pedigree with supportive functional studies. Sources: Literature |
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| Mendeliome v1.911 | TAPT1 | Paul De Fazio reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36697720, 36652330; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.908 | PRSS8 |
Lucy Spencer gene: PRSS8 was added gene: PRSS8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRSS8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRSS8 were set to 36715754 Phenotypes for gene: PRSS8 were set to ichthyosis MONDO:0019269, PRSS8-related Review for gene: PRSS8 was set to AMBER Added comment: PMID: 36715754 1 family with 3 affected sons with congenital ichthyosis, consanguineous parents. All 3 affected members are homozygous for a canonical splice in PRSS8, quantitative RT-PCR showed a significant reduction in normal PRSS8 transcript. A second family with 4 affected members (proband and 3 cousins) with ichthyosis (3 also had autism), also consanguineous. Only the proband was tested who is homozygous for a missense in PTSS8. However this patient also had a TAAR1 missense (no disease association, but the paper suggests this could be responsible for the autism phenotype- KO mice have abnormal learning behaviour). Sources: Literature |
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| Mendeliome v1.906 | NSUN6 |
Michelle Torres gene: NSUN6 was added gene: NSUN6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NSUN6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NSUN6 were set to 37226891 Phenotypes for gene: NSUN6 were set to neurodevelopmental disorder MONDO:0700092, NSUN6-related Review for gene: NSUN6 was set to AMBER Added comment: Three unrelated consanguineous families with developmental delay, intellectual disability, motor delay, and behavioral anomalies. WES detected homozygous variants: - p.(Leu9Glufs*3): even though authors say is is predicted to cause NMD, it actually is NMD escape. No further studies were performed. A deceased affected sibling and parents were NOT tested. - p.(Asp323Asn): Shown to result in a misfolded protein. Methylation assay showed mutant could not catalyze m5C deposition in transcribed tRNACys and tRNAThr substrates in vitro. One of the parents and both unaffected siblings were shown to be carriers. - p.(Glu441Profs*15): truncation (full protein is 470aa) which would result in loss of residues involved in recognition and methylation. Shown to result in a misfolded protein. Parents were shown carriers. Sources: Literature |
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| Mendeliome v1.898 | NPR1 |
Lilian Downie gene: NPR1 was added gene: NPR1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPR1 were set to PMID: 37080586 Phenotypes for gene: NPR1 were set to Genetic hypertension MONDO:0015512 Review for gene: NPR1 was set to GREEN Added comment: 4 sibs with systemic hypertension in the neonatal period - presenting with cardiogenic shock, with homozygous variants (consanguineous parents), parents confirmed heterozygotes. 3/4 infants had increased NT (>3.5) in utero RT-PCR shows dramatic reduction of RNA levels 2 sibs in a second family, normal NT and pregnancy, neonatal systematic hypertension presenting with cardiogenic shock, Sources: Literature |
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| Mendeliome v1.896 | U2AF2 | Paul De Fazio reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34112922, 37092751, 36747105, 37134193; Phenotypes: Neurodevelopmental disorder, U2AF2-related (MONDO:0700092); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.895 | SLC26A1 | Ain Roesley reviewed gene: SLC26A1: Rating: RED; Mode of pathogenicity: None; Publications: 36719378; Phenotypes: perichondritis, hyposulphatemia, renal sulphate wasting; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.883 | UNC13A | Ain Roesley reviewed gene: UNC13A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO#0700092, UNC13A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.879 | GATAD2A |
Bryony Thompson changed review comment from: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5 PMID: 17565372 - null mouse model is embryonic lethal. Sources: Literature; to: PMID: 37181331 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5 PMID: 17565372 - null mouse model is embryonic lethal. Sources: Literature |
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| Mendeliome v1.877 | ARFGEF3 | Ain Roesley reviewed gene: ARFGEF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.853 | RARA |
Zornitza Stark commented on gene: RARA: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER). Both individuals had severe craniosynostosis (sagittal or bicoronal). Other shared phenotypic features included: - Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs) - Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic nasal bones, and oligodontia) - Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency. The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors. |
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| Mendeliome v1.850 | RARA |
Zornitza Stark edited their review of gene: RARA: Added comment: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER). Both individuals had severe craniosynostosis (sagittal or bicoronal). Other shared phenotypic features included: - Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs) - Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic nasal bones, and oligodontia) - Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency. The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.; Changed rating: AMBER; Changed publications: 31343737, 37086723; Changed phenotypes: Craniosynostosis - MONDO:0015469, Syndromic chorioretinal coloboma; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Mendeliome v1.842 | LHX2 |
Manny Jacobs gene: LHX2 was added gene: LHX2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LHX2 were set to PMID: 37057675 Phenotypes for gene: LHX2 were set to Neurodevelopmental disorder (MONDO: 0700092) Review for gene: LHX2 was set to GREEN Added comment: PMID: 37057675 Case series of 19 individuals across 18 families. 1 whole gene deletion, 7 missense, 10 predicted LoF variants. Proposed loss-of-function mechanism. Variable phenotype, with variable intellectual disability and behavioural (ASD/ADHD) features. Microcephaly in 7 individuals. 1 variant inherited from a mildly affected parent, all other variants with parental genotype available shown to be de novo. Sources: Literature |
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| Mendeliome v1.839 | CBX1 |
Daniel Flanagan gene: CBX1 was added gene: CBX1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CBX1 were set to PMID: 37087635 Phenotypes for gene: CBX1 were set to Neurodevelopmental disorder (MONDO#0700092), CBX1-related Review for gene: CBX1 was set to GREEN Added comment: Three different de novo missense variants identified in three unrelated individuals with developmental delay, hypotonia, autistic features, and variable dysmorphic features such as broad forehead and head circumference above average. Mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Functional studies confirmed the reduction of mutant HP1β binding to heterochromatin. Sources: Expert list |
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| Mendeliome v1.837 | DNAH7 |
Chern Lim gene: DNAH7 was added gene: DNAH7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DNAH7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAH7 were set to 34476482; 35543642 Phenotypes for gene: DNAH7 were set to non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related Review for gene: DNAH7 was set to GREEN gene: DNAH7 was marked as current diagnostic Added comment: PMID: 34476482 (Wei et al 2021): - Hom/chet missense DNAH7 variants in three unrelated infertile patients with idiopathic asthenozoospermia, presented with primary ciliary dyskinesia (PCD)-associated symptoms. - Functional studies showed expression of DNAH7 in the spermatozoa from the DNAH7-defective patients was significantly decreased. PMID: 35543642 (Gao et al 2022): - One proband with idiopathic asthenozoospermia, presented a history of PCD-like symptoms. Hom frameshift variant predicted to cause NMD, both parents are heterozygous. - Immunofluorescent staining showed DNAH7 signal significantly decreased or was even completely absent in the sperm from the investigated patient. Sources: Literature |
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| Mendeliome v1.836 | SRSF1 |
Paul De Fazio gene: SRSF1 was added gene: SRSF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SRSF1 were set to 37071997 Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder, SRSF1-related MONDO:0700092 Review for gene: SRSF1 was set to GREEN gene: SRSF1 was marked as current diagnostic Added comment: 17 individuals from 16 families reported with mostly de novo variants. Variants were a mixture of missense, nonsense/frameshift (both NMD-predicted and not NMD-predicted) and microdeletions. In one family, only one parent was available for testing. In another family, 2 affected siblings had the variant but the variant was not identified in either parent suggesting germline mosaicism. Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. Episignature analysis (EpiSign) on patient DNA from blood showed a specific DNA methylation signature in patients with the variants classified pathogenic but not those classified VUS. Phenotypes included mainly neurological abnormalities (mild to moderate ID/dev delay, motor delay, speech delay, and behavioural disorders) and facial dysmorphisms. Other features included hypotonia (11/16), variable brain abnormalities on MRI (6/12), variable cardiac malformations (6/14). urogenital malformations e.g. hypospadias, cryptorchidism (6/13), scoliosis (5/17) and/or variable other skeletal abnormalities (10/17). Sources: Literature |
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| Mendeliome v1.834 | SLC30A9 |
Lucy Spencer gene: SLC30A9 was added gene: SLC30A9 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC30A9 were set to 37041080 Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome (MIM#617595) Review for gene: SLC30A9 was set to GREEN Added comment: PMID:37041080 - 2 families previously reported and this paper describes 4 more with biallelic SLC30A9 variants. Original 2 families: 6 affected members all hom for Ala350del, and 1 affected member chet for 2 frameshifts. 4 families from this paper: 2 families have the same homozygous missense (Gly418Val), family 3 has 4 affected sibs hom for Ala350del, family 4 1 affected chet for a frameshift and a synonymous. So 2 fams homs for Ala350del and 2 fams hom for Gly418Val. All have Brik-Landau-Perez syndrome: all with ID, movement disorder and dystonia, and many with oculomotor apraxia, renal abnormalitie, ptosis, some had hearing impairment. Sources: Literature |
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| Mendeliome v1.831 | ERG | Ain Roesley reviewed gene: ERG: Rating: GREEN; Mode of pathogenicity: None; Publications: 36928819; Phenotypes: primary lymphoedema MONDO#0019175, ERG-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.830 | GATAD2A |
Bryony Thompson gene: GATAD2A was added gene: GATAD2A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372 Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related Review for gene: GATAD2A was set to GREEN Added comment: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5 PMID: 17565372 - null mouse model is embryonic lethal. Sources: Literature |
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| Mendeliome v1.807 | TSPAN7 | Ain Roesley reviewed gene: TSPAN7: Rating: AMBER; Mode of pathogenicity: None; Publications: 26350204, 36625203; Phenotypes: Intellectual developmental disorder, X-linked 58, MIM #300210, MONDO:0010266; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.807 | ROBO1 | Zornitza Stark Phenotypes for gene: ROBO1 were changed from Congenital heart disease; Pituitary anomalies; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; intellectual disability, MONDO:0001071 to Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; Neurooculorenal syndrome, MIM# 620305 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.806 | ROBO1 | Zornitza Stark edited their review of gene: ROBO1: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303, Nystagmus 8, congenital, autosomal recessive, MIM# 257400, Neurooculorenal syndrome, MIM# 620305 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.793 | MAP3K3 |
Zornitza Stark gene: MAP3K3 was added gene: MAP3K3 was added to Mendeliome. Sources: Literature somatic tags were added to gene: MAP3K3. Mode of inheritance for gene: MAP3K3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAP3K3 were set to 33729480; 35355835; 33891857; 36995941; 10700190; 25728774 Phenotypes for gene: MAP3K3 were set to Cerebral malformation, MONDO:0016054, MAP3K3-related Mode of pathogenicity for gene: MAP3K3 was set to Other Review for gene: MAP3K3 was set to GREEN Added comment: Recurrent somatic missense variant (p.I441M) identified in sporadic cases of cerebral and spinal cavernous malformation. Recent publication demonstrates that this missense variant can drive CCM formation (in vitro and in vivo studies). Sources: Literature |
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| Mendeliome v1.776 | CRIPT |
Karina Sandoval changed review comment from: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome, two new identified and 4 were already published. 5 were hom, 1 was chet, all with different variants. Additionally all presented with neuro dev delay and seizures. CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors, c.132del p.(Ala45Glyfs*82), hom c.227G>A, p.(Cys76Tyr), hom c.133_134insGG,p.(Ala45Glyfs*82),hom c.141del p.(Phe47Leufs*84), hom c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet c.7_8del; p.(Cys3Argfs*4), hom; to: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome characterised by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. Two new variants identified and 4 were already published. 5 were hom, 1 was chet, all with different variants. All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures. CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors, c.132del p.(Ala45Glyfs*82), hom c.227G>A, p.(Cys76Tyr), hom c.133_134insGG,p.(Ala45Glyfs*82),hom c.141del p.(Phe47Leufs*84), hom c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet c.7_8del; p.(Cys3Argfs*4), hom |
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| Mendeliome v1.776 | CEP162 |
Paul De Fazio gene: CEP162 was added gene: CEP162 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP162 were set to 36862503 Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related Penetrance for gene: CEP162 were set to unknown Review for gene: CEP162 was set to AMBER gene: CEP162 was marked as current diagnostic Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior. Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation. Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients. Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background). Sources: Literature |
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| Mendeliome v1.775 | ESAM |
Chern Lim gene: ESAM was added gene: ESAM was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ESAM were set to 36996813 Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related Review for gene: ESAM was set to GREEN gene: ESAM was marked as current diagnostic Added comment: PMID 36996813 - Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice. - Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. - One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect. - The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin) Sources: Literature |
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| Mendeliome v1.774 | SNAPC4 |
Ee Ming Wong gene: SNAPC4 was added gene: SNAPC4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNAPC4 were set to 36965478 Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related Review for gene: SNAPC4 was set to GREEN gene: SNAPC4 was marked as current diagnostic Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4 - Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice - Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts Sources: Literature |
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| Mendeliome v1.769 | MB |
Elena Savva gene: MB was added gene: MB was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MB were set to 35527200; 30918256 Phenotypes for gene: MB were set to Myopathy, sarcoplasmic body MIM#620286 Mode of pathogenicity for gene: MB was set to Other Review for gene: MB was set to GREEN Added comment: PMID: 30918256: - Recurrent c.292C>T (p.His98Tyr) in fourteen members of six European families with AD progressive myopathy. - Mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. - GOF hypothesised - 2/3 of myoglobin knockout mice die in utero, 1/3 live to adulthood with little sign of functional effects, likely due to multiple compensatory mechanisms. PMID: 35527200: - single adult patient with myoglobinopathy - same recurring p.His98Tyr variant Sources: Literature |
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| Mendeliome v1.768 | FILIP1 |
Paul De Fazio gene: FILIP1 was added gene: FILIP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FILIP1 were set to 36943452 Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168 Penetrance for gene: FILIP1 were set to unknown Review for gene: FILIP1 was set to GREEN gene: FILIP1 was marked as current diagnostic Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings. Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism. Sources: Literature |
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| Mendeliome v1.757 | NPPA | Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.757 | RYR3 | Chern Lim reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25262651; Phenotypes: developmental and epileptic encephalopathy (MONDO:0100062); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.752 | PRDM10 |
Achchuthan Shanmugasundram gene: PRDM10 was added gene: PRDM10 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRDM10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRDM10 were set to 36440963 Phenotypes for gene: PRDM10 were set to Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086 Review for gene: PRDM10 was set to RED Added comment: PMID:36440963 reported a family presenting with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with Birt-Hogg-Dubé syndrome (BHD, MIM #135150) based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. A heterozygous missense variant (p.Cys677Tyr) was identified, which co-segregated with the phenotype in the family. Functional studies show that Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN. This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature |
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| Mendeliome v1.719 | DPYSL2 |
Zornitza Stark gene: DPYSL2 was added gene: DPYSL2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DPYSL2 were set to 27249678; 35861646 Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071, DPYSL2-related Review for gene: DPYSL2 was set to AMBER Added comment: Two unrelated cases with monoallelic variants in DPYSL2/ CRMP2, supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients. PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus. It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype. Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability. Sources: Literature |
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| Mendeliome v1.702 | PLXND1 |
Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles. This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles. This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM. |
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| Mendeliome v1.702 | PLXND1 |
Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles. This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM. |
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| Mendeliome v1.701 | CYB561 |
Zornitza Stark gene: CYB561 was added gene: CYB561 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYB561 were set to 29343526; 31822578 Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182 Review for gene: CYB561 was set to GREEN Added comment: Three families reported. Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood. Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa) Sources: Expert Review |
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| Mendeliome v1.699 | FTH1 | Paul De Fazio reviewed gene: FTH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36778397; Phenotypes: Neuroferritinopathy (MONDO:0011638); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.695 | TEFM |
Ee Ming Wong gene: TEFM was added gene: TEFM was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TEFM were set to 36823193 Phenotypes for gene: TEFM were set to Mitochondrial disease (MONDO#0044970), TEFM-related Review for gene: TEFM was set to GREEN gene: TEFM was marked as current diagnostic Added comment: - Seven TEFM variants (4 missense, 2 fs, 1 in-frame del) in seven individuals across five unrelated families - Muscle and primary fibroblast from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts - TEFM knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function Sources: Literature |
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| Mendeliome v1.691 | HMGB1 |
Ain Roesley edited their review of gene: HMGB1: Added comment: PMID:36755093 4 new families with de novo protein truncating variants. In addition with PMID 34159400 ( all de novos) c.556_559delGAAG;p.(Glu186Argfs*42) - 1 family c.551_554delAGAA;p.(Lys184Argfs*44) - 4 families; Changed rating: GREEN; Changed publications: 34159400, 36755093; Changed phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Set current diagnostic: yes |
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| Mendeliome v1.689 | LGR4 |
Elena Savva changed review comment from: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein. Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation gnomAD: no hom PTCs PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; to: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein. Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation gnomAD: no hom PTCs PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes). |
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| Mendeliome v1.689 | LGR4 |
Elena Savva edited their review of gene: LGR4: Added comment: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein. Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation gnomAD: no hom PTCs PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; Changed publications: PMID: 32493844, 36538378; Changed phenotypes: {Bone mineral density, low, susceptibility to} MIM#615311; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v1.684 | ELOC |
Achchuthan Shanmugasundram gene: ELOC was added gene: ELOC was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ELOC was set to Unknown Publications for gene: ELOC were set to 35323939 Phenotypes for gene: ELOC were set to von Hippel-Lindau disease, MONDO:0008667; renal cell carcinoma, MONDO:0005086; retinal hemangioblastoma, MONDO:0003343 Review for gene: ELOC was set to RED Added comment: Comment on gene classification: This gene should be rated red as there is only one case with germline variant found so far. A female patient was identified with a germline de novo missense variant in ELOC gene (c.236A>G/ p.Tyr79Cys) and satisfied the clinical diagnostic criteria for von Hippel-Lindau (VHL) disease. The patient had left retinal haemangioblastomas, renal cell carcinomas, cyst of the right kidney, spinal haemangioblastoma, a haemangioblastoma at the cervicomedullary junction and Henoch-Schonlein purpura (PMID:35323939). This is the only germline variant detected in ELOC gene and was associated with VHL so far. However, ~20 somatic ELOC variants have been reported to be associated with renal cell carcinomas so far. This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype. Sources: Literature |
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| Mendeliome v1.665 | WNT11 |
Achchuthan Shanmugasundram gene: WNT11 was added gene: WNT11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WNT11 were set to 34875064 Phenotypes for gene: WNT11 were set to osteoporosis, MONDO:0005298; osteoarthritis, MONDO:0005178; recurrent fractures Review for gene: WNT11 was set to GREEN Added comment: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene. Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures. A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures. A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met). This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells. This gene has not yet been reported with any phenotypes either in OMIM or in G2P. Sources: Literature |
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| Mendeliome v1.654 | KBTBD13 | Bryony Thompson reviewed gene: KBTBD13: Rating: AMBER; Mode of pathogenicity: None; Publications: 36335629; Phenotypes: Cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.651 | RRAGD | Zornitza Stark Phenotypes for gene: RRAGD were changed from Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.649 | RRAGD |
Hazel Phillimore changed review comment from: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature; to: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature |
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| Mendeliome v1.649 | RRAGD |
Hazel Phillimore gene: RRAGD was added gene: RRAGD was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RRAGD were set to PMID: 34607910 Phenotypes for gene: RRAGD were set to Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis Review for gene: RRAGD was set to GREEN Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature |
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| Mendeliome v1.649 | PMEL |
Paul De Fazio gene: PMEL was added gene: PMEL was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PMEL were set to 36166100; 36207673 Phenotypes for gene: PMEL were set to Oculocutaneous albinism, PMEL-related MONDO:0018910 Review for gene: PMEL was set to RED gene: PMEL was marked as current diagnostic Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR. Some evidence that polymorphisms in this gene influence pigmentation in cattle. Sources: Literature |
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| Mendeliome v1.649 | SPTSSA | Seb Lunke Added comment: Comment on list classification: Three individuals but only two variants with different inheritance. Amber despite functional data. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.635 | TPCN2 | Paul De Fazio reviewed gene: TPCN2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 36641477; Phenotypes: Hypopigmentation of the skin, TPCN2-related MONDO:0019290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.635 | MIR145 |
Lucy Spencer gene: MIR145 was added gene: MIR145 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MIR145 were set to 36649075 Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452), MIR145-related Review for gene: MIR145 was set to RED Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p. Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts. Sources: Literature |
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| Mendeliome v1.632 | PCK2 | Ain Roesley reviewed gene: PCK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.630 | TRU-TCA1-1 |
Paul De Fazio gene: TRU-TCA1-1 was added gene: TRU-TCA1-1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927 Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425 Review for gene: TRU-TCA1-1 was set to AMBER gene: TRU-TCA1-1 was marked as current diagnostic Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA. PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy. Sources: Literature |
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| Mendeliome v1.628 | TTI1 | Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.625 | NPTX1 |
Ain Roesley gene: NPTX1 was added gene: NPTX1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436 Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related Review for gene: NPTX1 was set to GREEN gene: NPTX1 was marked as current diagnostic Added comment: PMID:34788392 5 families with multigenerational segregations - late onset ataxia 4 families with p.(Gly389Arg) + 1x p.(Glu327Gly) functional studies done Note: case report of a family member published elsewhere (PMID:35288776) PMID:35285082 1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome p.(Arg143Leu) PMID:35560436 1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy p.(Gln370Arg) Sources: Literature |
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| Mendeliome v1.621 | AGR2 | Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.620 | AGR2 | Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.614 | LY96 |
Zornitza Stark gene: LY96 was added gene: LY96 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LY96 were set to 36462957 Phenotypes for gene: LY96 were set to Inborn error of immunity, MONDO:0003778, LY96-related Review for gene: LY96 was set to RED Added comment: Single individual with infantile colitis associated with failure-to-thrive, bloody diarrhoea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Found to have homozygous inflame deletion. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation. Sources: Expert Review |
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| Mendeliome v1.601 | TRPC5 |
Hazel Phillimore gene: TRPC5 was added gene: TRPC5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890 Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder Review for gene: TRPC5 was set to AMBER Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570: Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents. Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened). (This variant is absent in gnomAD v2.1.1). Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted. Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include: PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested). In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*). NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1). However, looking further into the three references, the evidence is not as clear or as accurate as was stated. The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929). Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned. Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2). Sources: Literature |
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| Mendeliome v1.601 | BSN |
Krithika Murali changed review comment from: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development. In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected. Association between biallelic variants and epilepsy stronger than for monoallelic. Sources: Literature; to: Ye et al 2022, Neurogenetics - https://jmg.bmj.com/content/early/2022/12/12/jmg-2022-108865 Identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development. In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected. Association between biallelic variants and epilepsy stronger than for monoallelic. Sources: Literature |
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| Mendeliome v1.601 | RIC1 | Paul De Fazio reviewed gene: RIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36493769; Phenotypes: Cleft lip/palate MONDO:0016044, RIC1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.595 | UHRF1 |
Chern Lim changed review comment from: PMID: 29574422 Begemann et al. 2018 - Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense.; to: PMID: 29574422 Begemann et al. 2018 - Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense. Her cotwin was clinically and epigenetically normal |
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| Mendeliome v1.593 | UHRF1 |
Chern Lim edited their review of gene: UHRF1: Added comment: PMID: 36458887 Unoki et al. 2022 - One patient with compound het missense and nonsense variants, both parents are carriers (hets). - The patient has chromosome instability with hypomethylation of the pericentromeric satellite-2 repeats and facial anomalies as typical symptoms of the ICF syndrome, but did not exhibit immunodeficiency, and developed an adrenocortical adenoma; characteristics that were atypical. - Genome-wide methylation analysis revealed the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes. - Structural and biochemical analyses revealed that the R296W variant disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1, and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and PAF15.; Changed publications: 36458887; Changed phenotypes: chromosome instability; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Mendeliome v1.589 | ARHGEF38 |
Paul De Fazio gene: ARHGEF38 was added gene: ARHGEF38 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARHGEF38 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ARHGEF38 were set to 36493769 Phenotypes for gene: ARHGEF38 were set to Cleft lip/palate MONDO:0016044, ARHGEF38-related Review for gene: ARHGEF38 was set to AMBER gene: ARHGEF38 was marked as current diagnostic Added comment: PMID:36493769 identified an intragenic deletion by high-res microarray of the same exon (exon 3) in 4 individuals with non-syndromic cleft lip/palate. Deletion of exon 3 is present in 6 individuals in gnomAD. Inheritance information was not available. Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos. Sources: Literature |
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| Mendeliome v1.588 | COBLL1 |
Paul De Fazio gene: COBLL1 was added gene: COBLL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: COBLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: COBLL1 were set to 36493769 Phenotypes for gene: COBLL1 were set to Cleft lip/palate MONDO:0016044, COBLL1-related gene: COBLL1 was marked as current diagnostic Added comment: PMID:36493769 identified the same multi-exon intragenic deletion by high-res microarray in 3 individuals with non-syndromic cleft lip/palate. The deletion is absent from gnomAD. Inheritance information was only available for 1 individual, in whom it was inherited from an unaffected father. Note that the gene is not quite LOF constrained in gnomAD. Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos. Sources: Literature |
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| Mendeliome v1.588 | BSN |
Krithika Murali gene: BSN was added gene: BSN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: BSN were set to Epilepsy MONDO:0005027 Review for gene: BSN was set to GREEN Added comment: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development. In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected. Association between biallelic variants and epilepsy stronger than for monoallelic. Sources: Literature |
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| Mendeliome v1.587 | PHLDB1 |
Seb Lunke gene: PHLDB1 was added gene: PHLDB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PHLDB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PHLDB1 were set to 36543534 Phenotypes for gene: PHLDB1 were set to osteogenesis imperfecta, MONDO:0019019 Review for gene: PHLDB1 was set to AMBER Added comment: 5 children from two consanguineous families with recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment. Two independent nonsense variants were identified in the families, NM_001144758.3:c.2392dup (p.Leu798Profs*4) and NM_001144758.3:c.2690_2693del (p.Leu897Glnfs*24). RT-PCR and western blot analysis confirmed loss of transcript and protein product, respectively, but no further functional data provided. Sources: Literature |
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| Mendeliome v1.583 | OXGR1 |
Sarah Pantaleo gene: OXGR1 was added gene: OXGR1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OXGR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: OXGR1 were set to PMID:35671463 Phenotypes for gene: OXGR1 were set to Nephrolithiasis/nephrocalcinosis MONDO:0008171, OXGR1-related Penetrance for gene: OXGR1 were set to unknown Review for gene: OXGR1 was set to AMBER Added comment: Candidate disease gene for human calcium oxalate nephrolithiasis. Performed exome sequencing and directed sequencing of the OXGR1 locus in a worldwide nephrolithiasis/nephrocalcinosis (NL/NC) cohort, and putatively deleterious rare OXGR1 variants were functionally characterised. A heterozygous OXGR1 missense variant (c.371T>G; p.Leu124Arg) co-segregated with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals. Interrogation of the OXGR1 locus in 1,107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls. Four missense variants and one frameshift variant. Four of five NL/NC-associated missense variants revealed impaired AKG-dependent calcium ion uptake, demonstrating loss of function. Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. Six potentially deleterious variants were identified in six of 1,108 NL/NC families (0.54%). Limitations: only probands were able to be recruited for four of six families. In the future, it will be important to determine whether any of the affected family members share the identified OXGR1 variant. They also observe OXGR1 variants in 0.16% of ExAC subjects (selected on the basis of the absence of paediatric disease). Sources: Literature |
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| Mendeliome v1.580 | CCIN |
Chern Lim gene: CCIN was added gene: CCIN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCIN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCIN were set to 36546111; 36527329 Phenotypes for gene: CCIN were set to Teratozoospermia Review for gene: CCIN was set to GREEN gene: CCIN was marked as current diagnostic Added comment: Two papers with three unrelated patients with teratozoospermia: PMID: 36546111 - Two families reported: One with homozygous missense (fam is consanguineous) and another with compound heterozygous missense + nonsense variants, patients suffering from teratozoospermia. - Homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* knock-in mice generated. Spermatozoa from homozygous male mice exhibited abnormalities of sperm head shape revealed by Diff-Quick staining. When mated with WT mice, both homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* male mice were infertile, whereas the mutant female mice could generate offspring and displayed no defects in fertility. PMID: 36527329 - One consanguineous family reported: homozygous missense, with asthenoteratozoospermia. - Transfected HEK cells showed reduced CCIN protein level. Sources: Literature |
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| Mendeliome v1.576 | TRA2B |
Elena Savva gene: TRA2B was added gene: TRA2B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TRA2B were set to PMID: 36549593 Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092) Review for gene: TRA2B was set to GREEN Added comment: PMID: 36549593 - 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12 - All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased. - Apparently het mice K/O are normal, but complete K/O cannot develop embryonically. - DN mechanism suggested Sources: Literature |
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| Mendeliome v1.572 | ZMYM3 |
Belinda Chong gene: ZMYM3 was added gene: ZMYM3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZMYM3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: ZMYM3 were set to 36586412; 24721225 Phenotypes for gene: ZMYM3 were set to Neurodevelopmental disorders (NDDs) Review for gene: ZMYM3 was set to GREEN Added comment: PMID: 36586412 Using the MatchMaker Exchange - Described 27 individuals with rare, variation in the ZMYM3. Most individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) with de novo variants. Overlapping features included developmental delay, intellectual disability, behavioural abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441 (R441W), a site at which variation has been previously seen in NDD-affected siblings (24721225), and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. Sources: Literature |
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| Mendeliome v1.563 | SLC26A6 |
Arina Puzriakova gene: SLC26A6 was added gene: SLC26A6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SLC26A6 were set to 35115415; 21170874; 32660969 Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969) SLC26A6 is currently not associated with any human phenotype in OMIM or G2P. Sources: Literature |
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| Mendeliome v1.554 | SETD2 |
Zornitza Stark edited their review of gene: SETD2: Added comment: PMID 32710489: 12 unrelated patients, ranging from 1 month to 12 years of age, with a multisystemic neurodevelopmental disorder associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740W). Key clinical features: severely impaired global development apparent from infancy, feeding difficulties with failure to thrive, small head circumference, and dysmorphic facial features. Affected individuals have impaired intellectual development and hypotonia; they do not achieve walking or meaningful speech. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and possibly endocrine. Further 3 unrelated patients identified with mild to moderately impaired intellectual development associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740Q). These are distinct clinically from Luscan-Lumish syndrome, which is characterised by overgrowth.; Changed publications: 29681085, 32710489; Changed phenotypes: Luscan-Lumish syndrome, MIM#616831, Rabin-Pappas syndrome,MIM# 620155, Intellectual developmental disorder, autosomal dominant 70, MIM# 620157 |
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| Mendeliome v1.547 | IL2RB |
Zornitza Stark changed review comment from: Five families reported. Sources: Expert list; to: Five families reported. Affected individuals present in infancy with features of both abnormal activation of certain immune signaling pathways, resulting in lymphoid proliferation, dermatitis, enteropathy, and hypergammaglobulinemia, as well as features of immunodeficiency, such as recurrent infections and increased susceptibility to viral infections, especially CMV. Laboratory studies show increased NK cells that show impaired differentiation, as well as abnormal T cell populations or responses. Some patients may die in childhood; hematopoietic bone marrow transplantation is curative. Sources: Expert list |
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| Mendeliome v1.538 | CHUK | Zornitza Stark edited their review of gene: CHUK: Added comment: PMID 34533979: single individual reported with homozygous missense variant in this gene and recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine. Supportive functional data.; Changed publications: 25691407, 20961246, 10195895, 10195896, 29523099, 28513979, 34533979 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.535 | LIG1 | Zornitza Stark Phenotypes for gene: LIG1 were changed from Combined immunodeficiency; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis to Immunodeficiency 96, MIM# 619774; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.530 | MPC2 |
Zornitza Stark gene: MPC2 was added gene: MPC2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MPC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MPC2 were set to 36417180 Phenotypes for gene: MPC2 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related Review for gene: MPC2 was set to AMBER Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels. Sources: Literature |
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| Mendeliome v1.526 | TIMMDC1 | Paul De Fazio reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36349561, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31 MIM#618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.511 | NPC1 |
Naomi Baker gene: NPC1 was added gene: NPC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPC1 were set to 36417180 Phenotypes for gene: NPC1 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related Review for gene: NPC1 was set to AMBER Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels. Sources: Literature |
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| Mendeliome v1.507 | GABRA3 |
Sarah Pantaleo gene: GABRA3 was added gene: GABRA3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GABRA3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: GABRA3 were set to PMID: 29053855 Phenotypes for gene: GABRA3 were set to Epilepsy, intellectual disability, dysmorphic features, Penetrance for gene: GABRA3 were set to Incomplete Review for gene: GABRA3 was set to GREEN Added comment: Six variants in GABRA3 encoding the alpha3-subunit of the GABA(A) receptor. Five missense variants and one micro duplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. Mechanism suggested - three detected missense variants are localised in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the alpha3-subunit. Functional studies in Xenopus leaves oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. Results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern. Sources: Literature |
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| Mendeliome v1.505 | TCEAL1 |
Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. 1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features. 4 PTCs, 2 CNVs, 2 missense reported. Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. 1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features. 4 PTCs, 2 CNVs, 2 missense reported. Sources: Literature |
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| Mendeliome v1.504 | TCEAL1 |
Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. 1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features. 4 PTCs, 2 CNVs, 2 missense reported. Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. 1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features. 4 PTCs, 2 CNVs, 2 missense reported. Sources: Literature |
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| Mendeliome v1.504 | TCEAL1 |
Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. 1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features. 4 PTCs, 2 CNVs, 2 missense reported. Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. 1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features. 4 PTCs, 2 CNVs, 2 missense reported. Sources: Literature |
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| Mendeliome v1.504 | UQCRH |
Chern Lim gene: UQCRH was added gene: UQCRH was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UQCRH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UQCRH were set to 34750991 Phenotypes for gene: UQCRH were set to Mitochondrial complex III deficiency, nuclear type 11, MIM#620137 Review for gene: UQCRH was set to AMBER gene: UQCRH was marked as current diagnostic Added comment: PMID: 34750991: - Two affected cousins, presented with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. - Both have a 2.2 kb homozygous deletion of exons 2 and 3 of UQCRH, predicted to culminate in an in-frame deletion exons 2 and 3 of the four-exon UQCRH gene, resulting in a shortened product. - Mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh-/-) also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. - Patient fibroblasts and Uqcrh-/- mouse tissues showed a CIII defect. - Expression of wild-type UQCRH in patient fibroblasts ameliorates the CIII defect. Sources: Literature |
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| Mendeliome v1.504 | FEM1C |
Paul De Fazio gene: FEM1C was added gene: FEM1C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FEM1C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FEM1C were set to 36336956; 28135719; 33398170; 33398168 Phenotypes for gene: FEM1C were set to Neurodevelopmental disorder, FEM1C-related MONDO:0700092 Review for gene: FEM1C was set to GREEN gene: FEM1C was marked as current diagnostic Added comment: PMID:36336956 describes a 9-year-old boy with severe DD, lack of speech, pyramidal signs, and limb ataxia who had a de novo missense variant Asp126His in FEM1C ascertained by WES. The equivalent variant introduced into the nematode C.elegans resulted in disabled locomotion caused by synaptic abnormalities and not muscle dysfunction. An alternate change Asp126Val was reported in the DDD study de novo in a patient with uncharacterised developmental delay (PMID:28135719). The Asp126 residue (but not either of the variants above specifically) was shown to be functionally important by in vitro studies (PMID:33398170;33398168). The residue is highly conserved and located in a region of missense constraint. Borderline green, 2 patients and an animal model. Note all evidence points to the Asp126 residue being of specific importance. Sources: Literature |
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| Mendeliome v1.504 | TCEAL1 |
Melanie Marty gene: TCEAL1 was added gene: TCEAL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TCEAL1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: TCEAL1 were set to PMID: 36368327 Phenotypes for gene: TCEAL1 were set to hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features. Review for gene: TCEAL1 was set to GREEN Added comment: 7 individuals (males and females) with de novo variants involving TCEAL1. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. 1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features. 4 PTCs, 2 CNVs, 2 missense reported. Sources: Literature |
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| Mendeliome v1.503 | KDM2B |
Ain Roesley gene: KDM2B was added gene: KDM2B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KDM2B were set to 36322151 Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#070009, KDM2B-related Review for gene: KDM2B was set to GREEN gene: KDM2B was marked as current diagnostic Added comment: 27 individuals from 22 families were recruited 12 SNV classified LP/P, all de novo except 2 familial cases 5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function) Sources: Literature |
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| Mendeliome v1.489 | PIGN |
Zornitza Stark edited their review of gene: PIGN: Added comment: Large cohort study of 21 new and review of 40 previously published cases in PMID 36322149 Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon.; Changed publications: 36322149; Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563, Fryns syndrome |
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| Mendeliome v1.481 | KCNJ16 | Zornitza Stark Phenotypes for gene: KCNJ16 were changed from Renal tubulopathy; deafness to Inherited renal tubular disease, MONDO:0015962, KCNJ16-related; Renal tubulopathy; deafness | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.480 | KCNJ16 | Zornitza Stark edited their review of gene: KCNJ16: Changed phenotypes: Inherited renal tubular disease, MONDO:0015962, KCNJ16-related, Renal tubulopathy, deafness | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.478 | FOXI1 | Zornitza Stark reviewed gene: FOXI1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive distal renal tubular acidosis MONDO:0018440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.476 | PDIA6 | Chirag Patel edited their review of gene: PDIA6: Added comment: 2nd patient with large polycystic kidneys, death and end stage renal failure at 18 months, microcephaly, bilateral inguinal hernias, umbilical hernia, developmental delay, bilateral sensorineural hearing loss, visual impairment, steatorrhea, fibrotic changes in liver, and insulin-dependent diabetes. WGS found homozygous stop-gain variant (Tyr368*) in PDIA6. Segregation not performed.; Changed rating: AMBER; Changed publications: PMID: 35856135; Changed phenotypes: Polycystic kidney disease, infancy-onset diabetes, and microcephaly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.472 | MTSS1 |
Zornitza Stark gene: MTSS1 was added gene: MTSS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MTSS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTSS1 were set to 36067766 Phenotypes for gene: MTSS1 were set to Intellectual disability, MTSS1-related (MONDO#0001071) Review for gene: MTSS1 was set to GREEN Added comment: Five individuals with the same heterozygous de novo variant in MTSS2 (NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals presented with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. Sources: Literature |
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| Mendeliome v1.465 | NF1 | Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34476477; Phenotypes: Neurofibromatosis, type 1, MIM# 162200, MONDO:0018975, renovascular hypertension, MONDO:0006947; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.463 | IRF2BP2 | Zornitza Stark edited their review of gene: IRF2BP2: Added comment: Reports of additional patients: 4yo with chronic diarrhea, severe eczema, anemia, failure to thrive, fevers, short stature, recurrent infections, cataracts, hypodontia, hypotrichosis alopecia, hypogammaglobulinemia. The 33-year-old male presented with recurrent respiratory infections since childhood, colitis and RA beginning at age 25 years.; Changed rating: GREEN; Changed publications: 27016798, 32048120, 36193988, 33864888; Changed phenotypes: Immunodeficiency, common variable, 14, MIM# 617765 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.452 | WDR5 |
Bryony Thompson gene: WDR5 was added gene: WDR5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WDR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157 Phenotypes for gene: WDR5 were set to Neurodevelopmental disorder MONDO:0700092, WDR5-related Mode of pathogenicity for gene: WDR5 was set to Other Review for gene: WDR5 was set to GREEN Added comment: Six different missense variants were identified (de novo) in 11 affected individuals with neurodevelopmental disorders, with a broad spectrum of additional features, including epilepsy, aberrant growth parameters, skeletal and cardiac abnormalities. In vivo and in vitro functional suggest that loss-of-function is not the mechanism of disease. The mechanism of disease is yet to be established. Sources: Literature |
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| Mendeliome v1.445 | ATP11A | Chern Lim reviewed gene: ATP11A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36300302; Phenotypes: Deafness, autosomal dominant 84 (MIM#619810); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.442 | THAP1 |
Michelle Torres commented on gene: THAP1: Monoallelic is well established with reduced penetrance. Biallelic was seen in 3 families generally with severe and early onset dystonia: PMID: 36205328: consanguineous family (gene panel), proband homozygous for p.Lys162Asn with early onset multifocal dystonia with severe oromandibular/laryngeal dysfunction; both parents were confirmed carriers with milder features (47 yo father with tightness and difficulty with fine motor tasks, 41 yo mother with tightness). PMID: 21425335: 3 siblings are homozygous for the p.Leu32His with early-onset generalized dystonia. Carriers were unaffected. PMID: 20211909: a homozygous variant was identified in an individual with with writer's dystonia initially and then developing segmental dystonia, onset at 57 yo, parents could not be tested. |
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| Mendeliome v1.440 | FICD |
Alison Yeung gene: FICD was added gene: FICD was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FICD were set to 36136088 Phenotypes for gene: FICD were set to Hereditary motor neurone disease, FICD-related, MONDO:0024257 Review for gene: FICD was set to GREEN Added comment: Three unrelated families with recurrent homozygous missense variant: p.Arg374His One further family with Chet variants: p.Arg 374His and p.Gly370GlufsTer53 Fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP. Onset of symptoms in childhood with progressive course. Presentation with severe lower limb spasticity and mild upper limb spascticity, nerve conduction test shows motor neuropathy. Sources: Literature |
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| Mendeliome v1.437 | FOXI3 |
Paul De Fazio gene: FOXI3 was added gene: FOXI3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FOXI3 were set to 36260083 Phenotypes for gene: FOXI3 were set to Dysostosis with predominant craniofacial involvement (MONDO:0800085) Penetrance for gene: FOXI3 were set to Incomplete Review for gene: FOXI3 was set to GREEN gene: FOXI3 was marked as current diagnostic Added comment: Ten affected individuals from 4 families reported with monoallelic variants, 2 with missense variants affecting the nuclear localisation sequence and 2 with frameshift variants. The missense variants were associated with isolated microtia with aural atresia and affected subcellular localisation of the protein, while the frameshift variants were associated with microtia and mandubular hypoplasia, suggesting dosage sensitivity. Rated green but CAUTION for incomplete penetrance. 3 of the 4 families had unaffected carriers. Family 1 in particular had 25 genotyped individuals, of which 15 were carriers, of which 5 were affected. Sources: Literature |
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| Mendeliome v1.435 | CBFB |
Ain Roesley gene: CBFB was added gene: CBFB was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CBFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CBFB were set to 36241386 Phenotypes for gene: CBFB were set to cleidocranial dysplasia (MONDO#0007340), CBFB-related Penetrance for gene: CBFB were set to Complete Review for gene: CBFB was set to GREEN gene: CBFB was marked as current diagnostic Added comment: 5 families with 8 individuals, including 2 de novos and 1 intragenic exon 4 deletion In 1 family, the mother did not report skeletal concerns but had dental abnormalities during childhood Sources: Literature |
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| Mendeliome v1.418 | PRDM16 | Paul De Fazio reviewed gene: PRDM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 29367541, 29447731, 30847666, 33082984, 32183154, 33500567, 34540771, 34350506, 34935411; Phenotypes: Cardiomyopathy, dilated, 1LL MIM#615373, Left ventricular noncompaction 8 MIM#615373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.414 | NFAT5 | Zornitza Stark Phenotypes for gene: NFAT5 were changed from Recurrent infections; Autoimmune enterocolopathy to Immune deficiency disease, MONDO:0003778, NFAT5-related; Recurrent infections; Autoimmune enterocolopathy; EBV susceptibility; HLH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.411 | NFAT5 | Zornitza Stark edited their review of gene: NFAT5: Added comment: Two additional individuals with missense variants reported in PMID 36238298: one with EBV infection with hepatitis and enterocolitis, and one with fatal HLH.; Changed rating: AMBER; Changed publications: 25667416, 36238298; Changed phenotypes: Immune deficiency disease, MONDO:0003778, NFAT5-related, Recurrent infections, Autoimmune enterocolopathy, EBV susceptibility, HLH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.403 | ARNT2 |
Bryony Thompson gene: ARNT2 was added gene: ARNT2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARNT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARNT2 were set to 11381139; 24022475 Phenotypes for gene: ARNT2 were set to Webb-Dattani syndrome MONDO:0014404 Review for gene: ARNT2 was set to AMBER Added comment: A homozygous frameshift (c.1373_1374dupTC) in six affected children from a highly consanguineous family with a syndromic phenotype including microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract. In a Arnt2(-/-) mouse model embryos die perinatally and exhibit impaired hypothalamic development. Sources: Literature |
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| Mendeliome v1.401 | FRMD5 |
Zornitza Stark gene: FRMD5 was added gene: FRMD5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FRMD5 were set to 36206744 Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder MONDO:0700092, FRMD5-related Review for gene: FRMD5 was set to GREEN Added comment: Eight individuals reported with missense variants in this gene, de novo in 6 where parents were available. Clinical presentation was with ID, seizures, ataxia. Fly model. Sources: Literature |
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| Mendeliome v1.392 | SEPT4 |
Bryony Thompson gene: SEPT4 was added gene: SEPT4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEPT4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEPT4 were set to 36135717; 15737931; 15737930 Phenotypes for gene: SEPT4 were set to male infertility MONDO:0005372 Review for gene: SEPT4 was set to GREEN Added comment: Two unrelated cases with primary male infertility (asthenoteratozoospermia) from consanguineous Chinsese families with 2 difference homozygous stopgain variants (Patient 1: c.721A>T, p.R241* and Patient 2: c.205C>T, p.R69*). Multiple supporting mouse models where the male mice are sterile. Sources: Literature |
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| Mendeliome v1.379 | ALG5 | Zornitza Stark Phenotypes for gene: ALG5 were changed from Cystic renal disease MONDO:0002473, ALG5-related to Polycystic kidney disease 7, MIM# 620056 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.372 | LETM1 |
Ee Ming Wong gene: LETM1 was added gene: LETM1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LETM1 were set to 36055214 Phenotypes for gene: LETM1 were set to Mitochondrial disease MONDO#0044970, LETM1-related gene: LETM1 was marked as current diagnostic Added comment: -18 affected individuals from 11 unrelated families harbouring ultra-rare bi-allelic missense and loss-of-function LETM1 variants -Most of the affected individuals (14/18, 78%) had an infantile-onset disease manifestation, and 4/18 (22%) presented first symptoms between the ages of 1.5 and 2 years -Variant types included missense, frameshift, stop loss, in-frame deletion and splice defect -From biochemical and morphological studies, bi-allelic LETM1 variants are associated with defective mitochondrial K efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components Sources: Literature |
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| Mendeliome v1.369 | DUT |
Daniel Flanagan gene: DUT was added gene: DUT was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DUT were set to 28073829; 35611808 Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome (MIM#620044) Review for gene: DUT was set to GREEN Added comment: Homozygous missense (p.(Tyr142Cys)) identified in eight affected individuals from four unrelated consanguineous families (French, Egyptian, two Libyan) with diabetes and bone marrow failure. DUT silencing in human and rat pancreatic b-cells results in apoptosis via the intrinsic cell death pathway. p.(Tyr142Cys) has 11 heterozygotes and no homozygotes in gnomAD. Sources: Expert list |
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| Mendeliome v1.369 | DACT1 | Paul De Fazio reviewed gene: DACT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36066768; Phenotypes: Townes-Brocks syndrome 2 MONDO:0054582; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.366 | LAMA5 | Belinda Chong reviewed gene: LAMA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29534211, 16790509, 29764427, 30808327, 24130771, 35419533; Phenotypes: Nephrotic syndrome, type 26 620049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.366 | MED11 |
Ain Roesley gene: MED11 was added gene: MED11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED11 were set to 36001086 Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related Review for gene: MED11 was set to GREEN gene: MED11 was marked as current diagnostic Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*). Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes NO evidence of founder effect from haplotype analysis 7/7 cerebral dysgyria, cortical atrophy 5/7 limb contracture 4/7 epilepsy 3/7 families with IUGR 3/7 GDD 3/7 hearing loss 3/7 undescended testis 2/7 nystagmus 1/7 congenital cataract Sources: Literature |
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| Mendeliome v1.354 | NAPB |
Paul De Fazio gene: NAPB was added gene: NAPB was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAPB were set to 26235277; 28097321; 33189936 Phenotypes for gene: NAPB were set to Developmental and epileptic encephalopathy 107 MIM#620033 Review for gene: NAPB was set to GREEN gene: NAPB was marked as current diagnostic Added comment: PMID 26235277: homozygous nonsense variant identified in a 6 year old girl by trio WES with early-onset epileptic encephalopathy characterised by multifocal seizures and profound GDD PMID 28097321: exome sequencing in 152 consanguineous families with at least one member affected with ID. Homozygous nonsense variant identified in a patient with profound ID, seizures, feeding difficulties in infancy, muscularhypotonia, microcephaly, and impaired vision PMID 33189936: homozygous canonical splice variant identified by trio exome sequencing in two siblings with seizures, intellectual disability and global developmental delay, microcephaly (<-3SD), and muscular hypotonia. Sources: Literature |
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| Mendeliome v1.351 | GCSH | Ain Roesley reviewed gene: GCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 36190515; Phenotypes: glycine encephalopathy MONDO#0011612, GCSH-related, neurodevelopmental disorder MONDO#0700092, GCHS-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.348 | FOSL2 |
Krithika Murali gene: FOSL2 was added gene: FOSL2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FOSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FOSL2 were set to 36197437 Phenotypes for gene: FOSL2 were set to Neurodevelopmental disorder, MONDO:0700092, FOSL2-related Review for gene: FOSL2 was set to GREEN Added comment: PMID 36197437 Cospain et al 2022 report 11 individuals from 10 families with heterozygous PTC variants in exon 4/4 of the FOSL2 gene. All variants were predicted to escape NMD resulting in a truncated protein, with the truncation occurring proximal to the C-terminal domain (supportive functional studies). In 10/11 families the variant occurred de novo in a single affected proband. In one family with 2 affected siblings, the variant was present in the siblings but absent in the unaffected parent likely due to gonadal mosaicism. Clinical features included: - Cutis aplasia congenital of the scalp (10/11) - Tooth enamel hypoplasia and discolouration (8/9) - Multiple other ectodermal features also noted e.g. small brittle nails, hypotrichosis/hypertrichosis, lichen sclerosis - 5 individuals had cataracts (mostly bilateral, congenital/early childhood onset) - 6/9 IUGR - 5/9 postnatal growth restriction - 7/9 developmental delay/ID - 5/7 ADHD/ASD - 2/9 seizures Sources: Literature |
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| Mendeliome v1.346 | TRAF3 | Zornitza Stark edited their review of gene: TRAF3: Added comment: PMID 35960817: Nine individuals from five unrelated families with childhood-onset immune diseases and recurrent infections. All patients had suffered recurrent ear and sinopulmonary infections, including pneumonias from encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenza, resulting in early-onset bronchiectasis in several individuals; Changed rating: GREEN; Changed publications: 20832341, 35960817; Changed phenotypes: Autoinflammatory syndrome, TRAF3-related, MONDO:0019751, hypergammaglobulinemia, lymphadenopathy, splenomegaly, Sjögren’s syndrome, {?Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 5}, MIM# 614849 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.342 | ACVR1 |
Zornitza Stark changed review comment from: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner. Multiple unrelated families reported. The R206H variant is recurrent. Note variants in this gene are also associated with congenital heart disease, PMID 29089047.; to: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner. Multiple unrelated families reported. The R206H variant is recurrent. Clinical trial with palovarotene Note variants in this gene are also associated with congenital heart disease, PMID 29089047. |
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| Mendeliome v1.339 | DPP9 |
Zornitza Stark gene: DPP9 was added gene: DPP9 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: DPP9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DPP9 were set to 36112693 Phenotypes for gene: DPP9 were set to Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias Review for gene: DPP9 was set to GREEN Added comment: Three unrelated families with Hatipoğlu syndrome with biochemical and cellular assays, mouse and zebrafish models. Immunological features of recurrent fevers, repeated infections, herpes susceptibility, cytopenias. Sources: Expert Review |
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| Mendeliome v1.338 | APRT |
Zornitza Stark changed review comment from: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic.; to: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic. Treatable: allopurinol or febuxostat, low purine diet. |
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| Mendeliome v1.332 | PTPA |
Zornitza Stark gene: PTPA was added gene: PTPA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPA were set to 36073231 Phenotypes for gene: PTPA were set to Intellectual disability, MONDO: 36073231, PTPA-related Review for gene: PTPA was set to AMBER Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below. There is currently no associated phenotype in OMIM, G2P, PanelApp UK or SysID. Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports. ------ Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants. These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation. Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies. Role of the gene: As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders. Variant studies: Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt. Drosophila / animal models: Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment. Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice. Sources: Literature |
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| Mendeliome v1.325 | MYH8 | Ain Roesley reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: 15590965, 17041932, 15282353; Phenotypes: Carney complex variant MIM#60883; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.323 | NODAL |
Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad. The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED. A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance. Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987 |
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| Mendeliome v1.310 | SLC31A1 |
Daniel Flanagan gene: SLC31A1 was added gene: SLC31A1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC31A1 were set to PMID: 35913762 Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) Review for gene: SLC31A1 was set to RED Added comment: SLC31A1 is also referred to as CTR1. Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality. Sources: Expert list |
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| Mendeliome v1.289 | TMEM147 |
Naomi Baker gene: TMEM147 was added gene: TMEM147 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM147 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM147 were set to PMID: 36044892 Phenotypes for gene: TMEM147 were set to Neurodevelopmental disorder (MONDO:0700092), TMEM147-related Review for gene: TMEM147 was set to GREEN Added comment: PMID: 36044892; Twelve different variants reported in 23 affected individuals from 15 unrelated families with biallelic variants. All individuals had global developmental delay and intellectual disability. Consistent facial dysmorphisms included coarse facies, prominent forehead, board depressed nasal root, tented mouth, long smooth philtrum, and low-set ears. In vitro studies of missense variants demonstrated accelerated protein degradation via the autophagy-lysosomal pathway, while analysis of primary fibroblasts and granulocytes provided functional evidence of ER and nuclear envelope dysfunction. Sources: Literature |
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| Mendeliome v1.289 | SARS | Ee Ming Wong reviewed gene: SARS: Rating: RED; Mode of pathogenicity: Other; Publications: 36041817; Phenotypes: neurodevelopmental disorder, MONDO#070009, SARS1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.286 | CBLB |
Alison Yeung gene: CBLB was added gene: CBLB was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CBLB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CBLB were set to 36006710 Phenotypes for gene: CBLB were set to Autoimmune disease, MONDO:0007179 Review for gene: CBLB was set to GREEN Added comment: Distinct homozygous mutations in CBLB were identified in three unrelated children with early onset autoimmunity. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyper-proliferation in response to antigen receptor cross-linking. Sources: Literature |
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| Mendeliome v1.285 | TYMS |
Lucy Spencer gene: TYMS was added gene: TYMS was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TYMS was set to Other Publications for gene: TYMS were set to 35931051 Phenotypes for gene: TYMS were set to Dyskeratosis congenita MONDO:0015780 Review for gene: TYMS was set to RED Added comment: 8 families with dyskeratosis congenita and heterozygous variants in TYMS. 4 PTCs, 2 missense and 1 splice (2 families had the same frameshift). However in all families 1 unaffected parent was also heterozygous for the same TYSM variant. The other parent in 3 of these families was then shown to carry a heterozygous variant in ENOSF1 which each affected child was also heterozygous for. ENOSF1 has been shown to modify TYMS expression at the RNA level by acting as an antisense molecule to TYMS. ENOSF1 partially overlaps TYMS on chromosome 18 and is transcribed in the opposite direction to TYMS. This paper is suggesting digenic inheritance. The TYMS wild type parent from another family was seen to have a TYMSOS variant which was also observed along with the TYMS variant in their 2 affected children. Immunoblotting showed a stark reduction in TYMS protein level in the cells of affected probands when compared to the parent carrier, wild-type parent, and the controls. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. Sources: Literature |
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| Mendeliome v1.285 | CEP104 | Belinda Chong reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 34196201, 35359234; Phenotypes: CEP104 Neurodevelopmental disorder, MONDO:0014770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.285 | MET | Zornitza Stark Phenotypes for gene: MET were changed from Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884 to Arthrogryposis, distal, type 11 (MIM#620019), AD; Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.276 | SAT1 | Ee Ming Wong reviewed gene: SAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35977808; Phenotypes: Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.276 | ADAMTS15 |
Naomi Baker changed review comment from: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5). Sources: Literature; to: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: contractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5). Sources: Literature |
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| Mendeliome v1.276 | ADAMTS15 |
Naomi Baker gene: ADAMTS15 was added gene: ADAMTS15 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAMTS15 were set to PMID: 35962790 Phenotypes for gene: ADAMTS15 were set to Arthrogryposis (MONDO:0008779), ADMATS15-related Review for gene: ADAMTS15 was set to GREEN Added comment: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5). Sources: Literature |
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| Mendeliome v1.276 | CAPRIN1 |
Paul De Fazio gene: CAPRIN1 was added gene: CAPRIN1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CAPRIN1 were set to 35979925 Phenotypes for gene: CAPRIN1 were set to Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092 Review for gene: CAPRIN1 was set to GREEN gene: CAPRIN1 was marked as current diagnostic Added comment: 12 individuals reported with ID and language impairment. Other features included seizures (4 individuals), hands and feet malformations (5 individuals), breathing problems (6 individuals), ocular problems (4 individuals) and hearing problems (3 individuals). All of the variants were nonsense (NMD-predicted) or splicing variants. 10 were de novo, 1 was inherited from an affected father. Functional studies supported pathogenicity. Sources: Literature |
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| Mendeliome v1.275 | NOTCH1 | Chern Lim reviewed gene: NOTCH1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 35947102; Phenotypes: leukoencephalopathy and calcifications; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.268 | NPNT | Zornitza Stark Phenotypes for gene: NPNT were changed from Renal agenesis, no OMIM # to Renal agenesis, MONDO:0018470, NPNT-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.266 | NPNT | Zornitza Stark reviewed gene: NPNT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal agenesis, MONDO:0018470, NPNT-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.261 | CCDC82 |
Chirag Patel gene: CCDC82 was added gene: CCDC82 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC82 were set to PMID: 35373332, 35118659, 27457812 Phenotypes for gene: CCDC82 were set to Intellectual disability and spastic paraparesis, no OMIM # Review for gene: CCDC82 was set to GREEN Added comment: 4 consanguineous families with 9 affected individuals with developmental delay/intellectual disability, and 2 families had spasticity and 1 had epilepsy. WES identified 3 homozgyous truncating variants, segregating with disease and parents as carriers. No functional studies. Sources: Literature |
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| Mendeliome v1.259 | NPNT |
Chirag Patel gene: NPNT was added gene: NPNT was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPNT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPNT were set to PMID: 35246978, 34049960, 17537792 Phenotypes for gene: NPNT were set to Renal agenesis, no OMIM # Review for gene: NPNT was set to GREEN Added comment: 3 consanguineous families with multiple affecteds with bilateral renal agenesis. Whole-exome sequencing (WES)-based homozygosity mapping identified 2 homozygous truncating variants. Reverse transcription polymerase chain reaction data showing complete nonsense-mediated decay of the NPNT transcript. Loss of nephronectin (NPNT) is known to lead to failure of metanephric kidney development with resulting renal agenesis in murine models. Sources: Literature |
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| Mendeliome v1.252 | FOCAD |
Zornitza Stark gene: FOCAD was added gene: FOCAD was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: FOCAD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FOCAD were set to 35864190 Phenotypes for gene: FOCAD were set to Liver disease, severe congenital, MIM# 619991 Review for gene: FOCAD was set to GREEN Added comment: Moreno Traspas et al 2022 reported 14 children from ten unrelated families with syndromic form of pediatric liver cirrhosis. Genome/exome sequencing analysis reveled biallelic variants in the FOCAD gene. Most of the mutations were nonsense, frameshift, or splice site alterations, predicted to result in a loss of function, but there were also 3 missense variants at highly conserved residues. Western blot analysis of dermal fibroblasts derived from 2 patients showed near absent FOCAD expression in cellular extracts. There were also decreased levels of the SKIC2 protein, suggesting that FOCAD may contribute to the stability of RNA helicase (OMIM: 619991). Sources: Expert Review |
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| Mendeliome v1.246 | TRAC | Seb Lunke Added comment: Comment on list classification: Single variant reported to date in 6 patients; 2 unrelated children from consanguineous families of Pakistani descent (PMID: 21206088); 1 non-consanguineous family from North-west India (PMID: 33909184) and 1 consanguineous parents of East Indian (https://lymphosign.com/doi/10.14785/lymphosign-2022-0001) Also note annotation issues in certain variant curation and annotation tools. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.237 | TAF4 | Ee Ming Wong reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846, 28191890, 35904126; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TAF4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.228 | OTULIN | Zornitza Stark changed review comment from: Autoinflammatory disorder presenting in the newborn period with recurrent fever, erythematous rash with painful nodules, painful joints, diarrhoea and lipodystrophy.; to: Bi-allelic variants: Autoinflammatory disorder presenting in the newborn period with recurrent fever, erythematous rash with painful nodules, painful joints, diarrhoea and lipodystrophy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.220 | SARS | Ain Roesley reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: neurodevelopmental disorder MONDO#070009, SARS1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.212 | PSMC1 |
Hazel Phillimore gene: PSMC1 was added gene: PSMC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PSMC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PSMC1 were set to PMID: 35861243 Phenotypes for gene: PSMC1 were set to spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes Mode of pathogenicity for gene: PSMC1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: PSMC1 was set to AMBER Added comment: Homozygosity mapping on one large consanguineous Bedouin kindred showed three affected children (out of the ten) to be homozygous for NM_002802.3:c.983T>C; p.(Ile328Thr). Drosophila rescue experiments were carried out. Transgenic studies using drosophila with the silenced ortholog Rpt2 gene were rescued by the human wild-type PSMC1. Three of the ten offspring of healthy consanguineous parents of Bedouin Israeli ancestry were affected with a similar phenotype of failure to thrive, developmental delay and severe intellectual disability, spastic tetraplegia with central hypotonia, chorea, as well as hearing loss. None of the three achieved verbal communication or ambulation (sitting / standing) at any age. They had mild dysmorphism of borderline dolichocephaly and microcephaly, prominent bushy eyebrows, flat midface, long nasal bridge and micrognathia. All three had micropenis with undescended testes. One of the affected (as a toddler) underwent thorough endocrinological analysis: testosterone and gonadotropin levels were low. Sources: Literature |
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| Mendeliome v1.212 | KIF15 |
Krithika Murali gene: KIF15 was added gene: KIF15 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KIF15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIF15 were set to 28150392 Phenotypes for gene: KIF15 were set to ?Braddock-Carey syndrome 2 - MIM#619981 Review for gene: KIF15 was set to GREEN Added comment: PMID 28150392 Sleiman et al 2017 report one individual with homozygous R501* variant (NMD-predicted) from a consanguineous family. The child had thrombocytopenia, PRS, microcephaly -3SD by age 6, dysmorphic facies, bilateral external auditory canal atresia and deafness, microphthalmia, clinodactyly, short stature. Variant absent from gnomAD. Parents confirmed to be carriers and unaffected siblings were carriers/homozygous wild-type. No other SNVs reported in ClinVar. Variant is absent from gnomAD. Authors note phenotypic similarities with Braddock-Carey syndrome (21q22 contiguous deletion also involving RUNX1). Sources: Literature |
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| Mendeliome v1.211 | BMP3 |
Seb Lunke gene: BMP3 was added gene: BMP3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BMP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BMP3 were set to 35089417 Phenotypes for gene: BMP3 were set to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129 Review for gene: BMP3 was set to AMBER Added comment: Single missense variant identified segregating with disease following WES screen in a family with coloboma and/or microphthalmia in BMP3. Two additional unrelated patients identified with different missense in BMP3. Pathogenicity however largely on in-silicos, with one of the 3 missense having 29 hets in gnomAD. Additional functional work in bmp3 -/- zebra fish and some supporting evidence but not conclusive Sources: Literature |
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| Mendeliome v1.208 | ALG5 | Chern Lim edited their review of gene: ALG5: Changed phenotypes: Cystic renal disease MONDO:0002473, ALG5-related, Multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline, few or no liver cysts. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.208 | ALG5 |
Chern Lim gene: ALG5 was added gene: ALG5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ALG5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ALG5 were set to 35896117 Phenotypes for gene: ALG5 were set to Cystic renal disease MONDO:0002473, ALG5-related Review for gene: ALG5 was set to GREEN gene: ALG5 was marked as current diagnostic Added comment: PMID:35896117: - Five unrelated families, including 23 affected individuals with non-enlarged cystic kidneys and few or no liver cysts, 8 of them reached end-stage kidney disease from 62 to 91 years of age. Variant confirmed in all but one individual. - Various variant types: frameshift, nonsense, two missense, splice. - Functional studies showed haploinsufficiency is the disease mechanism. Sources: Literature |
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| Mendeliome v1.208 | PPFIBP1 | Ee Ming Wong reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35830857; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.208 | SLITRK2 |
Paul De Fazio gene: SLITRK2 was added gene: SLITRK2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLITRK2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: SLITRK2 were set to 35840571 Phenotypes for gene: SLITRK2 were set to Neurodevelopmental disorder, SLITRK2-related MONDO:0700092 Review for gene: SLITRK2 was set to GREEN gene: SLITRK2 was marked as current diagnostic Added comment: 6 missense variants and 1 nonsense variant (NOT NMD-predicted, single-exon gene) reported in 7 males and 1 female with neurodevelopmental disorders. Phenotypes included dev delay, mild to severe ID, delayed or absent speech, seizures and brain MRI anomalies (in some patients). The nonsense variant was identified in two affected brothers but not in the mother, suggesting it was de novo in the maternal germline. The variant in the one affected female was de novo. All other variants in hemizygous males were inherited from an unaffected mother. In one case, the variant was also identified in the unaffected grandmother. Functional studies showed some but not all variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Conditional knockout mice exhibited impaired long-term memory and abnormal gait. Sources: Literature |
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| Mendeliome v1.206 | C18orf32 |
Naomi Baker gene: C18orf32 was added gene: C18orf32 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: C18orf32 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C18orf32 were set to PMID:35107634 Phenotypes for gene: C18orf32 were set to Neurodevelopmental disorder (MONDO:0700092), C18orf32-related Review for gene: C18orf32 was set to RED Added comment: Two siblings reported as affected, although sequencing only performed in one sibling, with homozygous loss-of-function variant identified. Clinical presentation included developmental delay, recurrent lower respiratory tract infections, sparse rough hair, roving eye movements, hypotonia, bilateral ankle contractures and inverted nipples. Sources: Literature |
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| Mendeliome v1.205 | RFC1 | Ain Roesley reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35883251; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.204 | ADGRL1 |
Elena Savva gene: ADGRL1 was added gene: ADGRL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ADGRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ADGRL1 were set to PMID: 35907405 Phenotypes for gene: ADGRL1 were set to Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092) Review for gene: ADGRL1 was set to GREEN Added comment: PMID: 35907405 - 9 patients w/ ADHD (3/9), autism (4/9), mild-moderate ID (5/9) and epilepsy (2/9) and facial dysmorphism (7/9). Variants include missense (4) and PTCs (5), and were either de novo (7/9) or inherited from parents with learning difficulties/ID (2/9). Functional studies on both PTCs and missense variants show significant reductions in calcium signalling and surface protein. Het null mouse model shows neurological and developmental abnormalities, with hom null mice non-viable. Sources: Literature |
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| Mendeliome v1.202 | EHHADH |
Zornitza Stark edited their review of gene: EHHADH: Added comment: https://clinmedjournals.org/articles/jcnrc/journal-of-clinical-nephrology-and-renal-care-jcnrc-3-027.pdf Second case report, same variant, de novo. Also, experimental evidence. Assessed as MODERATE by ClinGen.; Changed rating: AMBER |
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| Mendeliome v1.185 | IKZF1 | Zornitza Stark Phenotypes for gene: IKZF1 were changed from Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset to Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset; Immune dysregulation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.183 | IKZF1 | Zornitza Stark edited their review of gene: IKZF1: Added comment: PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation.; Changed publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317, 35333544; Changed phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset, Immune dysregulation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.180 | IKZF2 | Zornitza Stark edited their review of gene: IKZF2: Added comment: Iranian male with homozygous missense variant with recurrent infection, hypogammaglobulinaemia. Extends inheritance to AR. Supportive functional data.; Changed publications: 34920454, 34826259; Changed phenotypes: Immunodeficiency, MONDO:0021094, IKZF2-related, Immune dysregulation; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.173 | PMM2 |
Zornitza Stark edited their review of gene: PMM2: Added comment: Association with HIPKD: Cabezas et al (2017) reported co-occurrence of hyperinsulinaemic hypoglycaemia and polycystic kidney disease (HIPKD in 17 children from 11 unrelated families. Patients presented with hyperinsulinaemic hypoglycaemia in infancy and enlarged kidneys with multiple kidney cysts. Some progressed to ESKD and some had liver cysts. Whole-genome linkage analysis in 5 informative families identified a single significant locus on chromosome 16p13.2. Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, they found in all patients a promoter mutation (c.-167G>T) in PMM2, either homozygous or in trans with PMM2 coding mutations. They found deglycosylation in cultured pancreatic β cells altered insulin secretion. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2. They proposed that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. None of the patients exhibited the typical clinical or diagnostic features of CDG1A. Serum transferrin glycosylation was normal in 11 patients who had assessment.; Changed publications: 28108845, 28373276, 32595772; Changed phenotypes: Congenital disorder of glycosylation, type Ia (MIM#212065), Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease (HIPKD), MONDO:0020642, PMM2-related |
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| Mendeliome v1.163 | CHD5 | Elena Savva Phenotypes for gene: CHD5 were changed from Intellectual disability; Epilepsy to Parenti-Mignot neurodevelopmental syndrome MIM#619873 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.162 | CHD5 | Elena Savva reviewed gene: CHD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33944996; Phenotypes: Parenti-Mignot neurodevelopmental syndrome MIM#619873; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.161 | GINS3 |
Zornitza Stark gene: GINS3 was added gene: GINS3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GINS3 were set to 35603789 Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome, MONDO:0016817, GINS3-related Review for gene: GINS3 was set to GREEN Added comment: 7 individuals from 5 families reported, presenting with prenatal and postnatal growth deficiency as well as other features. Three unique missense variants identified, two affecting p.Asp24. These variants are thought to be hypomorphic. Supportive mouse model. Sources: Literature |
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| Mendeliome v1.147 | CLDN5 |
Zornitza Stark gene: CLDN5 was added gene: CLDN5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CLDN5 were set to 35714222 Phenotypes for gene: CLDN5 were set to alternating hemiplegia, MONDO:0016210, CLDN5-related Mode of pathogenicity for gene: CLDN5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: CLDN5 was set to AMBER Added comment: PMID: 35714222; Hashimoto, Y. et al. (2022): Two unrelated cases (early-onset) with alternating hemiplegia with microcephaly were shown to have the same de novo variant, NM_001363066.2:c.178G>A, p.(Gly60Arg). One with Jewish / Tunisian ancestry: Onset was at 8 months, three episodes of febrile tonic-clonic 1 seizures of the four limbs, with eye rolling, loss of consciousness, transient left and right post-2 ictal hemiparesis and vomiting. The other with Asian / European ancestry: Onset was at 30 months with three iterative episodes of febrile and non-febrile hemiplegia and loss of 18 consciousness. The recurrent episodes alternatively involved the left-and 19 right-hand side, then generalised and were followed by post ictal hemiparesis. CT scans of both showed brain calcifications and aberrant blood flow patterns. Transfected cell lines with this variant, c178G>A, showed higher chloride ion permeability and lower sodium ion permeability when compared to wildtype. Sources: Literature |
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| Mendeliome v1.143 | PSMB9 | Zornitza Stark edited their review of gene: PSMB9: Added comment: Two additional individuals with neonatal onset autoinflammatory syndrome and a mouse model. De novo recurrent missense G156D.; Changed rating: GREEN; Changed publications: 26524591, 34819510; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.137 | NFATC2 |
Paul De Fazio gene: NFATC2 was added gene: NFATC2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NFATC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NFATC2 were set to 35789258 Phenotypes for gene: NFATC2 were set to Skeletal system disorder MONDO:0005172 Review for gene: NFATC2 was set to RED gene: NFATC2 was marked as current diagnostic Added comment: Patient born to consanguineous parents homozygous for a frameshift variant. No other (unaffected) members of the family were homozygous. Family history of recurrent childhood deaths. After a healthy birth the patient developed painless decreased range of motion at 1.5yrs leading to difficulty with ambulation at 3yrs. Formal orthopedic assessment at age 15 years demonstrated a neurodevelopmentally normal young man with marked bilateral fixed flexion contractures of knees, hips, and ankles. The main musculoskeletal findings were painless contractures of the large and small joints of the upper and lower limbs, osteochondromas, and osteopenia. Patient was diagnosed with B-cell lymphoma at age 18. Patient CD8+ T-cells show impaired polyfunctionality, and the patient had an accumulation of non-functional memory CD4+ T-cells. TFH cell function was also impaired. Sources: Literature |
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| Mendeliome v1.134 | CCDC155 |
Melanie Marty gene: CCDC155 was added gene: CCDC155 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCDC155 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC155 were set to 35674372; 35708642; 29790874; 35587281 Phenotypes for gene: CCDC155 were set to Non-obstructive azoospermia; Premature ovarian insufficiency Review for gene: CCDC155 was set to GREEN Added comment: Current HGNC name is KASH5 Summary: 4 families reported with non-obstructive azoospermia or premature ovarian insufficiency. Functional studies have been performed and mouse models recapitulate the phenotype. PMID: 35674372 CNV and frameshift variants in KASH5 were identified in a non-obstructive azoospermia affected patient and in his infertile sister by whole-exome sequencing and CNV array. Kash5 knockout mouse displayed similar phenotypes, including a meiotic arrest at a zygotene-like stage and impaired pairing and synapsis. PMID: 35708642 Hom splice identified in KASH5 in 2 sisters with premature ovarian insufficiency. In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1. Moreover, the Kash5 C-terminal deleted mice revealed defective meiotic homolog pairing and accelerated depletion of oocytes. PMID: 29790874 2 brothers with non-obstructive azoospermia with hom missense in CCDC155 35587281 2 siblings with hom missense in CCDC155 non-obstructive azoospermia and premature ovarian insufficiency. Sources: Literature |
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| Mendeliome v1.130 | SLC30A7 |
Naomi Baker gene: SLC30A7 was added gene: SLC30A7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC30A7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC30A7 were set to PMID: 35751429 Phenotypes for gene: SLC30A7 were set to Joubert syndrome (MONDO:0018772), SLC30A7-related Review for gene: SLC30A7 was set to AMBER Added comment: PMID: 35751429: Two individuals reported with de novo variants, one missense and one delins resulting in missense. The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. No functional studies reported. Sources: Literature |
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| Mendeliome v1.130 | ASPH | Paul De Fazio reviewed gene: ASPH: Rating: AMBER; Mode of pathogenicity: None; Publications: 35697689; Phenotypes: Exertional heat illness, malignant hyperthermia susceptibility; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.126 | CHMP3 |
Chern Lim gene: CHMP3 was added gene: CHMP3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHMP3 were set to PMID: 35710109 Phenotypes for gene: CHMP3 were set to Hereditary spastic paraplegia (MONDO:0019064), CHMP3-related Review for gene: CHMP3 was set to AMBER gene: CHMP3 was marked as current diagnostic Added comment: PMID: 35710109 - Single large family with consanguinity, homozygous missense variant in 5 affected individuals with intellectual and progressive motor disabilities, seizures and spastic quadriplegia. - Functional studies showed reduced CHMP3 protein in patient's fibroblasts, lenti-rescue study showed improved cellular phenotypes associated with impaired autophagy. Sources: Literature |
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| Mendeliome v1.119 | TAF8 |
Zornitza Stark changed review comment from: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. This is likely to be a founder variant. One family with different compound heterozygous variants. Sources: Literature; to: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. Unclear if this is a founder variant, families of different ethnicities. One family with different compound heterozygous variants. Sources: Literature |
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| Mendeliome v1.118 | TAF8 |
Zornitza Stark gene: TAF8 was added gene: TAF8 was added to Mendeliome. Sources: Literature founder tags were added to gene: TAF8. Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TAF8 were set to 29648665; 35759269 Phenotypes for gene: TAF8 were set to Neurodevelopmental disorder, MONDO:0700092, TAF8-related Review for gene: TAF8 was set to GREEN Added comment: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. This is likely to be a founder variant. One family with different compound heterozygous variants. Sources: Literature |
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| Mendeliome v1.111 | TNFSF13 |
Zornitza Stark gene: TNFSF13 was added gene: TNFSF13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TNFSF13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TNFSF13 were set to 32298700 Phenotypes for gene: TNFSF13 were set to Hypogammaglobulinaemia, MONDO:0015977, TNSF13-related Review for gene: TNFSF13 was set to RED Added comment: Single individual, consanguineous parents. Sources: Literature |
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| Mendeliome v1.110 | POU2AF1 |
Zornitza Stark gene: POU2AF1 was added gene: POU2AF1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: POU2AF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POU2AF1 were set to 33571536 Phenotypes for gene: POU2AF1 were set to Agammaglobulinaemia, MONDO:0015977, POU2AF1-related Review for gene: POU2AF1 was set to RED Added comment: Single individual from consanguineous parents lacking immunoglobulins despite normal total B-cell numbers. Sources: Expert Review |
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| Mendeliome v1.105 | COPG1 |
Zornitza Stark gene: COPG1 was added gene: COPG1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: COPG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COPG1 were set to 33529166 Phenotypes for gene: COPG1 were set to Combined immunodeficiency MONDO:0015131, COPG1-related Review for gene: COPG1 was set to RED Added comment: Five Omani siblings, born to consanguineous parents, homozygous missense. Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. Sources: Expert Review |
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| Mendeliome v1.102 | IFNAR2 | Zornitza Stark edited their review of gene: IFNAR2: Added comment: Five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination; Changed rating: GREEN; Changed publications: 26424569, 35442417 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.99 | IFNAR1 | Zornitza Stark edited their review of gene: IFNAR1: Added comment: Seven children from five unrelated kindreds; Changed publications: 31270247, 35442418; Changed phenotypes: Immunodeficiency 106, susceptibility to viral infections, MIM# 619935, Severe disease caused by Yellow Fever vaccine and Measles vaccine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.98 | NEK8 | Zornitza Stark Phenotypes for gene: NEK8 were changed from Renal-hepatic-pancreatic dysplasia 2, MIM# 615415; MONDO:0014174 to Renal-hepatic-pancreatic dysplasia 2, MIM# 615415; MONDO:0014174; Familial renal cystic disease MONDO:0019741, NEK8-related, dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.96 | NEK8 | Zornitza Stark edited their review of gene: NEK8: Added comment: ESHG 2022: 12 families with paediatric renal cystic disease (enlarged kidneys, kidney cysts, ESKF <20yrs) -3 recurrent HTZ variants in NEK8 kinase domain (Arg45Trp, Ile150Met, Lys157Gln) -suspected dominant negative effect -patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8 (Note carriers of AR-NEK8 disease do not show renal manifestations, as variants are LOF); Changed phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415, MONDO:0014174, Familial renal cystic disease MONDO:0019741, NEK8-related, dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.77 | IL6ST | Zornitza Stark edited their review of gene: IL6ST: Changed phenotypes: Hyper-IgE recurrent infection syndrome 4A, autosomal dominant , MIM#619752, Hyper-IgE recurrent infection syndrome 4B, autosomal recessive, MIM# 618523, Stuve-Wiedemann syndrome 2, MIM# 619751: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response, Hyper-IgE syndrome, autosomal dominant, Immunodeficiency 94 with autoinflammation and dysmorphic facies, MIM# 619750 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.73 | KCNA5 | Chern Lim reviewed gene: KCNA5: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.49 | RRM1 |
Daniel Flanagan gene: RRM1 was added gene: RRM1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: RRM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RRM1 were set to 35617047 Phenotypes for gene: RRM1 were set to Multiple mitochondrial DNA deletion syndrome (MONDO:0016797) Review for gene: RRM1 was set to GREEN Added comment: Homozygous missense were identified in 4 four probands (p.Arg381Cys or p.Arg381His) from three families, who presented with ptosis and ophthalmoplegia, plus other manifestations and multiple mtDNA deletions in muscle. Heterozygous carriers were unaffected. An additional proband was heterozygous for a different RRM1 missense (p.Asn427Lys), another variant not identified. Sources: Expert list |
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| Mendeliome v1.45 | PTPN13 |
Ain Roesley gene: PTPN13 was added gene: PTPN13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPN13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPN13 were set to 35643866 Phenotypes for gene: PTPN13 were set to bone marrow failure syndrome MONDO#0000159, PTPN13-related Review for gene: PTPN13 was set to AMBER gene: PTPN13 was marked as current diagnostic Added comment: 2 families Family A: 3 affecteds only 2 sequenced. Hom for a missense 3/3 Anaemia, 1x thrombocytopaenia, 1x severe neutropaenia, bone marrow with pure red cell aplasia noted that the sibling who wasn't sequenced had normal bone marrow morphology Family B: Chet for a missense and inframe del of 1 amino acid Persistent hypogammaglobulinemia after transplant (at least 14 months after) with normal blood counts and Pre-B ALL with MLL rearrangement In vitro studies of individual variants were LoF, including defective erythroid and megakaryocytic differentiation, consistent with anaemia and thrombocytopaenia reported in family A Sources: Literature |
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| Mendeliome v1.44 | BUB1 |
Paul De Fazio gene: BUB1 was added gene: BUB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BUB1 were set to 35044816; 19772675; 19117986; 23209306 Phenotypes for gene: BUB1 were set to Intellectual disability and microcephaly Review for gene: BUB1 was set to GREEN gene: BUB1 was marked as current diagnostic Added comment: 2 unrelated patients with ID, microcephaly, short stature, dysmorphic features reported with biallelic variants: P1 (3yo male): homozygous start-loss variant (2 hets and 0 hom in gnomAD). Functional testing showed a small amount of full-length protein was translated, and BUB1 recruitment to kinetochores was nearly undetectable. P2 (16yo female): compound heterozygous for a canonical splice variant (1 het and no hom in gnomAD) and an NMD-predicted frameshift variant (absent from gnomAD). The splice variant was shown to result in an in-frame deletion of 54 amino acids in the kinase domain. P2 cells have reduced protein levels but essentially no kinase activity. BUB1 patient cells have impaired mitotic fidelity. Homozygous Bub1 disruption in mice is embryonic lethal (PMID:19772675). A hypomorphic mouse is viable with increased tumourigenesis with ageing and aneuploidy (PMID:19117986). A kinase-dead mouse does not show increased tumourigenesis but does have a high frequency of aneuploid cells (PMID:23209306) Sources: Literature |
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| Mendeliome v1.36 | SRRM2 | Michelle Torres reviewed gene: SRRM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35567594; Phenotypes: neurodevelopmental disorder MONDO:0700092 SRRM2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.35 | GIMAP6 |
Elena Savva gene: GIMAP6 was added gene: GIMAP6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GIMAP6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GIMAP6 were set to PMID: 35551368; 33328581 Phenotypes for gene: GIMAP6 were set to Autophagy, immune competence and inflammation Review for gene: GIMAP6 was set to AMBER Added comment: PMID: 35551368, PMID: 33328581 - K/O mice show autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)–containing lipids and die prematurely from microangiopathic glomerulosclerosis with immunodeficiency. - 2 unrelated families (3 patients) w/ a homozygous missense (p.Gly153Val) and nonsense (p.Trp86*). All unaffected siblings were heterozygous. Patient 1 (missense) presented with Coombs-positive hemolytic anemia, hepatosplenomegaly, Cranial MRI showed bilateral effusions, sulcal hyperintensity, and lateral parietal subcortical acute focal ischemic lesions. Patient 2 (nonsense) presented with recurrent purulent otitis media and a chronic wet cough, persistent jaundice, recurrent chest and ear infections, lingular consolidation, mild bronchiectasis, bibasilar bronchial wall thickening, right peribronchial consolidation, right lower lobe bronchiectasis, bilateral axillary lymphadenopathy, and splenomegaly. Patient 3 (nonsense) presented with suffered headaches, abdomen pain, mouth ulcers, and recurrent infections - Functional studies show patient 1 (missense) with reduced protein expression on western blot, and patient 2/3 (nonsense) with no protein expression. T cells of Pt 1 were similar to mouse K/O model (elevated basal LC3-II, reduced autophagic flux). gnomAD: 0 homozygous PTCs, but a very common canonical splice which is present in the non-canonical transcript Sources: Literature |
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| Mendeliome v1.34 | HEATR3 |
Chern Lim gene: HEATR3 was added gene: HEATR3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HEATR3 were set to PMID: 35213692 Phenotypes for gene: HEATR3 were set to Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability Review for gene: HEATR3 was set to GREEN gene: HEATR3 was marked as current diagnostic Added comment: PMID: 35213692: - 4 unrelated individuals with biallelic HEATR3 variants (missense and splice site variants), exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability. - Functional analysis showed HEATR3 variants destabilised the protein, resulting in a reduction of nuclear uL18 and impaired ribosome biogenesis. Sources: Literature |
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| Mendeliome v1.28 | SPTAN1 | Zornitza Stark edited their review of gene: SPTAN1: Added comment: Leveille et al (2019) - 2 patients with HSP with biallelic missense SPTAN1 variants Previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. Xie et al (2022) - 1 patient with complicated HSP and homozygous SPTAN1 mutation. Healthy parents and sister all carried the heterozygous mutation. Van de Vondel et al (2022) - 22 patients from 14 families with five novel heterozygous SPTAN1 variants. Presentations ranged from cerebellar ataxia, intellectual disability, epilepsy, and spastic paraplegia. A recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia. Through protein modeling they showed that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.; Changed publications: 20493457, 22258530, 32811770, 35150594, 34526651, 31515523; Changed phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477, Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.18 | TULP3 | Zornitza Stark Phenotypes for gene: TULP3 were changed from progressive degenerative liver fibrosis with variable fibrocystic kidney disease; hypertrophic cardiomyopathy MONDO:0005045 to Hepatorenocardiac degenerative fibrosis, MIM# 619902 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.17 | TULP3 | Zornitza Stark reviewed gene: TULP3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hepatorenocardiac degenerative fibrosis, MIM# 619902; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.12 | GFRA1 | Zornitza Stark Phenotypes for gene: GFRA1 were changed from Renal agenesis to Renal hypodysplasia/aplasia 4, MIM# 619887 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.11 | GFRA1 | Zornitza Stark edited their review of gene: GFRA1: Changed phenotypes: Renal hypodysplasia/aplasia 4, MIM# 619887 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.7 | PROSER1 |
Zornitza Stark gene: PROSER1 was added gene: PROSER1 was added to Mendeliome. Sources: Expert Review founder tags were added to gene: PROSER1. Mode of inheritance for gene: PROSER1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PROSER1 were set to 35229282 Phenotypes for gene: PROSER1 were set to Syndromic disease MONDO:0002254, PROSER1-related Review for gene: PROSER1 was set to RED Added comment: 4 children from 3 related families with developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, genitourinary malformations, and common facial features (arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing). WES revealed a homozygous frame-shift variant (p.Thr612Glnfs*22) in PROSER1. This encodes the proline and serine rich protein 1, part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation. No functional assays and 3 related families, likely founder effect. Sources: Expert Review |
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| Mendeliome v1.3 | RDH11 | Zornitza Stark edited their review of gene: RDH11: Added comment: 2nd case reported: 1 Chinese patient with retinitis pigmentosa, juvenile cataracts, intellectual disability, and myopathy. Trio-based WES and whole genomic CNV detection found compound heterozygous variants in RDH11 (p.Leu313Pro and c.75-3C>A) with biparental inheritance. Variant c.75-3C>A was confirmed to be a splice-site mutation by cDNA sequencing. It caused exon 2 skipping, resulting in a frameshift mutation and premature translation termination (p.Lys26Serfs*38). They found mislocalization of RDH11 protein in muscle cells of the patient by using immunofluorescence staining. Retinol dehydrogenase 11 (RDH11) is an 11-cis-retinol dehydrogenase that has a well-characterized, albeit auxiliary role in the retinoid cycle. Diseases caused by mutations in the RDH11 gene are very rare, and only one affected family with eye and intelligence involvement has been reported.; Changed rating: AMBER; Changed publications: 24916380, 15634683, 30731079, 18326732, 34988992 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14763 | DRD3 | Zornitza Stark Phenotypes for gene: DRD3 were changed from to {Essential tremor, hereditary, 1} - MIM#190300; {Schizophrenia, susceptibility to} - MIM#181500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14758 | DSC3 | Zornitza Stark Phenotypes for gene: DSC3 were changed from to Hypotrichosis and recurrent skin vesicles MIM#613102 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14728 | ETV2 |
Ain Roesley gene: ETV2 was added gene: ETV2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ETV2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ETV2 were set to 33359164 Phenotypes for gene: ETV2 were set to multiple fetal anomalies; congenital heart disease MONDO:000545, ETV2-related; vertebral malformations Review for gene: ETV2 was set to RED gene: ETV2 was marked as current diagnostic Added comment: 1 family with 4 fetus-es, cHet for a fs (NMD-predicted) and a missense 3/4 vertebral malformations 2/4 Tetralogy of Fallot 1/4 arterial septal defect 1/4 ventricular septal defect, aortic dilatation 1/4 pre-axial polydactyly Sources: Literature |
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| Mendeliome v0.14683 | GEMIN4 | Zornitza Stark Phenotypes for gene: GEMIN4 were changed from to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, MIM# 617913 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14662 | LYZ | Abhijit Kulkarni reviewed gene: LYZ: Rating: GREEN; Mode of pathogenicity: None; Publications: 1808634 8464497 15745733; Phenotypes: Amyloidosis, renal (MIM: 105200); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14658 | LYZ | Krithika Murali reviewed gene: LYZ: Rating: GREEN; Mode of pathogenicity: None; Publications: 1808634, 8464497, 15745733,; Phenotypes: Amyloidosis, renal - MIM#105200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14651 | LRP2 |
Chirag Patel commented on gene: LRP2: Donnai-Barrow syndrome (DBS) was first described as a distinct disorder characterized by diaphragmatic hernia, exomphalos, absent corpus callosum, myopia, agenesis of the corpus callosum and proteinuria, and sensorineural deafness. Kantarci et al. (2007) identified biallelic LRP2 mutations in 6 families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. |
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| Mendeliome v0.14647 | GEMIN4 | Chirag Patel reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25558065, 30237576, 27878435; Phenotypes: Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, MIM# 617913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14488 | MET | Zornitza Stark Phenotypes for gene: MET were changed from to Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14486 | MET | Zornitza Stark edited their review of gene: MET: Changed phenotypes: Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074, Papillary renal cell carcinoma MONDO:0017884 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14486 | MET | Zornitza Stark reviewed gene: MET: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Papillary renal cell carcinoma MONDO:0017884; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14375 | RNF139 | Zornitza Stark Phenotypes for gene: RNF139 were changed from to Renal cell carcinoma MIM#144700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14345 | RBFOX2 |
Chern Lim gene: RBFOX2 was added gene: RBFOX2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RBFOX2 were set to PMID: 26785492; 27670201; 27485310; 25205790; 35137168 Phenotypes for gene: RBFOX2 were set to Hypoplastic left heart syndrome (HLHS) Review for gene: RBFOX2 was set to AMBER gene: RBFOX2 was marked as current diagnostic Added comment: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. - PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492. - PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing. - PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS. - PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS. Sources: Literature |
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| Mendeliome v0.14344 | GRIA4 | Ain Roesley reviewed gene: GRIA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35518358, 29220673; Phenotypes: Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14343 | GRID2 | Ain Roesley reviewed gene: GRID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622959, 32170608; Phenotypes: Spinocerebellar ataxia, autosomal recessive 18 MIM#616204; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14341 | GRIN2D | Ain Roesley reviewed gene: GRIN2D: Rating: GREEN; Mode of pathogenicity: None; Publications: 27616483, 30280376; Phenotypes: Developmental and epileptic encephalopathy 46 617162; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14341 | BICC1 | Abhijit Kulkarni reviewed gene: BICC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: renal dysplasia, cystic, susceptibility to; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14341 | RMND1 | Belinda Chong reviewed gene: RMND1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 11 MIM#614922; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14291 | DRD3 | Krithika Murali reviewed gene: DRD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Essential tremor, hereditary, 1} - MIM#190300, {Schizophrenia, susceptibility to} - MIM#181500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14291 | DSCAM |
Krithika Murali edited their review of gene: DSCAM: Added comment: No OMIM gene disease association. Variants predominantly identified from large cohort studies with limited phenotypic information. Associations with ID, ASD, Hirschsprung disease reported. One homozygous splice site variant reported with no parental phenotypes provided. PMID 34253863 Lim et al 2021 - 12 yo proband with severe autism spectrum disorder diagnosed age 3, de novo heterozygous c.2051 del p.(L684X) variant identified (absent from gnomAD). Skin fibroblast human iPSC cells generated from proband and healthy controls. Forebrain-like induced neuronal cells showed reduced mRNA expression for NMDA-R subunits. PMID 28600779 Monies et al 2017 - Homozygous splice site variant identified in proband from consanguineous Saudi family. Proband had growth restriction, microcephaly, developmental delay. Parental phenotype not provided. PMID 30095639 and PMID 23671607 - report association between DSCAM polymorphisms and Hirschsprung disease in Chinese and European populations. PMID 27824329 Wang et al 2016 - 2 denovo mutations in mixed ID/ASD cohort of 1,045; including comparison of previously published cases 6 LOF out of 4,998 cases. PMID 28191889 2 denovo LOF in 13,407 mixed ID/ASD cases plus 4 previosly published cases our ot 6158; conclude denovo LOF enriched in cases vs controls PMID 21904980; mouse model – het LOF mice show hydrocephalus, decreased motor function and impaired motor learning ability, Evidence for missense lacking currently; Changed publications: 34253863, 32807774, 28600779, 21904980, 28191889, 27824329, 30095639, 23671607 |
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| Mendeliome v0.14244 | FXYD2 | Bryony Thompson Phenotypes for gene: FXYD2 were changed from to Renal hypomagnesemia 2 MONDO:0007937 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14239 | FXYD2 | Bryony Thompson reviewed gene: FXYD2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 17980699, 12763862, 18448590, 11062458, 25765846, 27014088; Phenotypes: Renal hypomagnesemia 2 MONDO:0007937; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14232 | MYOCD |
Zornitza Stark changed review comment from: Congenital megabladder (MGBL) is characterized by a massively dilated bladder with disrupted smooth muscle in the bladder wall. MGBL is a sex-limited trait with 95% male predominance, likely the result of differences in urethra and bladder development and length differences in urethra between males and females. Seven affected males from three families. Five females and one male with the variant were unaffected, suggesting incomplete penetrance. Additional family in PMID 35005812 as part of a large prenatal renal cohort.; to: Congenital megabladder (MGBL) is characterized by a massively dilated bladder with disrupted smooth muscle in the bladder wall. MGBL is a sex-limited trait with 95% male predominance, likely the result of differences in urethra and bladder development and length differences in urethra between males and females. Seven affected males from three families. Five females and one male with the variant were unaffected, suggesting incomplete penetrance. Additional family in PMID 35005812 as part of a large prenatal renal cohort. Mono allelic disease in males (megabladder), bi-allelic disease in males and females (megabladder and congenital heart disease). Mouse models. |
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| Mendeliome v0.14223 | FXN | Bryony Thompson edited their review of gene: FXN: Added comment: Well-established gene-disease association. 96% of cases are caused by biallelic intronic GAA triplet repeat expansion and 4% are attributable to biallelic single nucleotide variants and small indels. Loss of function is the mechanism of disease.; Changed rating: GREEN; Changed publications: 20301458, 26704351; Changed phenotypes: Friedreich ataxia MONDO:0100339; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14223 | RNF139 | Belinda Chong reviewed gene: RNF139: Rating: RED; Mode of pathogenicity: None; Publications: 9689122; Phenotypes: Renal cell carcinoma MIM#144700; Mode of inheritance: Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14219 | FUT1 | Bryony Thompson Added comment: Comment on list classification: Biallelic loss of function variants produce the Bombay blood group, which is a recessive H-deficient red blood cell phenotype. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion. No evidence for Mendelian disease associated with this gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14217 | FUT1 | Bryony Thompson Added comment: Comment on list classification: Biallelic loss of function variants cause Bombay phenotype, which is a recessive H-deficient red blood cell phenotype. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion. No evidence for Mendelian disease associated with this gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14203 | FSHR | Bryony Thompson reviewed gene: FSHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 16630814, 7553856, 9020851, 9769327, 20087398, 9854118, 12930928, 12930927, 17721928, 26911863; Phenotypes: Ovarian dysgenesis 1 MONDO:0024463, Ovarian hyperstimulation syndrome MONDO:0011972; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14191 | FXYD6 | Bryony Thompson Phenotypes for gene: FXYD6 were changed from to Schizophrenia MONDO:0005090 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14188 | FXYD6 | Bryony Thompson reviewed gene: FXYD6: Rating: RED; Mode of pathogenicity: None; Publications: 17357072, 26193471, 29895895; Phenotypes: Schizophrenia MONDO:0005090; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14185 | FBP2 |
Zornitza Stark gene: FBP2 was added gene: FBP2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: FBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBP2 were set to 33977262 Phenotypes for gene: FBP2 were set to Leukodystrophy, childhood-onset, remitting, MIM# 619864 Review for gene: FBP2 was set to AMBER Added comment: 8 individuals from 3 generations in a single family reported with a variant in this gene. The children presented with episode of regression and leukodystrophy in early childhood, from which they made a slow recovery. The adults had a broad range of neurobehavioural phenotypes but also had leukodystrophy on imaging. Some functional data presented (in vitro). Sources: Expert list |
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| Mendeliome v0.14172 | RP1 | Belinda Chong reviewed gene: RP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10391211, 10465120, 10465120, 10484783, 29425069, 31213501; Phenotypes: Retinitis pigmentosa 1 MIM#180100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14152 | FOXN1 | Bryony Thompson reviewed gene: FOXN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10206641, 20978268, 20978268, 28636882, 31566583, 31447097; Phenotypes: T-cell immunodeficiency, congenital alopecia, and nail dystrophy MONDO:0011132; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14152 | FOXI1 | Bryony Thompson Phenotypes for gene: FOXI1 were changed from to autosomal recessive distal renal tubular acidosis MONDO:0018440 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14149 | FOXI1 | Bryony Thompson reviewed gene: FOXI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843211, 12642503, 29242249, 17503324, 30268946, 27997596, 22285650, 23965030, 24860705, 32447495, 19204907; Phenotypes: autosomal recessive distal renal tubular acidosis MONDO:0018440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14126 | SLC22A12 | Zornitza Stark Phenotypes for gene: SLC22A12 were changed from to Hypouricemia, renal, MIM# 220150, MONDO:0020728 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14087 | FLVCR1 | Bryony Thompson edited their review of gene: FLVCR1: Added comment: At least 5 unrelated families reported with visual impairment and ataxia. Onset is usually in childhood.; Changed publications: 21070897, 22279524, 21267618; Changed phenotypes: posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14085 | FLNC | Bryony Thompson reviewed gene: FLNC: Rating: GREEN; Mode of pathogenicity: None; Publications: 15929027, 32112656; Phenotypes: Myofibrillar myopathy MONDO:0018943, Dilated cardiomyopathy MONDO:0005021, distal myopathy with posterior leg and anterior hand involvement MONDO:0013550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14072 | FLG | Bryony Thompson reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16444271, 19349982, 34608691; Phenotypes: Ichthyosis vulgaris MONDO:0024304; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14067 | FKTN | Bryony Thompson reviewed gene: FKTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 9690476, 19017726, 20301385, 28680109; Phenotypes: Muscular dystrophy-dystroglycanopathy MONDO:0018276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14064 | GSN |
Zornitza Stark changed review comment from: The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including lattice corneal dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported. Multiple families with same founder variant.; to: The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including lattice corneal dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported. Multiple families with same founder variant, p.Asp187Asn, though other variants also reported. |
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| Mendeliome v0.14049 | FKRP | Bryony Thompson reviewed gene: FKRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 11592034, 11741828, 14647208, 19299310, 19155270; Phenotypes: Muscular dystrophy-dystroglycanopathy MONDO:0018276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14039 | FHL1 | Bryony Thompson reviewed gene: FHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19716112, 20186852, 20301609, 18179901, 25274776, 34366191, 18274675, 19181672; Phenotypes: Reducing body myopathy MONDO:0019948, X-linked Emery-Dreifuss muscular dystrophy MONDO:0010680; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14034 | FH | Bryony Thompson Phenotypes for gene: FH were changed from to hereditary leiomyomatosis and renal cell cancer MONDO:0007888; fumaric aciduria MONDO:0011730 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14031 | FH | Bryony Thompson reviewed gene: FH: Rating: GREEN; Mode of pathogenicity: None; Publications: 11865300, 28300276, 8200987, 20549362, 31746132; Phenotypes: hereditary leiomyomatosis and renal cell cancer MONDO:0007888, fumaric aciduria MONDO:0011730; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14020 | FGFR3 |
Bryony Thompson changed review comment from: FGFR3 has many well-established gene-disease associations with various skeletal dysplasia phenotypes. Gain-of-function is the main mechanism of disease for these disorders, except camptodactyly-tall stature-scoliosis-hearing loss syndrome where bialellic loss-of-function is the expected mechanism of disease. Specific monoallelic variants cause different phenotypes: >99% achondroplasia is caused by variants leading to the missense change p.Gly380Arg; Cysteine substitutions and stop-loss protein elongation variants are highly specific for Thanatophoric dysplasia (TD) type 1; p.Lys650Glu is associated with TD type 2; p.Ala391Glu causes Crouzon syndrome with acanthosis nigricans; and p.Pro250Arg causes Muenke syndrome.; to: FGFR3 has many well-established gene-disease associations with various skeletal dysplasia phenotypes. Gain-of-function is the main mechanism of disease for these disorders, except camptodactyly-tall stature-scoliosis-hearing loss syndrome (CATSHL syndrome, see separate curation below). Specific monoallelic variants cause different phenotypes: >99% achondroplasia is caused by variants leading to the missense change p.Gly380Arg; Cysteine substitutions and stop-loss protein elongation variants are highly specific for Thanatophoric dysplasia (TD) type 1; p.Lys650Glu is associated with TD type 2; p.Ala391Glu causes Crouzon syndrome with acanthosis nigricans; and p.Pro250Arg causes Muenke syndrome. Moderate evidence for CATSHL syndrome, AD & AR: PMID: 8630492, 17033969, 27139183, 24864036, 32641982 - 2 apparently unrelated families segregating the same missense, p.Arg621His. One consanguineous family with 2 affected brothers with homozygous p.Thr546Lys. Heterozygous individuals in the family were unaffected. No functional assays were conducted for either missense to demonstrate loss of function. Null mouse and zebrafish models are similar to the human CATSHL syndrome phenotype. |
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| Mendeliome v0.14000 | ANXA5 | Elena Savva Phenotypes for gene: ANXA5 were changed from to {Pregnancy loss, recurrent, susceptibility to, 3} MIM#614391 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13991 | HAAO | Zornitza Stark reviewed gene: HAAO: Rating: GREEN; Mode of pathogenicity: None; Publications: 33942433; Phenotypes: Vertebral, cardiac, renal, and limb defects syndrome 1 MIM#617660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13991 | RP2 | Belinda Chong reviewed gene: RP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9697692, 10053026, 10942419, 11462235, 12417528, 8225316, 26143542; Phenotypes: Retinitis pigmentosa 2 MIM#312600; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13989 | LYZ | Alison Yeung Phenotypes for gene: LYZ were changed from to Amyloidosis, renal, MIM# 105200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13964 | FGFR3 | Bryony Thompson reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26740388, 20301331, 20301540, 20301650, 20301628, 24864036, 17033969; Phenotypes: achondroplasia MONDO:0007037, Thanatophoric dysplasia type 1 MONDO:0008546, Thanatophoric dysplasia type 2 MONDO:0008547, hypochondroplasia MONDO:0007793, Muenke syndrome MONDO:0011274, FGFR3-related chondrodysplasia MONDO:0019685, severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658, camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504, Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13962 | DNAJB6 | Ain Roesley reviewed gene: DNAJB6: Rating: GREEN; Mode of pathogenicity: None; Publications: 26847086, 26338452, 24170373; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 1 MIM#603511; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13958 | DNAH1 | Ain Roesley reviewed gene: DNAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31507630, 31765523, 25927852, 24360805, 33577779; Phenotypes: primary ciliary dyskinesia,37 MIM#617577, Spermatogenic failure 18 MIM#617576; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13956 | DNA2 | Ain Roesley reviewed gene: DNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24389050, 31045292, 23352259, 25635128, 28554558; Phenotypes: Seckel syndrome 8, MIM#615807, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6 MIM#615156; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13955 | DMP1 | Ain Roesley reviewed gene: DMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32920683, 17033625, 17033621; Phenotypes: Hypophosphatemic rickets MIM#241520; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13952 | DMD | Ain Roesley reviewed gene: DMD: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301298; Phenotypes: Becker muscular dystrophy MIM@300376 XLR, Cardiomyopathy, dilated, 3B MIM#302045 XL, Duchenne muscular dystrophy MIM#310200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13951 | DLX3 | Ain Roesley reviewed gene: DLX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9467018, 15666299, 18203197; Phenotypes: Amelogenesis imperfecta, type IV, MIM# 104510, Trichodontoosseous syndrome, MIM# 190320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13949 | DLAT | Ain Roesley reviewed gene: DLAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 34138529; Phenotypes: Pyruvate dehydrogenase E2 deficiency MIM#245348; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13949 | SLC22A12 | Manny Jacobs reviewed gene: SLC22A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 14655203, 34412930, 34756726, 34829836, 26821810; Phenotypes: Hypouricemia, renal, MIM# 220150, MONDO:0020728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13949 | DISC1 | Ain Roesley Phenotypes for gene: DISC1 were changed from to {Schizophrenia 9, susceptibility to} MIM#604906 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13948 | DISC1 | Ain Roesley reviewed gene: DISC1: Rating: RED; Mode of pathogenicity: None; Publications: 18945897; Phenotypes: {Schizophrenia 9, susceptibility to} MIM#604906; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13930 | LMBR1 | Alison Yeung reviewed gene: LMBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Laurin-Sandrow syndrome, MIM# 135750, Polydactyly, preaxial type II 174500, Triphalangeal thumb, type I, MIM# 174500, Syndactyly, type IV, MIM# 186200, Acheiropody, MIM# 200500, Triphalangeal thumb-polysyndactyly syndrome, MIM# 174500, Hypoplastic or aplastic tibia with polydactyly, MIM# 188740; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13928 | CYP27B1 | Ain Roesley reviewed gene: CYP27B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9486994, 9415400, 12050193, 27473561, 34492747, 33823104; Phenotypes: Vitamin D-dependent rickets, type I MIM#264700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13924 | CYP4V2 | Ain Roesley reviewed gene: CYP4V2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15042513, 22497028; Phenotypes: Bietti crystalline corneoretinal dystrophy, MIM# 210370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13922 | CYP2R1 | Ain Roesley reviewed gene: CYP2R1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15128933, 28548312; Phenotypes: Rickets due to defect in vitamin D 25-hydroxylation deficiency MIM#600081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13920 | CYP2D6 | Ain Roesley reviewed gene: CYP2D6: Rating: RED; Mode of pathogenicity: None; Publications: 18406467, 24458010; Phenotypes: {Codeine sensitivity} MIM#608902, {Debrisoquine sensitivity} MIM#608902; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13919 | CYP2C19 |
Ain Roesley changed review comment from: Voriconazole: Improved time to target concentration with genotype directed dosing (PMID 26616742), reduced underexposure (PMID: 31549389) (PMID 31549386) (PMID:27981572) Voriconazole, moderate strength. Poor metabolizer: "Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events." Ultrarapid metabolizer: "probability of attainment of therapeutic voriconazole concentrations is small with standard dosing."; to: Pharmacogenomics gene Voriconazole: Improved time to target concentration with genotype directed dosing (PMID 26616742), reduced underexposure (PMID: 31549389) (PMID 31549386) (PMID:27981572) Voriconazole, moderate strength. Poor metabolizer: "Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events." Ultrarapid metabolizer: "probability of attainment of therapeutic voriconazole concentrations is small with standard dosing." |
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| Mendeliome v0.13865 | ANXA5 | Elena Savva reviewed gene: ANXA5: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 17339269, 12665588, 34878150; Phenotypes: {Pregnancy loss, recurrent, susceptibility to, 3} MIM#614391; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13856 | CYP2C19 | Ain Roesley reviewed gene: CYP2C19: Rating: GREEN; Mode of pathogenicity: None; Publications: 27981572, 26616742, 31549386, 31549389; Phenotypes: Voriconazole; Mode of inheritance: Other; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13856 | CYP2B6 | Ain Roesley Phenotypes for gene: CYP2B6 were changed from to Efavirenz, poor metabolism of MIM#614546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13854 | CYP2B6 | Ain Roesley reviewed gene: CYP2B6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Efavirenz, poor metabolism of MIM#614546; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13851 | CYP2A6 | Ain Roesley reviewed gene: CYP2A6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Coumarin resistance MIM#122700; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13842 | CYP26C1 | Ain Roesley reviewed gene: CYP26C1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29263414, 23161670, 16530710; Phenotypes: Focal facial dermal dysplasia 4 MIM#614974; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13835 | CYP1A2 | Ain Roesley reviewed gene: CYP1A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13832 | CYP19A1 | Ain Roesley reviewed gene: CYP19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17164303, 25264451; Phenotypes: Aromatase deficiency (MIM#613546), AR, Aromatase excess syndrome (MIM#139300), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13830 | CYCS | Ain Roesley reviewed gene: CYCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24326104, 18345000, 30051457; Phenotypes: Thrombocytopenia 4, MIM# 612004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13826 | CYC1 | Ain Roesley reviewed gene: CYC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23910460, 34252606; Phenotypes: Mitochondrial complex III deficiency, nuclear type 6 MIM#615453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13798 | KLF4 |
Elena Savva gene: KLF4 was added gene: KLF4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KLF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KLF4 were set to PMID: 35168889; 10431239 Phenotypes for gene: KLF4 were set to Hereditary palmoplantar keratoderma MONDO:0019272, KFL4-related Review for gene: KLF4 was set to GREEN Added comment: PMID: 35168889 - 3 patients from 2 unrelated families with palmoplantar keratoderma. Two variants found, fs and a missense. Functional studies on patient skin biopsy shows "slightly but significantly decreased" protein expression in both children. Gene was shown to bind the DSG1 promoter and regulate expression. Transfected cells showed reduced DSG1 expression. PMID: 10431239 - mouse K/O died shortly after birth due to loss of skin barrier function gnomAD: single het fs in the population Sources: Literature |
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| Mendeliome v0.13796 | CDH4 |
Ain Roesley gene: CDH4 was added gene: CDH4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CDH4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDH4 were set to 35034853 Phenotypes for gene: CDH4 were set to coloboma MONDO#0001476, CDH4-related Review for gene: CDH4 was set to RED gene: CDH4 was marked as current diagnostic Added comment: 1x family with AD coloboma Also presented with ID and post natal microcephaly zebrafish KO model Sources: Literature |
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| Mendeliome v0.13793 | PDGFRA | Ain Roesley reviewed gene: PDGFRA: Rating: RED; Mode of pathogenicity: None; Publications: 35034853; Phenotypes: coloboma MONDO#0001476, PDGFRA-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13789 | BMPR1B | Ain Roesley reviewed gene: BMPR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 35034853; Phenotypes: coloboma MONDO#0001476, BMPR1B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13789 | DNAH14 |
Chern Lim gene: DNAH14 was added gene: DNAH14 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAH14 were set to PMID: 35438214 Phenotypes for gene: DNAH14 were set to Neurodevelopmental disorder, DNAH14-related (MONDO#0700092) Review for gene: DNAH14 was set to GREEN gene: DNAH14 was marked as current diagnostic Added comment: PMID: 35438214: - Three previously unreported patients with compound heterozygous DNAH14 variants, including one nonsense, one frameshift, and four missense variants. A spectrum of neurological and developmental phenotypes was observed, including seizures, global developmental delay, microcephaly, and hypotonia. Sources: Literature |
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| Mendeliome v0.13787 | ANK3 | Ain Roesley reviewed gene: ANK3: Rating: AMBER; Mode of pathogenicity: None; Publications: 35034853; Phenotypes: coloboma MONDO#0001476, ANK3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13778 | STX1A |
Ain Roesley gene: STX1A was added gene: STX1A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: STX1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Review for gene: STX1A was set to GREEN gene: STX1A was marked as current diagnostic Added comment: Preprint: 8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown) 7 unrelated since the 2 siblings share similar features: 7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria Sources: Literature |
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| Mendeliome v0.13761 | HSD3B2 | Zornitza Stark Phenotypes for gene: HSD3B2 were changed from to Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency, MIM# 201810 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13758 | HSD3B2 | Zornitza Stark reviewed gene: HSD3B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1363812, 18252794; Phenotypes: Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency, MIM# 201810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13755 | CUBN | Ain Roesley reviewed gene: CUBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 31613795, 21903995, 31497480; Phenotypes: Imerslund-Grasbeck syndrome 1 MIM#261100 AR, [Proteinuria, chronic benign] MIM#618884; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13753 | CTSF | Ain Roesley reviewed gene: CTSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 28749476, 27668283, 27524508; Phenotypes: Ceroid lipofuscinosis, neuronal, 13, Kufs type, MIM# 615362; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13752 | CTSC | Ain Roesley reviewed gene: CTSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 11106356, 32601924, 10581027, 14974080, 10662808; Phenotypes: Haim-Munk syndrome MIM#245010, Papillon-Lefevre syndrome MIM#245000, Periodontitis 1, juvenile MIM#170650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13747 | CTNS | Ain Roesley reviewed gene: CTNS: Rating: ; Mode of pathogenicity: None; Publications: 20301574, 9537412, 31068690; Phenotypes: Cystinosis, atypical nephropathic MIM#219800, Cystinosis, late-onset juvenile or adolescent nephropathic MIM#219900, Cystinosis, nephropathic MIM#219800, Cystinosis, ocular nonnephropathic MIM#219750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13745 | CTNNA1 | Ain Roesley reviewed gene: CTNNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26691986, 33497368; Phenotypes: Macular dystrophy, butterfly-shaped pigmentary, 2, MIM# 608970, Familial exudative vitreoretinopathy MONDO#0019516, CTNNA1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13743 | CTHRC1 | Ain Roesley reviewed gene: CTHRC1: Rating: RED; Mode of pathogenicity: None; Publications: 21791690; Phenotypes: Barrett esophagus/esophageal adenocarcinoma MIM#614266; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13741 | CSRP3 | Ain Roesley reviewed gene: CSRP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18505755, 30681346, 12507422, 14567970, 19412328; Phenotypes: hypertrophic cardiomyopathy12 MIM#612124, dilated cardiomyopathy 1M MIM#607482; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13739 | CRYGS | Ain Roesley reviewed gene: CRYGS: Rating: GREEN; Mode of pathogenicity: None; Publications: 34014271, 16141006, 18587492, 19262743; Phenotypes: Cataract 20, multiple types MIM#116100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13737 | CRYGB | Ain Roesley reviewed gene: CRYGB: Rating: RED; Mode of pathogenicity: None; Publications: 23288985; Phenotypes: Cataract 39, multiple types, autosomal dominant MIM#615188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13735 | CRYAB | Ain Roesley reviewed gene: CRYAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 31215171, 21337604, 21130652, 32420686, 33272090; Phenotypes: Cataract 16, multiple types MIM#613763 AD, AR, Myopathy, myofibrillar, 2 MIM#608810 AD, Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related MIM#613869 AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13733 | CRX | Ain Roesley reviewed gene: CRX: Rating: GREEN; Mode of pathogenicity: None; Publications: 12208271, 9931337, 9537410, 29568065, 27427859, 25270190, 32927963, 33910785; Phenotypes: Leber congenital amaurosis 7, MIM# 613829, Cone-rod retinal dystrophy-2 MIM#120970; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13729 | CREB1 | Ain Roesley reviewed gene: CREB1: Rating: RED; Mode of pathogenicity: None; Publications: 22267179; Phenotypes: corpus callosum agenesis, thyroid follicular hypoplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13727 | CRBN | Ain Roesley reviewed gene: CRBN: Rating: AMBER; Mode of pathogenicity: None; Publications: 15557513, 28143899; Phenotypes: Intellectual developmental disorder, autosomal recessive 2 MIM#607417; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13725 | CRB1 | Ain Roesley reviewed gene: CRB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30285347, 32922261, 31884620, 15459956; Phenotypes: Leber congenital amaurosis 8 MIM#613835, Pigmented paravenous chorioretinal atrophy MIM#172870, Retinitis pigmentosa-12 MIM#600105; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13723 | CPT1A | Ain Roesley reviewed gene: CPT1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 12189492, 25778941, 23430932; Phenotypes: CPT deficiency, hepatic, type IA, MIM# 255120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13722 | CPS1 | Ain Roesley reviewed gene: CPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8486760, 17310273, 21120950, 31268178; Phenotypes: Carbamoylphosphate synthetase I deficiency MIM#237300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13720 | CPOX | Ain Roesley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 30828546, 28349448, 23582006, 24156084; Phenotypes: Coproporphyria, MIM#121300, Harderoporphyria, MIM#121300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13717 | CPN1 | Ain Roesley reviewed gene: CPN1: Rating: RED; Mode of pathogenicity: None; Publications: 12560874, 7437116; Phenotypes: Carboxypeptidase N deficiency MIM#212070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13696 | HNF4A | Zornitza Stark Phenotypes for gene: HNF4A were changed from to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026; MODY, type I, OMIM # 125850 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13693 | HNF4A | Zornitza Stark reviewed gene: HNF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31875549, 24285859, 22802087, 30005691, 28458902; Phenotypes: Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026, MODY, type I, OMIM # 125850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13685 | COL9A1 | Ain Roesley reviewed gene: COL9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16909383, 21421862, 31090205; Phenotypes: Stickler syndrome, type IV, MIM# 614134; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13683 | CORIN | Ain Roesley reviewed gene: CORIN: Rating: AMBER; Mode of pathogenicity: None; Publications: 22437503; Phenotypes: Preeclampsia/eclampsia 5 MIM#614595; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13681 | COQ9 | Ain Roesley reviewed gene: COQ9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19375058, 26081641, 23255162, 31821167; Phenotypes: Coenzyme Q10 deficiency, primary, 5, MIM#614654; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13680 | COQ8B | Ain Roesley reviewed gene: COQ8B: Rating: GREEN; Mode of pathogenicity: None; Publications: 24270420; Phenotypes: Nephrotic syndrome, type 9 MIM#615573; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13679 | COQ8A | Ain Roesley reviewed gene: COQ8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32337771; Phenotypes: Coenzyme Q10 deficiency, primary, 4 MIM#612016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13678 | COQ7 | Ain Roesley reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26084283, 31240163, 33215859, 28409910; Phenotypes: Coenzyme Q10 deficiency, primary, 8 MIM#616733; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13677 | COQ6 | Ain Roesley reviewed gene: COQ6: Rating: GREEN; Mode of pathogenicity: None; Publications: 28125198; Phenotypes: Coenzyme Q10 deficiency, primary, 6 MIM#614650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13675 | COMP | Ain Roesley reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301302, 20301660; Phenotypes: Epiphyseal dysplasia, multiple, 1 MIM#132400, Pseudoachondroplasia MIM#177170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13674 | COL9A2 | Ain Roesley reviewed gene: COL9A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21671392, 31090205, 33356723, 10364514, 15633184, 20358595, 8528240; Phenotypes: Stickler syndrome, type V MIM#614284' Epiphyseal dysplasia, multiple, 2 MIM#600204; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13673 | COL6A3 | Ain Roesley reviewed gene: COL6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301676; Phenotypes: Bethlem myopathy 1 MIM#158810, Dystonia 27 MIM#616411, Ullrich congenital muscular dystrophy 1 MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13671 | COL6A2 | Ain Roesley reviewed gene: COL6A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301676; Phenotypes: Bethlem myopathy 1 MIM#158810, Ullrich congenital muscular dystrophy 1 MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13669 | COL6A1 | Ain Roesley reviewed gene: COL6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25535305, 15955946, 23738969, 29277723, 24443028; Phenotypes: Bethlem myopathy MIM#158810, Ullrich congenital muscular dystrophy MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13668 | COL5A2 | Ain Roesley reviewed gene: COL5A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301422; Phenotypes: Ehlers-Danlos syndrome, classic type, 2 MIM#130010; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13666 | COL4A4 | Ain Roesley reviewed gene: COL4A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301386; Phenotypes: Alport syndrome 2, autosomal recessive MIM#203780, Hematuria, familial benign MIM#141200; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13665 | COL4A3 | Ain Roesley reviewed gene: COL4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alport syndrome 2, autosomal recessive, MIM# 203780, Alport syndrome 3, autosomal dominant, MIM# 104200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13664 | COL4A2 | Ain Roesley reviewed gene: COL4A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33528536, 33912663, 22209246, 30315939, 22333902; Phenotypes: Cerebral Palsy MONDO#0006497, COL4A2-related, Brain small vessel disease 2 MIM# 614483; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13662 | COL4A1 | Ain Roesley reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24628545, 25719457, 21625620, 23225343, 23065703, 20818663, 20301768; Phenotypes: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps MIM#611773, Brain small vessel disease with or without ocular anomalies MIM#175780, Microangiopathy and leukoencephalopathy, pontine, autosomal dominant MIM#618564; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13656 | COL27A1 | Ain Roesley reviewed gene: COL27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24986830, 28276056, 28322503, 32360765, 33963180; Phenotypes: Steel syndrome, OMIM #615155; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13653 | COL1A2 | Ain Roesley reviewed gene: COL1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 32091183, 2993307, 30821104; Phenotypes: Ehlers-Danlos syndrome, arthrochalasia type, 2 MIM#617821, Ehlers-Danlos syndrome, cardiac valvular type MIM#225320; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13652 | COL1A1 | Ain Roesley reviewed gene: COL1A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301422, 20301667, 30071989, 28981071, 12362985, 28956891; Phenotypes: Caffey disease MIM#114000, Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 MIM#619115, Ehlers-Danlos syndrome, arthrochalasia type, 1 MIM#130060, Osteogenesis imperfecta, type I MIM#166200, Osteogenesis imperfecta, type II MIM#166210, Osteogenesis imperfecta, type III MIM#259420, Osteogenesis imperfecta, type IV MIM#166220; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13650 | COL18A1 | Ain Roesley reviewed gene: COL18A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27259167, 25456301; Phenotypes: Knobloch syndrome, type 1, MIM# 267750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13650 | COL17A1 | Ain Roesley Phenotypes for gene: COL17A1 were changed from to Epidermolysis bullosa, junctional 4, intermediate MIM#619787; Epithelial recurrent erosion dystrophy MIM#122400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13649 | COL17A1 |
Ain Roesley commented on gene: COL17A1: For Epithelial recurrent erosion dystrophy, AD: Multiple families reported, c.3156C>T is recurrent. For EB, AR: well established association (GeneReviews PMID:20301304) |
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| Mendeliome v0.13649 | COL17A1 | Ain Roesley reviewed gene: COL17A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27309958, 29708937, 25676728, 20301304; Phenotypes: Epidermolysis bullosa, junctional 4, intermediate MIM#619787, Epithelial recurrent erosion dystrophy MIM#122400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13647 | COL12A1 | Ain Roesley reviewed gene: COL12A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 31273343, 24334604; Phenotypes: Myopathic EDS, Bethlem myopathy 2 MIM#616471, Ullrich congenital muscular dystrophy 2 MIM#616470; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13645 | COL11A2 | Ain Roesley reviewed gene: COL11A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10581026, 25633957, 16033917, 25240749, 22796475, 20112039; Phenotypes: Stickler syndrome type 3, Deafness, autosomal dominant 13 MIM#601868, Deafness, autosomal recessive 53 MIM#609706, Fibrochondrogenesis 2 MIM#614524, Otospondylomegaepiphyseal dysplasia, autosomal dominant MIM#184840, Otospondylomegaepiphyseal dysplasia, autosomal recessive MIM#215150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13643 | COG7 | Ain Roesley reviewed gene: COG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 15107842, 17356545, 28883096; Phenotypes: Congenital disorder of glycosylation, type IIe , MIM#608779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13642 | COASY |
Ain Roesley changed review comment from: Green for both NBIA and PCH; to: Green for both NBIA and PCH only 2 variants reported for PCH - a fs (c.1549_1550delAG) and c.1486-3C>G (Recurrent) |
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| Mendeliome v0.13642 | COASY | Ain Roesley reviewed gene: COASY: Rating: GREEN; Mode of pathogenicity: None; Publications: 30089828, 28489334, 24360804, 35499143; Phenotypes: Neurodegeneration with brain iron accumulation 6 MIM#615643, Pontocerebellar hypoplasia, type 12 MIM#v618266; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13637 | HK1 |
Zornitza Stark edited their review of gene: HK1: Added comment: Mono-allelic variants and ID: PMID30778173, 7 patients from 6 unrelated families with denovo missense variants in the N-terminal half of HK1 Mono-allelic variants and RP: Seven families reported with the same heterozygous missense variant, p.Glu847Lys and RP from different ethnicities. Some supportive evidence. Variant is present in 3 hets in gnomad. Bi-allelic variants and haemolytic anaemia: more than 10 families reported.; Changed publications: 19536174, 30778173, 25316723, 25190649, 31621442, 32814480, 7655856, 12393545, 33361148, 31119733, 27282571; Changed phenotypes: Neuropathy, hereditary motor and sensory, Russe type , MIM#605285, Haemolytic anaemia due to hexokinase deficiency, MIM# 235700, Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547, Retinitis pigmentosa 79, MIM# 617460; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.13619 | SIL1 | Zornitza Stark Phenotypes for gene: SIL1 were changed from to Marinesco-Sjogren syndrome, MIM#248800; MONDO#0009567 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13616 | RPE65 | Belinda Chong reviewed gene: RPE65: Rating: GREEN; Mode of pathogenicity: None; Publications: 14962443, 12960219, 11786058, 21654732, 27307694, 9501220, 16754667, 15557452; Phenotypes: Leber congenital amaurosis 2 MIM#204100, Retinitis pigmentosa 20 MIM#613794, Retinitis pigmentosa 87 with choroidal involvement MIM#618697; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13613 | RRAS |
Belinda Chong changed review comment from: Catts et al (2021) identified a 7-year-old boy with a history of craniosynostosis, congenital heart defect, and mild dysmorphic features who was incidentally found to have pediatric MDS with monosomy 7 in the context of previously unrecognized germline RRAS mutation. A heterozygous c.116_118dup (NM_006270.5) variant resulting in p.G39dup was identified and excluded in an unaffected sibling, and both parents. Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen (reviewed 27/04/2018).; to: Catts et al (2021) identified a 7-year-old boy with a history of craniosynostosis, congenital heart defect, and mild dysmorphic features who was incidentally found to have pediatric MDS with monosomy 7 in the context of previously unrecognized germline RRAS mutation. A heterozygous c.116_118dup (NM_006270.5) variant resulting in p.G39dup was identified and excluded in an unaffected sibling, and both parents. Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen (reviewed 27/04/2018). |
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| Mendeliome v0.13592 | SIL1 | Samantha Ayres reviewed gene: SIL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24176978, 16282977, 20301371; Phenotypes: Marinesco-Sjogren syndrome, MIM#248800, MONDO#0009567; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13549 | HAAO | Zornitza Stark Phenotypes for gene: HAAO were changed from to Vertebral, cardiac, renal, and limb defects syndrome 1 MIM#617660; NAD deficiency | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13401 | PHIP |
Zornitza Stark changed review comment from: Chung-Jansen syndrome (CHUJANS) is characterized by global developmental delay apparent from infancy, impaired intellectual development or learning difficulties, behavioral abnormalities, dysmorphic features, and obesity. More than 20 individuals reported.; to: Chung-Jansen syndrome (CHUJANS) is characterized by global developmental delay apparent from infancy, impaired intellectual development or learning difficulties, behavioural abnormalities, dysmorphic features, and obesity. More than 20 individuals reported. |
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| Mendeliome v0.13387 | PIEZO2 |
Zornitza Stark changed review comment from: Bi-allelic variants: more than 5 unrelated families reported. Mono-allelic variants: DA5, more than 20 families reported. DA3, more than 10 families reported, R2686H is recurrent.; to: Bi-allelic variants: more than 5 unrelated families reported. Mono-allelic variants: DA5, more than 20 families reported. DA3, more than 10 families reported, R2686H is recurrent. Marden-Walker: 2 families reported. |
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| Mendeliome v0.13387 | PIEZO2 |
Zornitza Stark changed review comment from: Bi-allelic variants: more than 5 unrelated families reported. Mono-allelic variants: DA5, more than 20 families reported.; to: Bi-allelic variants: more than 5 unrelated families reported. Mono-allelic variants: DA5, more than 20 families reported. DA3, more than 10 families reported, R2686H is recurrent. |
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| Mendeliome v0.13384 | CNNM2 | Ain Roesley Phenotypes for gene: CNNM2 were changed from to Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13382 | CNNM2 | Ain Roesley reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34604137, 35170241; Phenotypes: Hypomagnesemia 6, renal MIM#613882, Hypomagnesemia, seizures, and mental retardation MIM#616418; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13377 | CNGB1 | Ain Roesley reviewed gene: CNGB1: Rating: ; Mode of pathogenicity: None; Publications: 11379879, 15557452, 23661369, 33847019; Phenotypes: Retinitis pigmentosa 45 MIM#613767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13375 | CNGA1 | Ain Roesley reviewed gene: CNGA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33633220, 32705276, 30652268, 20301590, 7479749]; Phenotypes: Retinitis pigmentosa 49 MIM#613756; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13374 | CLN8 | Ain Roesley reviewed gene: CLN8: Rating: GREEN; Mode of pathogenicity: None; Publications: 10508524, 15024724, 16570191; Phenotypes: Ceroid lipofuscinosis, neuronal, 8, MIM# 600143, Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant, MIM# 610003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13372 | CLN6 | Ain Roesley reviewed gene: CLN6: Rating: GREEN; Mode of pathogenicity: None; Publications: 11791207, 11727201, 21549341, 30561534; Phenotypes: Ceroid lipofuscinosis, neuronal, 6, MIM# 601780, Ceroid lipofuscinosis, neuronal, Kufs type, adult onset, MIM# 204300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13370 | CLEC7A | Ain Roesley edited their review of gene: CLEC7A: Changed publications: 19864674, 20807886; Changed phenotypes: {Aspergillosis, susceptibility to} MIM#614079, candidiasis, familial, 4, autosomal recessive MIM#613108; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13357 | CLDN19 | Zornitza Stark Phenotypes for gene: CLDN19 were changed from Hypomagnesemia 5, renal, with ocular involvement, MIM#248190 to Hypomagnesaemia 5, renal, with ocular involvement, MIM#248190 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13327 | BVES |
Zornitza Stark changed review comment from: PMID: 26642364 - 1 family (3 affecteds) with cardiac arrhythmia and limb-girdle muscular dystrophy. Supported by functional studies. The proband showed lower limb girdle weakness at ~40 years old with muscle biopsy proving dystrophic changes. His 2 affected grandchildren had onset in teenage years. PMID: 32528171 - 1 patient with limb girdle weakness. PMID: 31119192 - 3 families (4 affecteds) with limb-girdle muscular weakness and cardiac abnormalities/arrhythmia. All had onset in adulthood, with exercise intolerance or proximal weakness.; to: PMID: 26642364 - 1 family (3 affecteds) with cardiac arrhythmia and limb-girdle muscular dystrophy. Supported by functional studies: zebrafish model. The proband showed lower limb girdle weakness at ~40 years old with muscle biopsy proving dystrophic changes. His 2 affected grandchildren had onset in teenage years. PMID: 32528171 - 1 patient with limb girdle weakness. PMID: 31119192 - 3 families (4 affecteds) with limb-girdle muscular weakness and cardiac abnormalities/arrhythmia. All had onset in adulthood, with exercise intolerance or proximal weakness. |
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| Mendeliome v0.13326 | CLDN19 | Ain Roesley Phenotypes for gene: CLDN19 were changed from to Hypomagnesemia 5, renal, with ocular involvement, MIM#248190 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13324 | CLDN19 | Ain Roesley reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033971, 22422540, 27530400]; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM#248190; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13324 | CLDN16 | Ain Roesley Phenotypes for gene: CLDN16 were changed from to Hypomagnesemia 3, renal MIM#248250; amelogenesis imperfecta MONDO#0019507, CLDN16-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13323 | CLDN16 | Ain Roesley reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 26426912, 16501001, 10878661, 32869508; Phenotypes: Hypomagnesemia 3, renal MIM#248250, amelogenesis imperfecta MONDO#0019507, CLDN16-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13322 | CLDN1 | Ain Roesley reviewed gene: CLDN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12164927, 11889141, 29146216; Phenotypes: Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis MIM#607626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13320 | CLCNKB | Ain Roesley reviewed gene: CLCNKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 9326936, 15044642, 18310267; Phenotypes: Bartter syndrome, type 3, MIM# 607364, Bartter syndrome, type 4b, digenic, MIM# 613090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13318 | CLCF1 | Ain Roesley reviewed gene: CLCF1: Rating: ; Mode of pathogenicity: None; Publications: 16782820, 20400119, 21370513; Phenotypes: Cold-induced sweating syndrome 2 MIM#610313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13315 | CIT | Ain Roesley reviewed gene: CIT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27453578, 27503289, 27453579; Phenotypes: Microcephaly 17, primary, autosomal recessive (MIM#617090); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13314 | CISH | Ain Roesley reviewed gene: CISH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13313 | CISD2 | Ain Roesley reviewed gene: CISD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29237418, 28335035, 27459537, 26230298, 17846994; Phenotypes: Wolfram syndrome 2 MIM#604928; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13312 | CILP | Ain Roesley reviewed gene: CILP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13310 | CIC | Ain Roesley reviewed gene: CIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28288114, 21076407; Phenotypes: Intellectual developmental disorder, autosomal dominant 45 MIM#617600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13308 | CHST14 | Ain Roesley reviewed gene: CHST14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 25703627, 26373698; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1 MIM# 601776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13306 | CHRNA2 | Ain Roesley reviewed gene: CHRNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826524, 25770198, 30809122, 25847220; Phenotypes: Epilepsy, nocturnal frontal lobe, type 4 MIM#610353; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13304 | CHRM2 | Ain Roesley reviewed gene: CHRM2: Rating: RED; Mode of pathogenicity: None; Publications: 23743182, 18451336; Phenotypes: Familial Dilated Cardiomyopathy MONDO#0016333, CHRM2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13301 | CHN1 | Ain Roesley reviewed gene: CHN1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20301369; Phenotypes: Duane retraction syndrome 2,MIM#604356; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13299 | CHMP4B | Ain Roesley reviewed gene: CHMP4B: Rating: GREEN; Mode of pathogenicity: None; Publications: 34722561, 17701905, 10682967, 30078984; Phenotypes: Cataract 31, multiple types MIM#605387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13298 | CHM | Ain Roesley reviewed gene: CHM: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301511; Phenotypes: Choroideremia MIM#303100; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13297 | PDGFRA |
Krithika Murali changed review comment from: ?Suitability for Incidentalome versus Mendeliome based on adult age of diagnosis in reported cases. --- Six unrelated families reported with heterozygous germline variants associated with familial GIST and/or inflammatory fibroid polyps - IFP (benign lesions caused by excessive tissue proliferation and inflammatory cell infiltration into the lumen of the GI tract). Note that reported individuals diagnosed as adults. One individual reported with diagnosis of gastric mass/polyps age 22 (in 1977) raising the possibility of pre-symptomatic disease onset in adolescence. Green PanelApp England in the following panels: tumour predisposition - childhood onset; inherited predisposition to GIST; sarcoma cancer susceptibility. --- PMID 34107389 Hodan et al 2021 - report a 35 yo F with jejunal IFP and a heterozygous germline missense PDGFRA variant (c.1664A>G p.Y555C) . The variant segregated with 3 relatives with confirmed IFPs. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This variant was also reported in an unrelated family with multiple IFPs in 2006. PMID 29486293 Manley et al 2018 - proband is a 50 yo M with multiple ileal intusussceptions and IFPs and GIST. Heterozygous D846V germline variant identified. Variant identified in daughter and 2 siblings. Coarser face, coarser skin, broader hands and feet, unexplained premature loss of teeth requiring dentures in their 40s described in relatives with the variant, no polyps or tumour identified in screened family members. Pdgfra +/K mutant mice recapitulated the human phenotype. Mice with the constitutively activated mutant PDGFRA shown to have diffuse expansion of the gastrointestinal submucosa, which exhibits an increased number of spindled fibroblast-like cells and marked collagen deposition. Mutant mice also develop intestinal polyps morphologically similar to IFPs. The Pdgfra +/K mice also exhibit thickened skin due to excess collagen deposition within the dermis and subcutaneous tissues. PMID 25975287 Ricci et al 2015 - report a family with het germline P653L PDGFRA missense variant. The proband was a 67 yo M with multiple intra-abdominal GIST and gastric/colonic inflammatory fibroid polyps. Multiple adult relatives (youngest age 31) were diagnosed with IFPs/fibrous tumours with the variant segregating with disease. PMID: 18670346 Carney et al 2008 and PMID: 17566086 Pasini et al 2007 - heterozygous germline PDGFRA mutation (V561D) in an individual with GIST and multiple polyps, diagnosed initially aged 22 with multiple GIST/polyps. No other relatives available for genotyping and no other significant family history reported. PMID: 17087943 de Raedt et al 2006 - heterozygous PDGFRA(Y555C) variant reported in a family with multiple relatives affected by IFP, including one death from secondary bowel obstruction age 35. PMID: 14699510 Chompret et al 2004 - Heterozygous c.2675G>T D846Y germline variant detected in a French family with 5 relatives developing adult-onset GIST, variant segregated with disease. -- Gain of function somatic variants associated with sporadic GIST. Somatic chromosomal rearrangements resulting in PDGFRA and FIP1L1 gene fusion associated with idiopathic hypereosinophilic syndrome.; to: Six unrelated families reported with heterozygous germline variants associated with familial GIST and/or inflammatory fibroid polyps - IFP (benign lesions caused by excessive tissue proliferation and inflammatory cell infiltration into the lumen of the GI tract). Note that reported individuals diagnosed as adults. One individual reported with diagnosis of gastric mass/polyps age 22 (in 1977) raising the possibility of pre-symptomatic disease onset in adolescence. Green PanelApp England in the following panels: tumour predisposition - childhood onset; inherited predisposition to GIST; sarcoma cancer susceptibility. --- PMID 34107389 Hodan et al 2021 - report a 35 yo F with jejunal IFP and a heterozygous germline missense PDGFRA variant (c.1664A>G p.Y555C) . The variant segregated with 3 relatives with confirmed IFPs. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This variant was also reported in an unrelated family with multiple IFPs in 2006. PMID 29486293 Manley et al 2018 - proband is a 50 yo M with multiple ileal intusussceptions and IFPs and GIST. Heterozygous D846V germline variant identified. Variant identified in daughter and 2 siblings. Coarser face, coarser skin, broader hands and feet, unexplained premature loss of teeth requiring dentures in their 40s described in relatives with the variant, no polyps or tumour identified in screened family members. Pdgfra +/K mutant mice recapitulated the human phenotype. Mice with the constitutively activated mutant PDGFRA shown to have diffuse expansion of the gastrointestinal submucosa, which exhibits an increased number of spindled fibroblast-like cells and marked collagen deposition. Mutant mice also develop intestinal polyps morphologically similar to IFPs. The Pdgfra +/K mice also exhibit thickened skin due to excess collagen deposition within the dermis and subcutaneous tissues. PMID 25975287 Ricci et al 2015 - report a family with het germline P653L PDGFRA missense variant. The proband was a 67 yo M with multiple intra-abdominal GIST and gastric/colonic inflammatory fibroid polyps. Multiple adult relatives (youngest age 31) were diagnosed with IFPs/fibrous tumours with the variant segregating with disease. PMID: 18670346 Carney et al 2008 and PMID: 17566086 Pasini et al 2007 - heterozygous germline PDGFRA mutation (V561D) in an individual with GIST and multiple polyps, diagnosed initially aged 22 with multiple GIST/polyps. No other relatives available for genotyping and no other significant family history reported. PMID: 17087943 de Raedt et al 2006 - heterozygous PDGFRA(Y555C) variant reported in a family with multiple relatives affected by IFP, including one death from secondary bowel obstruction age 35. PMID: 14699510 Chompret et al 2004 - Heterozygous c.2675G>T D846Y germline variant detected in a French family with 5 relatives developing adult-onset GIST, variant segregated with disease. -- Gain of function somatic variants associated with sporadic GIST. Somatic chromosomal rearrangements resulting in PDGFRA and FIP1L1 gene fusion associated with idiopathic hypereosinophilic syndrome. |
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| Mendeliome v0.13296 | CHIT1 | Ain Roesley reviewed gene: CHIT1: Rating: RED; Mode of pathogenicity: None; Publications: 23430794; Phenotypes: [Chitotriosidase deficiency] MIM#614122; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13294 | CHD1 | Ain Roesley reviewed gene: CHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28866611; Phenotypes: Pilarowski-Bjornsson syndrome, MIM#617682; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13292 | CFP | Ain Roesley reviewed gene: CFP: Rating: GREEN; Mode of pathogenicity: None; Publications: 8871668, 10909851, 22229731, 9476131, 10698340, 10540191, 16511390, 19328743; Phenotypes: Properdin deficiency, X-linked MIM#312060; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13289 | CFI | Ain Roesley reviewed gene: CFI: Rating: GREEN; Mode of pathogenicity: None; Publications: 29292855, 28942469, 27091480, 20301541; Phenotypes: Complement factor I deficiency MIM#610984, {Hemolytic uremic syndrome, atypical, susceptibility to, 3} MIM#612923; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13289 | RSPH3 | Belinda Chong reviewed gene: RSPH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26073779; Phenotypes: Ciliary dyskinesia, primary, 32 MIM#616481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13263 | RSPH4A |
Belinda Chong changed review comment from: Radial spokes are regularly spaced along cilia, sperm, and flagella axonemes and have a multisubunit 'stalk' and 'head' that form a signal transduction scaffold between the central microtubule pair and dynein arms. RSPH4A is predicted to be a component of the radial spoke head based on homology with proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates (Castleman et al., 2009; PMID19200523) 9 families with primary ciliary dyskinesia without situs inversus (Kott et al. 2013 (PMID:23993197), Castleman et al., 2009 (PMID19200523) and Daniels et al. 2013; (PMID:23798057)): - In affected members of 4 Pakistani families with CILD11, Castleman et al. (2009) identified a homozygous mutation in the RSPH4A gene. - In affected members of a family of northern European descent with CILD11, Castleman et al. (2009) identified compound heterozygosity for 2 mutations in the RSPH4A gene - Kott et al. (2013) identified pathogenic mutations in the RSPH4A gene in 7 (14%) of 48 families with a specific CILD. Common founder mutation: - Daniels et al. (2013) identified a common founder mutation in the RSPH4A gene in 9 patients with CILD11, all of whom had Puerto Rican ancestry. Multiple individuals in ClinVar with primary ciliary dyskinesia; to: Radial spokes are regularly spaced along cilia, sperm, and flagella axonemes and have a multisubunit 'stalk' and 'head' that form a signal transduction scaffold between the central microtubule pair and dynein arms. RSPH4A is predicted to be a component of the radial spoke head based on homology with proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates (Castleman et al., 2009; PMID19200523) 9 families with primary ciliary dyskinesia without situs inversus (Kott et al. 2013 (PMID:23993197), Castleman et al., 2009 (PMID19200523) and Daniels et al. 2013; (PMID:23798057)): - In affected members of 4 Pakistani families with CILD11, Castleman et al. (2009) identified a homozygous mutation in the RSPH4A gene. - In affected members of a family of northern European descent with CILD11, Castleman et al. (2009) identified compound heterozygosity for 2 mutations in the RSPH4A gene - Kott et al. (2013) identified pathogenic mutations in the RSPH4A gene in 7 (14%) of 48 families with a specific CILD. Common founder mutation: - Daniels et al. (2013) identified a common founder mutation in the RSPH4A gene in 9 patients with CILD11, all of whom had Puerto Rican ancestry. Multiple individuals in ClinVar with primary ciliary dyskinesia PMID: 25789548; Frommer 2015: 8 PCD families reported, only 4 different variants identified. Functional studies performed. PMID: 22448264; Ziętkiewicz 2012: 4 additional families/variants reported. |
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| Mendeliome v0.13263 | RSPH4A | Belinda Chong reviewed gene: RSPH4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23798057, 23798057, 23798057; Phenotypes: Ciliary dyskinesia, primary, 11 OMIM#612649; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13263 | RSPH9 | Belinda Chong reviewed gene: RSPH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25789548, 22384920, 23993197, 19200523, 27626380; Phenotypes: Ciliary dyskinesia, primary, 12 MIM#612650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13179 | PDE11A | Zornitza Stark Phenotypes for gene: PDE11A were changed from to Pigmented nodular adrenocortical disease, primary, 2 - MIM#610475 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13158 | DNAJB11 | Elena Savva reviewed gene: DNAJB11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34177435, 29706351, 29777155, 33129895; Phenotypes: Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061, Ivermark II syndrome, Prenatal Polycystic Kidney Disease; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13143 | FGF23 | Bryony Thompson reviewed gene: FGF23: Rating: GREEN; Mode of pathogenicity: Other; Publications: 11062477, 14966565, 15590700, 16151858, 16030159, 25378588, 34444516; Phenotypes: autosomal dominant hypophosphatemic rickets MONDO:0008660, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome MONDO:0100251; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13141 | FGF14 | Bryony Thompson edited their review of gene: FGF14: Added comment: 4 families with spinocerebellar ataxia and 7 families with episodic ataxia. Supporting animal models for both SCA and EA.; Changed publications: 12123606, 12489043, 15470364, 29253853, 30017992, 32112487, 32162847; Changed phenotypes: spinocerebellar ataxia type 27 MONDO:0012247, hereditary episodic ataxia MONDO:0016227; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13138 | FGF10 | Bryony Thompson reviewed gene: FGF10: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916808, 15654336, 16501574, 16630169, 17213838, 33967277, 30639323; Phenotypes: congenital alveolar dysplasia due to FGF10 MONDO:0100090, acinar dysplasia caused by mutation in FGF10 MONDO:0600017; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13125 | FBXO7 | Bryony Thompson reviewed gene: FBXO7: Rating: GREEN; Mode of pathogenicity: None; Publications: 18513678, 19038853, 34781237; Phenotypes: parkinsonian-pyramidal syndrome MONDO:0009830; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13125 | RSPO1 | Belinda Chong reviewed gene: RSPO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17041600, 18085567, 18250098, 18250097; Phenotypes: Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal MIM#610644, Palmoplantar hyperkeratosis and true hermaphroditism MIM#610644; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13121 | FBP1 | Bryony Thompson reviewed gene: FBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9382095, 12126934, 27101822, 30858132; Phenotypes: fructose-1,6-bisphosphatase deficiency MONDO:0009251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13109 | FAS | Bryony Thompson reviewed gene: FAS: Rating: ; Mode of pathogenicity: None; Publications: 7540117, 7539157, 15459302, 33995372, 34171534; Phenotypes: autoimmune lymphoproliferative syndrome MONDO:0017979; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13106 | FARSB | Bryony Thompson reviewed gene: FARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573043, 30014610, 29979980; Phenotypes: Rajab interstitial lung disease with brain calcifications 1 MONDO:0100215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13103 | FARS2 | Bryony Thompson reviewed gene: FARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30250868, 30177229, 29126765, 28043061; Phenotypes: combined oxidative phosphorylation defect type 14 MONDO:0013986, hereditary spastic paraplegia 77 MONDO:0014882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13103 | FAM58A | Bryony Thompson Phenotypes for gene: FAM58A were changed from to syndactyly-telecanthus-anogenital and renal malformations syndrome MONDO:0010408 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13100 | FAM58A | Bryony Thompson reviewed gene: FAM58A: Rating: GREEN; Mode of pathogenicity: None; Publications: 18297069, 8818947, 28322501, 8818947; Phenotypes: syndactyly-telecanthus-anogenital and renal malformations syndrome MONDO:0010408; Mode of inheritance: Other; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13100 | PDE11A | Krithika Murali reviewed gene: PDE11A: Rating: RED; Mode of pathogenicity: None; Publications: 16767104, 18559625, 21047926, 17178847; Phenotypes: Pigmented nodular adrenocortical disease, primary, 2 - MIM#610475; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13097 | FAM161A | Bryony Thompson reviewed gene: FAM161A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20705278, 20705279, 31236346, 24833722; Phenotypes: retinitis pigmentosa 28 MONDO:0011630; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13095 | FAM126A | Bryony Thompson reviewed gene: FAM126A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16951682, 21911699, 23998934, 22749724; Phenotypes: hypomyelinating leukodystrophy 5 MONDO:0012514; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13090 | FAM111B | Bryony Thompson reviewed gene: FAM111B: Rating: ; Mode of pathogenicity: Other; Publications: 24268661, 26471370, 26495788, 27406236; Phenotypes: hereditary sclerosing poikiloderma with tendon and pulmonary involvement MONDO:0014310; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13086 | FAM111A | Bryony Thompson reviewed gene: FAM111A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23684011, 32996714, 32765931, 33010201; Phenotypes: autosomal dominant Kenny-Caffey syndrome MONDO:0007478; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13081 | FAH | Bryony Thompson reviewed gene: FAH: Rating: GREEN; Mode of pathogenicity: None; Publications: 8253378, 1401056, 8364576, 8318997, 25681080; Phenotypes: Tyrosinemia type I MONDO:0010161; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13059 | CFHR5 | Ain Roesley reviewed gene: CFHR5: Rating: GREEN; Mode of pathogenicity: None; Publications: 30844074, 30197990, 24067434, 21566112, 20800271, 27490940, 24334459; Phenotypes: Nephropathy due to CFHR5 deficiency, MIM#614809; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13058 | CFH | Ain Roesley reviewed gene: CFH: Rating: GREEN; Mode of pathogenicity: None; Publications: 27572114, 25814826, 20301541, 9312129, 10803850, 29888403, 30905644; Phenotypes: Basal laminar drusen MIM#126700, Complement factor H deficiency MIM#609814, {Hemolytic uremic syndrome, atypical, susceptibility to, 1} MIMI#235400; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13040 | CFD | Ain Roesley reviewed gene: CFD: Rating: GREEN; Mode of pathogenicity: None; Publications: 11457876, 16527897, 31440263; Phenotypes: Complement factor D deficiency MIM#613912; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13038 | CEP78 | Ain Roesley reviewed gene: CEP78: Rating: GREEN; Mode of pathogenicity: None; Publications: 28005958, 27588451, 27588452, 27627988; Phenotypes: Cone-rod dystrophy and hearing loss MIM#617236; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13037 | CEBPA | Ain Roesley reviewed gene: CEBPA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukemia, acute myeloid, somatic MIM#601626; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13036 | CEACAM16 | Ain Roesley reviewed gene: CEACAM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 21368133, 22544735, 29703829, 25589040, 31249509, 30514912; Phenotypes: Deafness, autosomal dominant 4B, MIM# 614614, Deafness, autosomal recessive 113, MIM# 618410; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13035 | CDKN2A | Ain Roesley reviewed gene: CDKN2A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Melanoma and neural system tumor syndrome} MIM#155755, {Melanoma, cutaneous malignant, 2} MIM#155601, {Melanoma-pancreatic cancer syndrome} MIM#606719; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13033 | CDKN1B | Ain Roesley reviewed gene: CDKN1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 24819502, 17030811, 23555276; Phenotypes: Multiple endocrine neoplasia type 4, MEN4, OMIM #610755; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13031 | CDK4 | Ain Roesley reviewed gene: CDK4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Melanoma, cutaneous malignant, 3} MIM#609048; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13030 | CDK10 | Ain Roesley reviewed gene: CDK10: Rating: GREEN; Mode of pathogenicity: None; Publications: 28886341, 34974531; Phenotypes: Al Kaissi syndrome MIM#617694; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13028 | CDHR1 | Ain Roesley reviewed gene: CDHR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20805371, 20087419, 34926197, 32277948, 32783370, 31387115, 32681094; Phenotypes: Cone-rod dystrophy 15 MIM#613660, Retinitis pigmentosa 65 MIM#613660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13027 | CDC73 | Ain Roesley reviewed gene: CDC73: Rating: GREEN; Mode of pathogenicity: None; Publications: 12434154; Phenotypes: Hyperparathyroidism-jaw tumour syndrome, MIM# 145001, Hyperparathyroidism, familial primary, MIM# 145000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13024 | CDC42 | Ain Roesley reviewed gene: CDC42: Rating: GREEN; Mode of pathogenicity: None; Publications: 29394990, 31601675, 32303876, 32231661; Phenotypes: Takenouchi-Kosaki syndrome, MIM#616737; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13022 | CDC14A | Ain Roesley reviewed gene: CDC14A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29293958, 2725905; Phenotypes: Deafness, autosomal recessive 32, with or without immotile sperm, MIM# 608653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13020 | CD79B | Ain Roesley reviewed gene: CD79B: Rating: GREEN; Mode of pathogenicity: None; Publications: 17709424, 17675462, 33733381, 24722855; Phenotypes: Agammaglobulinemia 6 MIM#612692; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13007 | PRKAR1A | Zornitza Stark Phenotypes for gene: PRKAR1A were changed from to Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Carney complex, type 1, MIM# 160980; Myxoma, intracardiac, MIM# 255960; Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13004 | PRKAR1A | Zornitza Stark reviewed gene: PRKAR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 10973256, 11115848, 12424709, 21651393; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800, Carney complex, type 1, MIM# 160980, Myxoma, intracardiac, MIM# 255960, Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12952 | PSTPIP1 | Zornitza Stark Phenotypes for gene: PSTPIP1 were changed from to Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12949 | PSTPIP1 | Zornitza Stark reviewed gene: PSTPIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11971877, 34938582, 34778321, 34745107, 34492165, 34047005; Phenotypes: Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12855 | PDCD1 |
Krithika Murali changed review comment from: No OMIM gene disease association. 1 individual from a consanguineous family reported with PDCD1 deficiency. PMID: 34183838 (Nat Medicine 2021) - proband is the son of consanguineous Turkish parents. He was diagnosed with type 1 diabetes (T1D), hypothyroidism, and juvenile idiopathic arthritis (JIA) at the age of three years. He developed abdominal TB age 10 and died from pulmonary alveolar haemorrhage age 11. WES identified homozygous intragenic PDCD1 gene duplication (c.105dupC p.T36Hfs*70). Absent from population databases and unaffected parents confirmed to be heterozygous. Supportive in vitro studies showing absent expression or function of PD-1 protein. Proband's older brother died at the age of 3 from unexplained pneumonitis and had a history of T1DM and juvenile idiopathic arthritis.; to: No OMIM gene disease association. 1 individual from a consanguineous family reported with PDCD1 deficiency. PMID: 34183838 (Nat Medicine 2021) - proband is the son of consanguineous Turkish parents. He was diagnosed with type 1 diabetes (T1D), hypothyroidism, and juvenile idiopathic arthritis (JIA) at the age of three years. He developed abdominal TB age 10 and died from pulmonary alveolar haemorrhage age 11. WES identified homozygous intragenic PDCD1 gene duplication (c.105dupC p.T36Hfs*70). Absent from population databases and unaffected parents confirmed to be heterozygous. Supportive in vitro studies showing absent expression or function of PD-1 protein. Proband's older brother died at the age of 3 from unexplained pneumonitis and had a history of T1DM and juvenile idiopathic arthritis. |
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| Mendeliome v0.12853 | CD79A | Ain Roesley reviewed gene: CD79A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29335801, 31696364, 24481606, 10525050, 11920841; Phenotypes: Agammaglobulinemia 3 MIM#613501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12851 | CD70 | Ain Roesley reviewed gene: CD70: Rating: GREEN; Mode of pathogenicity: None; Publications: 28011864, 28011863; Phenotypes: Lymphoproliferative syndrome 3, MIM# 618261; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12849 | CD55 | Ain Roesley reviewed gene: CD55: Rating: GREEN; Mode of pathogenicity: None; Publications: 28657829, 28657861; Phenotypes: Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy, MIM# 226300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12848 | CD46 | Ain Roesley reviewed gene: CD46: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301541, 26054645, 26826462; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to, 2} MIM#612922; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12846 | CD40 | Ain Roesley reviewed gene: CD40: Rating: GREEN; Mode of pathogenicity: None; Publications: 11675497, 12915844; Phenotypes: Immunodeficiency with hyper-IgM, type 3, MIM# 606843; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12844 | CD36 | Ain Roesley reviewed gene: CD36: Rating: GREEN; Mode of pathogenicity: None; Publications: 7686693, 11950861, 10890433, 24960640, 10890433; Phenotypes: Platelet glycoprotein IV deficiency MIM#608404, {Malaria, cerebral, reduced risk of} MIM#611162, {Malaria, cerebral, susceptibility to} MIM#611162; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12844 | CD36 | Ain Roesley reviewed gene: CD36: Rating: GREEN; Mode of pathogenicity: None; Publications: 7533783, 11950861, 10890433, 12506336; Phenotypes: {Malaria, cerebral, reduced risk of} MIM#611162, {Malaria, cerebral, susceptibility to} MIM#611162, Platelet glycoprotein IV deficiency MIM#608404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12843 | CD209 | Ain Roesley reviewed gene: CD209: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Dengue fever, protection against} MIM#614371, {HIV type 1, susceptibility to} MIM#609423, {Mycobacterium tuberculosis, susceptibility to} MIM#607948; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12841 | CD151 | Ain Roesley reviewed gene: CD151: Rating: GREEN; Mode of pathogenicity: None; Publications: 15265795, 29138120; Phenotypes: Nephropathy with pretibial epidermolysis bullosa and deafness, MIM#609057; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12839 | CCR5 | Ain Roesley reviewed gene: CCR5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: {Hepatitis C virus, resistance to} 609532, {HIV infection, susceptibility/resistance to}, {West nile virus, susceptibility to}MIM# 610379; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12838 | CCR2 | Ain Roesley changed review comment from: Currently no mendelian gene-disease association; to: Vall64Ile has been associated with reduction in the progression to AIDS. Mutant results in normal expression levels of the CCR2 receptor and has no effect on the incidence of HIV infection. However, in contrast to normal CCR2 peptides, the mutant protein preferentially dimerizes with the CXCR4 polypeptide, isolating it in the endoplasmic reticulum. It is also thought that the inhibitory effect is dependent on the stages of HIV-1 infection and interactions with other genetic variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12836 | CCR2 | Ain Roesley reviewed gene: CCR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12795 | EYS | Bryony Thompson reviewed gene: EYS: Rating: GREEN; Mode of pathogenicity: None; Publications: 18836446, 18976725, 34689181; Phenotypes: retinitis pigmentosa 25 MONDO:0011272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12793 | EXT1 | Bryony Thompson reviewed gene: EXT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7550340, 8981950, 20534475; Phenotypes: hereditary multiple osteochondromas MONDO:0005508, exostoses, multiple, type 1 MONDO:0007585; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12790 | EXOC3L2 | Bryony Thompson Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation; renal dysplasia; bone marrow failure to Dandy-Walker malformation, MONDO:0009072; renal dysplasia; bone marrow failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12784 | PDHA2 |
Zornitza Stark gene: PDHA2 was added gene: PDHA2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PDHA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDHA2 were set to 29581481; 35172124 Phenotypes for gene: PDHA2 were set to Spermatogenic failure-70, MIM#619828 Review for gene: PDHA2 was set to RED Added comment: Three individuals reported from different families with same homozygous missense variant. Same ethnic background, likely founder effect. Sources: Literature |
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| Mendeliome v0.12728 | RSPO2 | Belinda Chong reviewed gene: RSPO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29769720, 32457899; Phenotypes: Tetraamelia syndrome 2, MIM# 618021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12726 | ATP11A | Paul De Fazio reviewed gene: ATP11A: Rating: AMBER; Mode of pathogenicity: None; Publications: 35278131; Phenotypes: Deafness, autosomal dominant 84 MIM#619810; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12714 | AHSG |
Elena Savva gene: AHSG was added gene: AHSG was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AHSG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AHSG were set to PMID: 28054173; 9395485; 31288248; 17389622 Phenotypes for gene: AHSG were set to ?Alopecia-intellectual disability syndrome 1 MIM#203650; infantile cortical hyperostosis Review for gene: AHSG was set to RED Added comment: PMID: 28054173 - 7 relatives within a large consanguinous fam w/ alopecia and ID, and a hom missense (p.Arg317His). Modelling predicts this variant to be a phosphorylation site, functional studies show a difference in protein size. Unclear biological significance. Alt change with stronger GS (p.(Arg317Cys)) is a common poly with 19 homozygotes in gnomAD. No hom PTCs in gnomAD PMID: 9395485 - K/O mouse model shows no gross anatomical abnormalities, were fertile and "healthy". No mentioned of ID, alopecia PMID: 17389622 - K/O mouse model on the calcification resistant genetic background C57BL/6, shows uraemia and phosphate challenge. No mentioned of ID, alopecia PMID: 31288248 - 1 hom infant (p.K2*, within 5' NMD escape region) with infantile cortical hyperostosis, loss of enzyme in patient serum shown by ELISA. No mentioned of ID, alopecia Sources: Literature |
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| Mendeliome v0.12711 | MDFIC |
Belinda Chong gene: MDFIC was added gene: MDFIC was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MDFIC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MDFIC were set to 35235341 Phenotypes for gene: MDFIC were set to Central conducting lymphatic anomaly with lymphedema Review for gene: MDFIC was set to GREEN Added comment: Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. Sources: Literature |
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| Mendeliome v0.12709 | VPS16 | Ain Roesley reviewed gene: VPS16: Rating: GREEN; Mode of pathogenicity: None; Publications: 33938619, 34013567; Phenotypes: mucopolysaccharidosis-like disorder, VPS16-related MONDO#0100365; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12673 | SLC25A42 | Zornitza Stark Phenotypes for gene: SLC25A42 were changed from to Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression , MIM#618416 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12670 | SLC25A42 | Zornitza Stark reviewed gene: SLC25A42: Rating: GREEN; Mode of pathogenicity: None; Publications: 26541337, 29327420, 29923093, 34258143; Phenotypes: Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression , MIM#618416; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12667 | SLC2A2 |
Zornitza Stark changed review comment from: Fanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose. > 5 patients previously reported with the associated condition, which is a glycogen storage disease. SLC2A2 encodes for the glucose transporter, GLUT2.; to: Fanconi-Bickel syndrome is characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose. > 5 patients previously reported with the associated condition, which is a glycogen storage disease. SLC2A2 encodes for the glucose transporter, GLUT2. |
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| Mendeliome v0.12653 | SOX18 | Zornitza Stark Phenotypes for gene: SOX18 were changed from to Hypotrichosis-lymphedema-telangiectasia syndrome, MIM# 607823; Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome, MIM# 137940 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12650 | SOX18 | Zornitza Stark reviewed gene: SOX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 12740761, 24697860, 2484451, 26148450, 33851505; Phenotypes: Hypotrichosis-lymphedema-telangiectasia syndrome, MIM# 607823, Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome, MIM# 137940; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12595 | PAX2 | Zornitza Stark Phenotypes for gene: PAX2 were changed from to Papillorenal syndrome, MIM# 120330; Renal coloboma syndrome, MONDO:0007352; Glomerulosclerosis, focal segmental, 7 - MIM#616002 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12573 | RTN4IP1 | Belinda Chong reviewed gene: RTN4IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26593267, 31077085; Phenotypes: Optic atrophy 10 with or without ataxia, mental retardation, and seizures, MIM#616732; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12573 | RUNX1 | Belinda Chong reviewed gene: RUNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10508512, 11830488; Phenotypes: Platelet disorder, familial, with associated myeloid malignancy, MIM# 601399, Leukemia, acute myeloid, MIM# 601626; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12573 | PAX2 | Krithika Murali reviewed gene: PAX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21654726, 24676634, 31060108, 32203253; Phenotypes: Papillorenal syndrome, MIM# 120330, Renal coloboma syndrome, MONDO:0007352, Glomerulosclerosis, focal segmental, 7 - MIM#616002; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12559 | CCM2 | Ain Roesley reviewed gene: CCM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 14624391, 18779516, 30356112, 21543988; Phenotypes: Cerebral cavernous malformations-2 MIM#603284; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12558 | CCL2 | Ain Roesley reviewed gene: CCL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {HIV-1, resistance to} MIM#609423, {Mycobacterium tuberculosis, susceptibility to} MIM#607948, {Spina bifida, susceptibility to} MIM#182940; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12555 | CCDC88A | Ain Roesley reviewed gene: CCDC88A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26917597, 30392057; Phenotypes: PEHO syndrome-like, MIM# 617507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12552 | CCDC50 | Ain Roesley reviewed gene: CCDC50: Rating: GREEN; Mode of pathogenicity: None; Publications: 17503326, 27911912; Phenotypes: Deafness, autosomal dominant 44 MIM#607453; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12544 | CAV3 | Ain Roesley reviewed gene: CAV3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32004987, 28807458, 27312022, 10746614; Phenotypes: Myopathy, distal, Tateyama type MIM#614321, Rippling muscle disease 2 MIM#606072, Creatine phosphokinase, elevated serum MIM#123320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12542 | ETFDH | Bryony Thompson reviewed gene: ETFDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 17412732, 27038534, 19249206, 15710863, 32804429; Phenotypes: multiple acyl-CoA dehydrogenase deficiency MONDO:0009282; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12539 | CATSPER2 | Ain Roesley reviewed gene: CATSPER2: Rating: AMBER; Mode of pathogenicity: None; Publications: 17098888, 30629171, 12825070; Phenotypes: spermatogenic failure, non-syndromic hearing loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12536 | ETFB | Bryony Thompson reviewed gene: ETFB: Rating: GREEN; Mode of pathogenicity: None; Publications: 7912128, 12815589, 27081516, 12706375, 30626930; Phenotypes: multiple acyl-CoA dehydrogenase deficiency MONDO:0009282; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12534 | CATSPER1 | Ain Roesley edited their review of gene: CATSPER1: Changed rating: GREEN; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12525 | ETFA | Bryony Thompson reviewed gene: ETFA: Rating: GREEN; Mode of pathogenicity: None; Publications: 1430199, 1882842, 21347544; Phenotypes: multiple acyl-CoA dehydrogenase deficiency MONDO:0009282; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12524 | CAT | Ain Roesley reviewed gene: CAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 24025477; Phenotypes: Acatalasemia MIM#614097, hypocatalasemia; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12518 | ERLIN2 | Bryony Thompson reviewed gene: ERLIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23109145, 21330303, 21796390, 29528531, 32094424, 34734492; Phenotypes: hereditary spastic paraplegia 18 MONDO:0012639; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12501 | CASR | Ain Roesley reviewed gene: CASR: Rating: GREEN; Mode of pathogenicity: None; Publications: 7916660, 7726161, 8675635, 17698911, 22620673, 26646938, 22422767; Phenotypes: Hyperparathyroidism, neonatal MIM#239200, Hypocalcemia, autosomal dominant MIM#601198, Hypocalcemia autosomal dominant, with Bartter syndrome MIM#601198, hypercalcemia, type I MIM#145980; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12498 | CASQ1 | Ain Roesley reviewed gene: CASQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26136523, 30258016; Phenotypes: Myopathy, vacuolar, with CASQ1 aggregates MIM#616231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12457 | SLC2A9 | Zornitza Stark Phenotypes for gene: SLC2A9 were changed from to Hypouricaemia, renal, 2, MIM# 612076 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12454 | SLC2A9 | Zornitza Stark reviewed gene: SLC2A9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19026395, 19926891, 21810765, 25966807, 21256783; Phenotypes: Hypouricaemia, renal, 2, MIM# 612076; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12445 | SLC34A1 |
Zornitza Stark changed review comment from: Infantile hypercalcaemia and bi-allelic variants: More than 5 unrelated families reported. Nephrolithiasis and mono-allelic variants: multiple families reported.; to: Infantile hypercalcaemia and bi-allelic variants: More than 5 unrelated families reported. Nephrolithiasis and mono-allelic variants: multiple families reported. Single family reported with renal Fanconi and homozygous variant. |
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| Mendeliome v0.12413 | SLC4A4 | Zornitza Stark Phenotypes for gene: SLC4A4 were changed from to Renal tubular acidosis, proximal, with ocular abnormalities, MIM# 604278; Hemiplegic migraine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12410 | SLC4A4 | Zornitza Stark reviewed gene: SLC4A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 10545938, 11274232, 35260236, 33439394, 29914390; Phenotypes: Renal tubular acidosis, proximal, with ocular abnormalities, MIM# 604278, Hemiplegic migraine; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12407 | ENO3 | Bryony Thompson reviewed gene: ENO3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11506403, 31741825, 25267339, 18070103; Phenotypes: glycogen storage disease due to muscle beta-enolase deficiency MONDO:0013046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12404 | ENG | Bryony Thompson reviewed gene: ENG: Rating: GREEN; Mode of pathogenicity: None; Publications: 34012068, 30336550, 7894484, 10751092, 20414677, 30763665, 17384219, 20364125; Phenotypes: hereditary hemorrhagic telangiectasia MONDO:0019180; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12390 | ELOVL4 | Bryony Thompson reviewed gene: ELOVL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11138005, 15028284, 11726641, 17208947, 22100072, 24566826, 34227061, 24571530, 26010696; Phenotypes: congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome MONDO:0013760, spinocerebellar ataxia type 34 MONDO:0007574, Stargardt disease MONDO:0019353; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12387 | ELN | Bryony Thompson reviewed gene: ELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 8132745, 9580666, 9873040, 10190324, 10190538, 22573328, 28383366; Phenotypes: cutis laxa, autosomal dominant 1 MONDO:0007411, supravalvular aortic stenosis MONDO:0008504; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12386 | ARPC4 | Bryony Thompson edited their review of gene: ARPC4: Changed publications: 35047857; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12381 | SLC5A2 | Zornitza Stark Phenotypes for gene: SLC5A2 were changed from to Renal glucosuria, MIM# 233100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12379 | SLC5A2 | Zornitza Stark reviewed gene: SLC5A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal glucosuria, MIM# 233100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12370 | BNIP1 |
Bryony Thompson gene: BNIP1 was added gene: BNIP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BNIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BNIP1 were set to 35266227; 31344970 Phenotypes for gene: BNIP1 were set to spondyloepiphyseal dysplasia MONDO:0016761 Review for gene: BNIP1 was set to AMBER Added comment: Two apparently unrelated cases with spondyloepiphyseal dysplasia from India were identified with the same variant (c.84+3A>T). The kindred coefficient comparison of the 2 cases exome data suggested they were unrelated, however there was a stretch of shared homozygosity suggesting remote consanguinity. ~80% aberrantly spliced BNIP1 pre-mRNAs, reduced BNIP1 mRNA level to ~80%, and BNIP1 protein level reduction by ~50% were detected in one of the cases fibroblasts. A block at the terminal stage of autolysosome formation and/or clearance in patient fibroblasts was suggested based on the data. A drosophila model of the BNIP1 orthologue Sec20 also demonstrated defective autolysosome formation. Sources: Literature |
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| Mendeliome v0.12338 | PADI6 | Zornitza Stark Phenotypes for gene: PADI6 were changed from to Pre-implantation embryonic lethality 2 MIM#617234; Multi locus imprinting disturbance in offspring; Recurrent hydatiform mole | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12316 | EIF2B5 | Bryony Thompson reviewed gene: EIF2B5: Rating: GREEN; Mode of pathogenicity: None; Publications: 11704758, 12325082, 12707859, 14694060, 15136689, 18263758, 25843247, 25761052; Phenotypes: leukoencephalopathy with vanishing white matter MONDO:0011380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12311 | EIF2B4 | Bryony Thompson reviewed gene: EIF2B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11835386, 12707859, 18263758, 25843247, 25761052, 30014503; Phenotypes: leukoencephalopathy with vanishing white matter MONDO:0011380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12304 | EIF2B3 | Bryony Thompson reviewed gene: EIF2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11835386, 19158808, 21484434, 18263758, 25843247, 25761052, 28904586, 28597716; Phenotypes: leukoencephalopathy with vanishing white matter MONDO:0011380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12298 | EIF2B1 | Bryony Thompson reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11835386, 26285592, 15776425, 18263758, 25843247, 25761052, 30014503; Phenotypes: leukoencephalopathy with vanishing white matter MONDO:0011380, ataxia, spasticity, optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12296 | EIF2AK3 | Bryony Thompson Phenotypes for gene: EIF2AK3 were changed from to Wolcott-Rallison syndrome MONDO:0009192; neonatal diabetes mellitus; epiphyseal dysplasia/osteopenia; hepatic/renal dysfunction; intellectual disability/developmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12289 | EIF2AK3 | Bryony Thompson reviewed gene: EIF2AK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10932183, 12960215, 16813601, 11997520, 20202148; Phenotypes: Wolcott-Rallison syndrome MONDO:0009192, neonatal diabetes mellitus, epiphyseal dysplasia/osteopenia, hepatic/renal dysfunction, intellectual disability/developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12285 | PADI6 | Krithika Murali reviewed gene: PADI6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29693651, 33583041, 329228291, 33221824, 27545678; Phenotypes: Pre-implantation embryonic lethality 2 MIM#617234, Multi locus imprinting disturbance in offspring, Recurrent hydatiform mole; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12281 | ADRB2 | Elena Savva Phenotypes for gene: ADRB2 were changed from to Beta-2-adrenoreceptor agonist, reduced response to; {Asthma, nocturnal, susceptibility to} MIM#600807; {Obesity, susceptibility to} MIM#601665 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12276 | ADRB2 | Elena Savva reviewed gene: ADRB2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 15724149; Phenotypes: Beta-2-adrenoreceptor agonist, reduced response to, {Asthma, nocturnal, susceptibility to} MIM#600807, {Obesity, susceptibility to} MIM#601665; Mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12258 | EDNRB | Bryony Thompson reviewed gene: EDNRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 28502583, 25852447, 21373256, 16237557, 11773966, 11891690, 8001158, 10528251, 10528251, 19764031, 28236341; Phenotypes: Waardenburg syndrome type 4A (MONDO:0010192); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12154 | CA2 | Zornitza Stark Phenotypes for gene: CA2 were changed from to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM#259730 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12152 | CASP8 | Ain Roesley reviewed gene: CASP8: Rating: RED; Mode of pathogenicity: None; Publications: 12353035, 25814141, 12654726, 17213198, 16148088; Phenotypes: utoimmune lymphoproliferative syndrome, type IIB MIM#607271; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12150 | CASP8 | Ain Roesley reviewed gene: CASP8: Rating: RED; Mode of pathogenicity: None; Publications: 33356695; Phenotypes: Autoimmune lymphoproliferative syndrome, type IIB MIM#607271; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12148 | CASP10 | Ain Roesley reviewed gene: CASP10: Rating: GREEN; Mode of pathogenicity: None; Publications: 34329798, 34384744, 20301287; Phenotypes: Autoimmune lymphoproliferative syndrome, type II MIM#603909; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12134 | CASK | Ain Roesley reviewed gene: CASK: Rating: GREEN; Mode of pathogenicity: None; Publications: 24278995; Phenotypes: FG syndrome 4 MIM#300422, Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia MIM#300749, Mental retardation, with or without nystagmus MIM#300422; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12127 | CARD11 | Ain Roesley reviewed gene: CARD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561803, 12818158, 23374270, 28628108; Phenotypes: Immunodeficiency 11A, autosomal recessive, MIM# 615206, Immunodeficiency 11B with atopic dermatitis, autosomal dominant, MIM# 617638; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12126 | CALM3 | Ain Roesley reviewed gene: CALM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31983240; Phenotypes: Long QT syndrome 16 MIM#618782, CPVT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12124 | CALM2 | Ain Roesley reviewed gene: CALM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31983240; Phenotypes: Long QT syndrome 15 MIM#616249, CPVT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12122 | CALM1 | Ain Roesley reviewed gene: CALM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31170290; Phenotypes: Long QT syndrome 14 MIM#616247, Ventricular tachycardia, catecholaminergic polymorphic, 4 MIM#614916; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12117 | CACNA2D4 | Ain Roesley reviewed gene: CACNA2D4: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033974, 26560832, 26560832, 33927996, 34996991; Phenotypes: Retinal cone dystrophy 4 MIM#610478; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12100 | CACNA2D2 | Ain Roesley reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: Cerebellar atrophy with seizures and variable developmental delay MIM#618501; Phenotypes: 23339110, 24358150, 30410802, 29997391, 31402629, 11487633, 11756448, 4177347, 14660671, 15331424; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12097 | CACNA1F | Ain Roesley reviewed gene: CACNA1F: Rating: GREEN; Mode of pathogenicity: None; Publications: 17525176, 16505158, 23776498, 24124559, 26075273, 25999675; Phenotypes: Aland Island eye disease MIM#300600, Cone-rod dystrophy, X-linked, 3 MIM#300476, Night blindness, congenital stationary (incomplete), 2A, X-linked MIM#300071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12096 | SCARB2 | Zornitza Stark Phenotypes for gene: SCARB2 were changed from to Progressive Myoclonus Epilepsy, MONDO:0020074; Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12089 | CABP2 | Ain Roesley reviewed gene: CABP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22981119, 31661684, 28183797; Phenotypes: Deafness, autosomal recessive 93, MIM# 614899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12083 | CA2 | Ain Roesley reviewed gene: CA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34624559, 33555497, 12566520, 7627193; Phenotypes: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM#259730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12080 | CA12 | Ain Roesley reviewed gene: CA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21035102, 21184099, 26911677; Phenotypes: Hyperchlorhidrosis, isolated MIM#143860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12071 | ACER3 | Zornitza Stark edited their review of gene: ACER3: Added comment: Additional publication (Dehvani et al., 2021; PMID: 34281620) detailing three further unrelated cases, each with novel homozygous variants in the ACER3 gene. All individuals displayed features of progressive leukoencephalopathy, developmental delay, hypotonia, appendicular spasticity, and dystonia. Early development is apparently normal followed by symptoms of stagnation and neurologic regression (onset within first year of life).; Changed rating: GREEN; Changed publications: 32816236, 26792856, 34281620; Changed phenotypes: Leukodystrophy, progressive, early childhood-onset, MIM:617762 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12068 | LIAS | Alison Yeung reviewed gene: LIAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 22152680, 24334290, 26108146; Phenotypes: Hyperglycinemia, lactic acidosis, and seizures, MIM# 614462; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12066 | LHX4 | Alison Yeung reviewed gene: LHX4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 4, MIM# 262700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12064 | LHX3 | Alison Yeung reviewed gene: LHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 3, MIM# 221750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12062 | LHB | Alison Yeung reviewed gene: LHB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism 23 with or without anosmia, MIM# 228300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12062 | SCARB2 | Samantha Ayres reviewed gene: SCARB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18308289, 18424452, 23659519, 19847901, 18022370, 19933215; Phenotypes: Progressive Myoclonus Epilepsy, MONDO:0020074, Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12053 | LDLRAP1 | Alison Yeung reviewed gene: LDLRAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 4351242; Phenotypes: Hypercholesterolemia, familial, 4, MIM# 603813; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12046 | LCAT | Alison Yeung reviewed gene: LCAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 30720493, 6624548; Phenotypes: Lecithin:Cholesterol Acyltransferase Deficiency, MIM# 245900, Fish-Eye disease, MIM# 136120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11990 | TFAP2B |
Zornitza Stark changed review comment from: Well established association with syndromic and non-syndromic PDA.; to: Well established association with syndromic and non-syndromic PDA. Four individuals reported in PMID: 31292255 (Correction in PMID: 31405973) as part of a craniosynostosis cohort: 2 de novo and 2 inherited. There is evidence for reduced penetrance as in one case the variant was inherited from an unaffected parent (affected parent for the other inherited variant). |
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| Mendeliome v0.11946 | TBC1D1 | Zornitza Stark Phenotypes for gene: TBC1D1 were changed from to CAKUT; Non-syndromic renal or urinary tract malformation, MONDO:0019720 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11943 | TBC1D1 | Zornitza Stark reviewed gene: TBC1D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26572137; Phenotypes: CAKUT, Non-syndromic renal or urinary tract malformation, MONDO:0019720; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11932 | TANGO2 | Zornitza Stark Phenotypes for gene: TANGO2 were changed from to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11929 | TANGO2 | Zornitza Stark reviewed gene: TANGO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26805782, 30245509; Phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11906 | LAT | Alison Yeung reviewed gene: LAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27522155, 27242165, 10204488; Phenotypes: Immunodeficiency 52, MIM# 617514; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11874 | NLRP7 | Zornitza Stark Phenotypes for gene: NLRP7 were changed from to Hydatidiform mole, recurrent, 1 - MIM#231090 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11865 | LAS1L | Alison Yeung reviewed gene: LAS1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 25644381, 34653234, 25644381; Phenotypes: Wilson-Turner syndrome, MIM# 309585; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11864 | LARGE1 | Alison Yeung reviewed gene: LARGE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12966029, 19067344, 17436019, 21248746; Phenotypes: Muscular dystrophy-dystroglycanopathy type A6, MIM# 613154, Muscular dystrophy-dystroglycanopathy type B6, MIM# 608840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11864 | LAMC3 | Alison Yeung reviewed gene: LAMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21572413, 34354730; Phenotypes: Cortical malformations, occipital, MIM#614115; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11864 | LAMB2 |
Alison Yeung changed review comment from: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss. Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus. The two disorders are likely part of a spectrum. More than 5 unrelated families reported. ; to: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss. Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus. More than 5 unrelated families reported. |
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| Mendeliome v0.11864 | LAMB2 |
Alison Yeung changed review comment from: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss. Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus.; to: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss. Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus. The two disorders are likely part of a spectrum. More than 5 unrelated families reported. |
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| Mendeliome v0.11863 | L1CAM | Alison Yeung reviewed gene: L1CAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 11438988, 7920660, 8401593, 19565280; Phenotypes: Hydrocephalus due to aqueductal stenosis, MIM# 307000, MASA syndrome, MIM# 303350; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11860 | NLRP7 | Krithika Murali reviewed gene: NLRP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 23201303, 23125094, 25097207, 26606510, 19650864, 23880596, 22770628, 26544189, 28428943, 21623199, 21439709, 33583041, 32055942, 19246479, 19066229, 34189227; Phenotypes: Hydatidiform mole, recurrent, 1 - MIM#231090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11857 | STAR | Zornitza Stark Phenotypes for gene: STAR were changed from to Lipoid adrenal hyperplasia (MIM#201710) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11854 | STAR | Zornitza Stark reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 7892608, 8634702; Phenotypes: Lipoid adrenal hyperplasia (MIM#201710); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11788 | SYCP3 | Zornitza Stark Phenotypes for gene: SYCP3 were changed from to Spermatogenic failure 4, MIM# 270960; Pregnancy loss, recurrent, 4, MIM# 270960 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11784 | SYCP3 | Zornitza Stark reviewed gene: SYCP3: Rating: AMBER; Mode of pathogenicity: None; Publications: 14643120, 19110213, 33170803; Phenotypes: Spermatogenic failure 4, MIM# 270960, Pregnancy loss, recurrent, 4, MIM# 270960; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11764 | TXNRD2 |
Zornitza Stark changed review comment from: Further cases reported in this large cohort of paediatric primary adrenal insufficiency.; to: Further cases reported in this large cohort of paediatric primary adrenal insufficiency. Evidence for association with DCM is limited, considering pop frequency of variants reported. |
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| Mendeliome v0.11753 | SARS2 | Zornitza Stark Phenotypes for gene: SARS2 were changed from to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11750 | SARS2 | Zornitza Stark reviewed gene: SARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33751860; Phenotypes: Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11719 | SARS2 | Samantha Ayres reviewed gene: SARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24034276, 21255763; Phenotypes: Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11680 | USH2A | Belinda Chong reviewed gene: USH2A: Rating: ; Mode of pathogenicity: None; Publications: 12427073, 20507924, 17296898, 19881469, 18273898; Phenotypes: Usher syndrome, type 2A, MIM# 276901, Retinitis pigmentosa 39, MIM#613809; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11677 | USH1G | Belinda Chong reviewed gene: USH1G: Rating: GREEN; Mode of pathogenicity: None; Publications: 12588794, 21044053; Phenotypes: Usher syndrome, type 1G, MIM# 606943; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11665 | UCP3 |
Belinda Chong changed review comment from: Inheritance: Autosomal dominant, autosomal recessive and multifactorial PMID: 21544083 Identified four novel mutations in the UCP3 gene (V56M, A111V, V192I and Q252X) in 200 children with severe, early-onset obesity (body mass index-standard deviation score >2.5; onset: <4 years) living in Southern Italy. Indicated that protein UCP3 affects long-chain fatty acid metabolism and can prevent cytosolic triglyceride storage. Also suggested that telmisartan, which increases fatty acid oxidation in rat skeletal muscle, also improves UCP3 wt and mutant protein activity, including the dominant-negative UCP3 mutants (V56M & Q252X). All variants are present in GnomAD there are 56 - V56M, 325 - A111V, 9 - V192I and 2 - A252X; to: Inheritance: Autosomal dominant, autosomal recessive and multifactorial PMID: 21544083 Identified four novel mutations in the UCP3 gene (V56M, A111V, V192I and Q252X) in 200 children with severe, early-onset obesity (body mass index-standard deviation score >2.5; onset: <4 years) living in Southern Italy. Indicated that protein UCP3 affects long-chain fatty acid metabolism and can prevent cytosolic triglyceride storage. Also suggested that telmisartan, which increases fatty acid oxidation in rat skeletal muscle, also improves UCP3 wt and mutant protein activity, including the dominant-negative UCP3 mutants (V56M & Q252X). Single pathogenic variant in ClinVar All variants are present in GnomAD there are 56 - V56M, 325 - A111V, 9 - V192I and 2 - A252X |
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| Mendeliome v0.11665 | UROD | Belinda Chong reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: 23545314, 30514647, 9792863; Phenotypes: Porphyria cutanea tarda, Porphyria, hepatoerythropoietic (MIM#176100); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11665 | UQCRB | Belinda Chong reviewed gene: UQCRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23281071, 28275242, 12709789, 25446085, 23454382; Phenotypes: Mitochondrial complex III deficiency, nuclear type 3, MIM# 615158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11665 | UQCC2 | Belinda Chong reviewed gene: UQCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24385928, 28804536; Phenotypes: Mitochondrial complex III deficiency, nuclear type 7 - MIM#615824; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11665 | UNG | Belinda Chong reviewed gene: UNG: Rating: GREEN; Mode of pathogenicity: None; Publications: 12958596; Phenotypes: Immunodeficiency with hyper IgM, type 5, MIM#608106; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11665 | UNC13D | Belinda Chong reviewed gene: UNC13D: Rating: GREEN; Mode of pathogenicity: None; Publications: 14622600, 16825436, 17993578; Phenotypes: Hemophagocytic lymphohistiocytosis, familial, 3 MIM#608898; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11662 | C9 | Ain Roesley reviewed gene: C9: Rating: GREEN; Mode of pathogenicity: None; Publications: 9570574, 9703418, 9144525, 31440263, 9634479; Phenotypes: C9 deficiency MIM#613825; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11659 | C8B | Ain Roesley reviewed gene: C8B: Rating: GREEN; Mode of pathogenicity: None; Publications: 8098723, 33563058, 27183977, 9476133, 19434484; Phenotypes: C8 deficiency, type II MIM#613789; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11659 | C8A |
Ain Roesley changed review comment from: 6 unrelated (2 japanese and 4 africans) with 3 different variants between them (2 splice - 1 with aberrant splicing proven on cDNA and 1 nonsense) PMID: 8098723; 3 families hom for a nonsense and 2 families 3rd het for the same nonsense and unknown 2nd allele Amber because no other reports apart from these papers and comprehensive sequencing was not done even in the 2020 paper.; to: 6 unrelated (2 japanese and 4 africans) with 3 different variants between them (2 splice - 1 with aberrant splicing proven on cDNA and 1 nonsense) Amber because no other reports apart from these papers and comprehensive sequencing was not done even in the 2020 paper. |
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| Mendeliome v0.11659 | C8A | Ain Roesley reviewed gene: C8A: Rating: AMBER; Mode of pathogenicity: None; Publications: 9759902, 32769119, 8098723; Phenotypes: C8 deficiency, type I MIM#613790; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11659 | UNC119 | Belinda Chong reviewed gene: UNC119: Rating: GREEN; Mode of pathogenicity: None; Publications: 11006213, 23563732, 27079236; Phenotypes: Cone-rod dystrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11656 | C7 | Ain Roesley reviewed gene: C7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22206826, 20591074, 17407100, 16771861, 16552475; Phenotypes: C7 deficiency MIM#610102; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11652 | C6 | Ain Roesley reviewed gene: C6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23537992, 24378253, 17257682, 22668955, 32670577; Phenotypes: C6 deficiency MIM#612446; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11649 | C5 | Ain Roesley reviewed gene: C5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23743184, 15488949, 15778377, 23371790; Phenotypes: C5 deficiency MIM#609536; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11649 | C4A | Ain Roesley reviewed gene: C4A: Rating: RED; Mode of pathogenicity: None; Publications: 22387014, 22737222, 15998580, 10529130, 15294999; Phenotypes: C4a deficiency MIM#614380, susceptibility systemic lupus erythematosus; Mode of inheritance: Other; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11649 | C4B | Ain Roesley reviewed gene: C4B: Rating: RED; Mode of pathogenicity: None; Publications: 34764957, 12626442, 22387014, 17503323; Phenotypes: susceptibility to autoimmune disease; Mode of inheritance: Other; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11645 | C3 | Ain Roesley reviewed gene: C3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15781264, 1944729, 11813855, 26847111; Phenotypes: C3 deficiency MIM#613779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11600 | VPS33B | Zornitza Stark Phenotypes for gene: VPS33B were changed from to Arthrogryposis, renal dysfunction, and cholestasis 1 (MIM#208085) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11597 | VPS33B | Zornitza Stark reviewed gene: VPS33B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31240160, 31777725, 24415890, 15052268; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 1 (MIM#208085); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11586 | VIPAS39 | Zornitza Stark Phenotypes for gene: VIPAS39 were changed from to Arthrogryposis, renal dysfunction, and cholestasis 2, MIM#613404 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11583 | VIPAS39 | Zornitza Stark reviewed gene: VIPAS39: Rating: GREEN; Mode of pathogenicity: None; Publications: 20190753, 35151346; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 2, MIM#613404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11550 | EDARADD | Bryony Thompson reviewed gene: EDARADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301291, 34219261, 11780064, 26991760, 34573371, 20979233, 17354266, 26440664; Phenotypes: autosomal dominant hypohidrotic ectodermal dysplasia MONDO:0015884, autosomal recessive hypohidrotic ectodermal dysplasia MONDO:0016619; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11547 | EDAR | Bryony Thompson reviewed gene: EDAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 10431241, 20301291, 16435307, 20979233, 23401279, 18384562; Phenotypes: autosomal dominant hypohidrotic ectodermal dysplasia MONDO:0015884, autosomal recessive hypohidrotic ectodermal dysplasia MONDO:0016619; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11540 | NDUFAF4 |
Krithika Murali edited their review of gene: NDUFAF4: Added comment: 3 unrelated families reported with patient-specific functional evidence provided for each. PMID: 32949790 - report two siblings with facial dysmorphism and lactic acidosis diagnosed neonatally with subsequent fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Cerebral white matter anomalies reported in one patient and cardiomyopathy in the other. WES identified homozygous nonsense NDUFAF4 variants with absent NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I–containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network. PMID: 28853723 - report one patient born at 38 weeks after IOL for IUGR. Presented age 7 months with developmental regression, growth failure and central hypotonia. Brain MRI revealed diffuse bilateral signal alterations in the basal ganglia and thalami and an EEG showed generalized slowing with multifocal spikes consistent with an epileptogenic focus. Homozygous missense NDUFAF4 variants identified. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and assembly defect PMID 18179882 - report multiple affected individuals from one family. Most presented soon after birth with severe metabolic acidosis and high plasma lactate levels. Patients who survived longer were repeatedly admitted because of exacerbation of the acidosis during intercurrent infections. One long-term survivor had profound ID.; Changed publications: 32949790, 28853723, 18179882 |
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| Mendeliome v0.11422 | TYRP1 | Manny Jacobs reviewed gene: TYRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9345097; Phenotypes: Albinism, oculocutaneous, type III, MIM# 203290, MONDO:0008747; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11388 | C2 | Ain Roesley reviewed gene: C2: Rating: ; Mode of pathogenicity: None; Publications: 16026838, 8621452, 35272074, 32385807; Phenotypes: C2 deficiency MIM#217000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11386 | C1S | Ain Roesley reviewed gene: C1S: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 30071989, 27745832, 31921203, 19155518, 20191570, 18062908, 11390518, 9856483; Phenotypes: Ehlers-Danlos syndrome, periodontal type, 2 MIM#617174, C1s deficiency MIM#613783; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11384 | C1R | Ain Roesley Phenotypes for gene: C1R were changed from to Ehlers-Danlos syndrome, periodontal type, 1 MIM# 130080 Current Edit | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11382 | C1R | Ain Roesley reviewed gene: C1R: Rating: GREEN; Mode of pathogenicity: None; Publications: 27745832, 28306229; Phenotypes: Ehlers-Danlos syndrome, periodontal type, 1 MIM# 130080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11377 | C1QTNF5 | Ain Roesley reviewed gene: C1QTNF5: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 33949280, 12944416, 30451557, 28939808, : 32036094; Phenotypes: Retinal degeneration, late-onset, autosomal dominant MIM#605670; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11372 | C1QC | Ain Roesley reviewed gene: C1QC: Rating: GREEN; Mode of pathogenicity: None; Publications: 21654842, 8630118, 24157463; Phenotypes: C1q deficiency MIM#613652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11365 | C1QB | Ain Roesley reviewed gene: C1QB: Rating: GREEN; Mode of pathogenicity: None; Publications: 2894352, 17513176; Phenotypes: C1q deficiency, MIM# 613652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11360 | C1GALT1C1 | Ain Roesley reviewed gene: C1GALT1C1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18537974, 16251947; Phenotypes: Tn polyagglutination syndrome, somatic MIM#300622; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11358 | C12orf57 | Ain Roesley reviewed gene: C12orf57: Rating: GREEN; Mode of pathogenicity: None; Publications: 29383837, 31853307; Phenotypes: Temtamy syndrome MIM#218340; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11354 | C12orf4 | Ain Roesley reviewed gene: C12orf4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34967075, 31334606, 27311568, 25558065, 28097321; Phenotypes: Intellectual developmental disorder, autosomal recessive 66 MIM#618221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11304 | ECHS1 | Bryony Thompson reviewed gene: ECHS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33528536, 34364746, 32858208, 31399326, 25125611, 25393721, 32677093; Phenotypes: Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, MIM# 616277, Leigh syndrome MONDO:0009723, cerebral palsy MONDO:0006497, paroxysmal dystonia MONDO:0016058; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11301 | ARHGAP35 | Ain Roesley reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11298 | KHDC3L | Zornitza Stark Phenotypes for gene: KHDC3L were changed from to Hydatiform mold recurrent 2, MIM#614293 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11295 | KHDC3L | Zornitza Stark reviewed gene: KHDC3L: Rating: GREEN; Mode of pathogenicity: None; Publications: 23232697, 31847873, 23125094, 21885028; Phenotypes: Hydatiform mold recurrent 2 MIM#614293; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11295 | KIAA1109 |
Zornitza Stark changed review comment from: ALKKUCS is an autosomal recessive severe neurodevelopmental disorder characterized by arthrogryposis, brain abnormalities associated with cerebral parenchymal underdevelopment, and global developmental delay. Most affected individuals die in utero or soon after birth. Additional abnormalities may include hypotonia, dysmorphic facial features, and involvement of other organ systems, such as cardiac or renal. The few patients who survive have variable intellectual disability and may have seizures.; to: ALKKUCS is an autosomal recessive severe neurodevelopmental disorder characterized by arthrogryposis, brain abnormalities associated with cerebral parenchymal underdevelopment, and global developmental delay. Most affected individuals die in utero or soon after birth. Additional abnormalities may include hypotonia, dysmorphic facial features, and involvement of other organ systems, such as cardiac or renal. The few patients who survive have variable intellectual disability and may have seizures. More than 10 families reported. |
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| Mendeliome v0.11268 | TLN1 |
Bryony Thompson gene: TLN1 was added gene: TLN1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TLN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TLN1 were set to 30888838 Phenotypes for gene: TLN1 were set to idiopathic spontaneous coronary artery dissection MONDO:0007385 Review for gene: TLN1 was set to AMBER Added comment: 10 unique rare heterozygous missense variants in 11 individuals were identified in a 2 generation SCAD family and 56 unrelated individuals with sporadic SCAD. All variants had a MAF of less than 0.06% and occurred within highly conserved β-integrin, F-actin, or vinculin binding domains. Incomplete penetrance was evident in the familial case and five individuals with sporadic SCAD from whom parental DNA was available. No functional assays were conducted. Sources: Literature |
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| Mendeliome v0.11199 | PNPLA3 | Paul De Fazio reviewed gene: PNPLA3: Rating: RED; Mode of pathogenicity: None; Publications: 18820647; Phenotypes: Susceptibility to nonalcoholic fatty liver disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11186 | EARS2 | Bryony Thompson reviewed gene: EARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22492562, 23008233, 25854774, 26619324, 26893310, 27206875, 27571996, 27117034; Phenotypes: Leigh syndrome MONDO:0009723, Combined oxidative phosphorylation deficiency 12 MIM#614924, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome MONDO:0013971; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11169 | KYNU | Zornitza Stark Phenotypes for gene: KYNU were changed from to Hydroxykynureninuria MIM#236800; Vertebral, cardiac, renal, and limb defects syndrome 2 MIM#617661; Disorders of histidine, tryptophan or lysine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11117 | RRM2B | Zornitza Stark Phenotypes for gene: RRM2B were changed from Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) MIM#612075; Mitochondrial DNA depletion syndrome 8B (MNGIE type) MIM#612075 to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) MIM#612075; Mitochondrial DNA depletion syndrome 8B (MNGIE type) MIM#612075; Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction, MIM# 268315 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11115 | RRM2B | Zornitza Stark reviewed gene: RRM2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32827185; Phenotypes: Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction, MIM# 268315; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11109 | HIST1H4E |
Paul De Fazio changed review comment from: 17 patients identified with de novo missense variants affecting Lys31, Pro32, Arg35, Leu37, Arg40 (recurrent), Arg45 (recurrent), Tyr98 (recurrent). All individuals had ID/dev delay. Additional phenotypes in some but not all individuals included epilepsy, hypotonia, facial dysmorphism. Most had reduced birth length, OFC, weight (-1 to -3SD). A zebrafish model has developmental defects. Sources: Literature; to: HGNC recognised gene: H4C5 17 patients identified with de novo missense variants affecting Lys31, Pro32, Arg35, Leu37, Arg40 (recurrent), Arg45 (recurrent), Tyr98 (recurrent). All individuals had ID/dev delay. Additional phenotypes in some but not all individuals included epilepsy, hypotonia, facial dysmorphism. Most had reduced birth length, OFC, weight (-1 to -3SD). A zebrafish model has developmental defects. Sources: Literature |
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| Mendeliome v0.11103 | HIST1H4E |
Paul De Fazio gene: HIST1H4E was added gene: HIST1H4E was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HIST1H4E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HIST1H4E were set to 35202563 Phenotypes for gene: HIST1H4E were set to Neurodevelopmental disorder, HIST1H4E-related MONDO:0700092 Review for gene: HIST1H4E was set to GREEN gene: HIST1H4E was marked as current diagnostic Added comment: 17 patients identified with de novo missense variants affecting Lys31, Pro32, Arg35, Leu37, Arg40 (recurrent), Arg45 (recurrent), Tyr98 (recurrent). All individuals had ID/dev delay. Additional phenotypes in some but not all individuals included epilepsy, hypotonia, facial dysmorphism. Most had reduced birth length, OFC, weight (-1 to -3SD). A zebrafish model has developmental defects. Sources: Literature |
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| Mendeliome v0.11103 | HIST1H4D |
Paul De Fazio gene: HIST1H4D was added gene: HIST1H4D was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HIST1H4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HIST1H4D were set to 35202563 Phenotypes for gene: HIST1H4D were set to Neurodevelopmental disorder, HIST1H4D-related MONDO:0700092 Review for gene: HIST1H4D was set to AMBER gene: HIST1H4D was marked as current diagnostic Added comment: Single individual described with a de novo missense variant Arg41His (Arg40 in H4 nomenclature). Apart from language delay and moderate ID, phenotypes included facial dysmorphisms and cochlear abnormalities and arhinencephaly on MRI. Hearing was normal. Birth length, OFC, weight were all reduced (-2 to -2.5SD). A zebrafish model has developmental defects. Sources: Literature |
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| Mendeliome v0.11101 | HIST1H4C | Paul De Fazio reviewed gene: HIST1H4C: Rating: GREEN; Mode of pathogenicity: None; Publications: 35202563; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1 MIM#619758, Neurodevelopmental disorder MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11099 | CPSF3 |
Belinda Chong gene: CPSF3 was added gene: CPSF3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CPSF3 were set to 35121750 Phenotypes for gene: CPSF3 were set to Intellectual disability syndrome Review for gene: CPSF3 was set to GREEN Added comment: study of a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes Six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. - Four identified through Icelandic geneology (p.Gly468Glu), three carrier couples total of four children who had died prematurely. Tested archival samples for two of these children, and confirm a homozygous genotype. - Two of Mexican descent (p.Ile354Thr), first-degree cousins Sources: Literature |
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| Mendeliome v0.11099 | ZBTB11 | Chern Lim reviewed gene: ZBTB11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:35104841; Phenotypes: Intellectual developmental disorder, autosomal recessive 69 (MIM#618383), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11095 | NRCAM |
Ee Ming Wong gene: NRCAM was added gene: NRCAM was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NRCAM were set to PMID: 35108495 Phenotypes for gene: NRCAM were set to neurodevelopmental disorder, MONDO:0700092 Penetrance for gene: NRCAM were set to unknown Review for gene: NRCAM was set to GREEN gene: NRCAM was marked as current diagnostic Added comment: -Ten individuals from 8 families with developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. - Affected individuals are biallelic for missense and/or LoF variants which are mainly in the fibronectin type III (Fn-III) domain - Zebrafish mutants lacking the third Fn-III domain displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03) and a trend toward increased amounts of alpha-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections Sources: Literature |
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| Mendeliome v0.11092 | ATP6V0A1 | Chern Lim reviewed gene: ATP6V0A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:34909687; Phenotypes: Neurodevelopmental disorder MONDO:0700092, ATP6V0A1-associated; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11089 | EHD1 |
Zornitza Stark gene: EHD1 was added gene: EHD1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EHD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EHD1 were set to 35149593 Phenotypes for gene: EHD1 were set to Inherited renal tubular disease, MONDO:0015962, EHD1-related Review for gene: EHD1 was set to AMBER Added comment: Six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit reported with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Single founder variant but two animal models, hence Amber Sources: Literature |
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| Mendeliome v0.11088 | IL6ST | Zornitza Stark Phenotypes for gene: IL6ST were changed from Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann syndrome 2, MIM# 619751: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response; Hyper-IgE syndrome, autosomal dominant; Immunodeficiency 94 with autoinflammation and dysmorphic facies, MIM# 619750 to Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann syndrome 2, MIM# 619751: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response; Hyper-IgE recurrent infection syndrome 4A, autosomal dominant, MIM# 619752; Immunodeficiency 94 with autoinflammation and dysmorphic facies, MIM# 619750 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11087 | IL6ST | Zornitza Stark Phenotypes for gene: IL6ST were changed from Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann syndrome 2, MIM# 619751: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response; Hyper-IgE syndrome, autosomal dominant to Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann syndrome 2, MIM# 619751: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response; Hyper-IgE syndrome, autosomal dominant; Immunodeficiency 94 with autoinflammation and dysmorphic facies, MIM# 619750 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11086 | IL6ST | Zornitza Stark edited their review of gene: IL6ST: Changed phenotypes: Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523, Stuve-Wiedemann syndrome 2, MIM# 619751: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response, Hyper-IgE syndrome, autosomal dominant, Immunodeficiency 94 with autoinflammation and dysmorphic facies, MIM# 619750 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11081 | RECQL4 | Seb Lunke reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Baller-Gerold syndrome, MIM# 218600, RAPADILINO syndrome, MIM# 266280, Rothmund-Thomson syndrome, type 2,MIM# 268400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11078 | AP3D1 | Zornitza Stark edited their review of gene: AP3D1: Added comment: Now four affected individuals from two unrelated families, with a mouse model that recapitulates the human phenotype.; Changed rating: GREEN; Changed publications: 26744459, 9697856, 30472485; Changed phenotypes: Hermansky-Pudlak syndrome 10, MIM# 617050, Oculocutaneous albinism, Severe neutropaenia, Recurrent infections, Seizures, Hearing loss, Neurodevelopmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11076 | PPP2R3C |
Zornitza Stark gene: PPP2R3C was added gene: PPP2R3C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PPP2R3C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPP2R3C were set to 30893644; 34714774; 34750818 Phenotypes for gene: PPP2R3C were set to Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, OMIM # 618419 Review for gene: PPP2R3C was set to GREEN Added comment: Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy (GDRM) is characterized by 46,XY complete gonadal dysgenesis in association with extragonadal anomalies, low birth weight, typical facial gestalt, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. 11 unrelated families with syndromic complete gonadal dysgenesis. 9 families had 46,XY females with complete gonadal dysgenesis, but 2 families had 46,XX patients with hypergonadotropic hypogonadism, nonvisualized gonads, primary amenorrhea, and absence of secondary sexual characteristics. Variants segregated with disease in each family and were not found in ethnically matched controls or in public variant databases. The heterozygous fathers exhibited morphologic abnormalities of spermatozoa and reduced fertility. Sources: Literature |
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| Mendeliome v0.11075 | CDX2 | Zornitza Stark Phenotypes for gene: CDX2 were changed from Persistent cloaca to Genetic multiple congenital anomalies/dysmorphic syndrome, MONDO:0043005; Congenital abnormalities of anus, renal and urogenital system, vertebrae and/or the limbs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11071 | CDX2 | Chirag Patel edited their review of gene: CDX2: Added comment: 9 families, with heterozygous variants identified with WES, presenting with congenital abnormalities affecting the development of the anus, the renal and urogenital system, the vertebrae and/or the limbs in varying sequences and severity (incl. sirenomelia and persistent cloaca). A recurrent pathogenic missense variant in the HOX domain of the protein p.(Arg237His) was found in 3 unrelated families. In the mouse cdx2 is essential for anteroposterior patterning of embryonal axis and morphogenesis of cloacal structures. Cdx2 heterozygous conditional mutant mice show a variable phenotype (including imperforate anus, sirenomelia, posterior vertebral truncations, and bladder anomalies).; Changed rating: GREEN; Changed publications: PMID: 29177441, 34671974; Changed phenotypes: Congenital abnormalities of anus, renal and urogenital system, vertebrae and/or the limbs; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11071 | CHKA |
Konstantinos Varvagiannis gene: CHKA was added gene: CHKA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHKA were set to 35202461 Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature Penetrance for gene: CHKA were set to Complete Review for gene: CHKA was set to GREEN Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants. Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6. Eventual previous genetic testing was not discussed. Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies. Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype. 3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2): - c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families], - c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents], - c.2T>C/p.(Met1?) [1 hmz individual born to related parents], - c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual. CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes. CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP. As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants]. Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc. CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect. In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine). Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively). NMD is thought to underly the deleterious effect of the frameshift one (not studied). The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein. Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714). There is no associated phenotype in OMIM, Gene2Phenotype or SysID. Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset). Sources: Literature |
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| Mendeliome v0.11058 | HSF2BP | Zornitza Stark edited their review of gene: HSF2BP: Added comment: An additional two patients are described with homozygous missense variants, with supportive in vitro functional assay. PMID: 35174157 Now there are 5 affected patients from three independent families and three different biallelic missense variants associated with the condition.; Changed rating: GREEN; Changed publications: 32845237, 35174157 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11058 | SLC22A4 | Ain Roesley reviewed gene: SLC22A4: Rating: RED; Mode of pathogenicity: None; Publications: 15184985, 24972750; Phenotypes: susceptibility to rheumatoid arthritis MIM#180300; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11047 | RRM2B | Zornitza Stark Phenotypes for gene: RRM2B were changed from to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) MIM#612075; Mitochondrial DNA depletion syndrome 8B (MNGIE type) MIM#612075 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11020 | OGG1 | Zornitza Stark Phenotypes for gene: OGG1 were changed from to Renal cell carcinoma, clear cell, somatic MIM#144700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11011 | TBC1D24 | Ain Roesley reviewed gene: TBC1D24: Rating: GREEN; Mode of pathogenicity: None; Publications: 25719194; Phenotypes: Deafness, autosomal dominant 65 MIM#616044, Deafness, autosomal recessive 86 MIM#614617, Developmental and epileptic encephalopathy 16 MIM#615338, DOORS syndrome MIM#220500, Epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp MIM#608105, Myoclonic epilepsy, infantile, familial MIM#605021; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11011 | SUCLG1 | Ain Roesley reviewed gene: SUCLG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33230783, 28358460; Phenotypes: Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) MIM#245400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11011 | RUNX2 | Ain Roesley reviewed gene: RUNX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301686; Phenotypes: Cleidocranial dysplasia MIM#119600, Cleidocranial dysplasia, forme fruste, dental anomalies only MIM#119600, Cleidocranial dysplasia, forme fruste, with brachydactyly MIM#119600, Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly MIM#156510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11011 | RRM2B | Ain Roesley reviewed gene: RRM2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 24741716; Phenotypes: Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) MIM#612075, Mitochondrial DNA depletion syndrome 8B (MNGIE type) MIM#612075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11011 | RNASET2 | Ain Roesley reviewed gene: RNASET2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31349848, 19525954, 27091087, 29336640, 18545798, 15851732; Phenotypes: Leukoencephalopathy, cystic, without megalencephaly MIM#612951; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11009 | RNASEH2A | Ain Roesley reviewed gene: RNASEH2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 15870678, 25604658, 23592335, 20301648; Phenotypes: Aicardi-Goutieres syndrome 4 MIM#610333; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11009 | IL6ST | Zornitza Stark Phenotypes for gene: IL6ST were changed from Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response; Hyper-IgE syndrome, autosomal dominant to Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann syndrome 2, MIM# 619751: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response; Hyper-IgE syndrome, autosomal dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11008 | IL6ST | Zornitza Stark edited their review of gene: IL6ST: Changed phenotypes: Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523, Stuve-Wiedemann syndrome 2, MIM# 619751: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response, Hyper-IgE syndrome, autosomal dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11004 | SPATA16 | Paul De Fazio reviewed gene: SPATA16: Rating: AMBER; Mode of pathogenicity: None; Publications: 17847006, 27086357, 29065458; Phenotypes: ?Spermatogenic failure 6 MIM#102530, Spermatogenic failure 6 MONDO:0007060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11004 | TNFRSF10B | Paul De Fazio reviewed gene: TNFRSF10B: Rating: RED; Mode of pathogenicity: None; Publications: 9721851; Phenotypes: Squamous cell carcinoma, head and neck MIM#275355; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11004 | MAPK8IP1 | Paul De Fazio reviewed gene: MAPK8IP1: Rating: RED; Mode of pathogenicity: None; Publications: 10700186; Phenotypes: Susceptibility to diabetes mellitus, noninsulin-dependent MIM#125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11004 | SMIM1 | Paul De Fazio reviewed gene: SMIM1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Blood group, Vel system MIM#615264; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11004 | ACKR1 | Paul De Fazio reviewed gene: ACKR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Blood group, Duffy system MIM#110700; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11004 | OGG1 | Paul De Fazio reviewed gene: OGG1: Rating: RED; Mode of pathogenicity: None; Publications: 10987279, 29305130; Phenotypes: Renal cell carcinoma, clear cell, somatic MIM#144700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11004 | B3GALNT1 | Paul De Fazio reviewed gene: B3GALNT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Blood group, globoside system MIM#615021; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11004 | SERPINA7 | Paul De Fazio reviewed gene: SERPINA7: Rating: GREEN; Mode of pathogenicity: None; Publications: 34126618, 32266677, 17887925, 28553659, 29733970, 16947003; Phenotypes: Thyroxine-binding globulin QTL MIM#300932, Thyroxine-binding globulin deficiency; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10999 | TBK1 | Chern Lim reviewed gene: TBK1: Rating: RED; Mode of pathogenicity: None; Publications: 25803835, 26581300; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (MIM#616439), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10992 | DLD | Belinda Chong reviewed gene: DLD: Rating: GREEN; Mode of pathogenicity: None; Publications: 3769994, 8506365, 9934985, 17404228, 21558426, 21930696; Phenotypes: Dihydrolipoamide dehydrogenase deficiency MIM#246900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10953 | FUZ |
Ain Roesley gene: FUZ was added gene: FUZ was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FUZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FUZ were set to 21840926 Phenotypes for gene: FUZ were set to {Neural tube defects, susceptibility to} MIM#182940 Penetrance for gene: FUZ were set to unknown Review for gene: FUZ was set to RED gene: FUZ was marked as current diagnostic Added comment: Spina bifida cohort. Negative for VANGL1 and VANGL2, only FUZ was sequenced. Variants identified in 5 individuals. Arg404Gln (39 hets in gnomAD) and Asp354Tyr (6 hets in gnomAD). These variants are listed as risk factor in ClinVar Pro39Ser (absent in gnomAD) was de novo by parental sanger and showed reduced cell mobility on scratch assays. 2 other variants Gly140Glu and Ser142Thr were deemed non-causative due to poor in silicos and conservation Finally, hom KO mouse models were done to prove neural tube defects Sources: Literature |
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| Mendeliome v0.10953 | FTSJ1 | Ain Roesley reviewed gene: FTSJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15342698, 18081026, 15162322, 26310293; Phenotypes: Intellectual developmental disorder, X-linked 9 MIM#309549; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10953 | FLAD1 | Ain Roesley reviewed gene: FLAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34454814, 34718578, 31392824, 30982706, 30311138, 30427553, 28433476, 27259049, 25058219; Phenotypes: Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency MIM#255100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10953 | FGF17 |
Ain Roesley changed review comment from: 31200363; 1x individual 31748124 3x unrelated individuals. 1 has p.48_52del and another variant in OTUD4 (no current mendelian disease association), 1x with Pro120Leu (5 hets in gnomAD) and 1x with Lys191Arg (55 hets in gnomad) 23643382 3x unrelated individuals, including 1 large consanguineous 10-generation French Canadian family. In this large family, 3 other variants in FGFR1, HS6ST1, and FLRT3 were identified. None of the other affecteds carried the FGF17 variant Summary: 3x individuals with convincing evidence; to: PMID:31200363; 1x individual PMID:31748124 3x unrelated individuals. 1 has p.48_52del and another variant in OTUD4 (no current mendelian disease association), 1x with Pro120Leu (5 hets in gnomAD) and 1x with Lys191Arg (55 hets in gnomad) PMID:23643382 3x unrelated individuals, including 1 large consanguineous 10-generation French Canadian family. In this large family, 3 other variants in FGFR1, HS6ST1, and FLRT3 were identified. None of the other affecteds carried the FGF17 variant Summary: 3x individuals with convincing evidence |
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| Mendeliome v0.10953 | FGF17 | Ain Roesley reviewed gene: FGF17: Rating: GREEN; Mode of pathogenicity: None; Publications: 31200363, 31748124, 23643382; Phenotypes: Hypogonadotropic hypogonadism 20 with or without anosmia MIM#615270; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10953 | ZFYVE26 | Ain Roesley reviewed gene: ZFYVE26: Rating: GREEN; Mode of pathogenicity: None; Publications: 34057829; Phenotypes: Spastic paraplegia 15, autosomal recessive MIM#270700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10953 | ZDHHC9 | Ain Roesley reviewed gene: ZDHHC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26000327, 29681091; Phenotypes: Mental retardation, X-linked syndromic, Raymond typeMIM# 300799; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10945 | BCO1 | Ain Roesley reviewed gene: BCO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10945 | PRKCH | Ain Roesley reviewed gene: PRKCH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10945 | ALDH2 | Ain Roesley reviewed gene: ALDH2: Rating: RED; Mode of pathogenicity: None; Publications: 31368097; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10940 | CPS1 | Belinda Chong reviewed gene: CPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8486760, 17310273, 21120950; Phenotypes: Carbamoylphosphate synthetase I deficiency MIM#237300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10938 | THUMPD1 |
Chern Lim gene: THUMPD1 was added gene: THUMPD1 was added to Mendeliome. Sources: Other Mode of inheritance for gene: THUMPD1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: THUMPD1 were set to Syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss and facial dysmorphism, AR Review for gene: THUMPD1 was set to GREEN gene: THUMPD1 was marked as current diagnostic Added comment: Broly, M. et al. (2022) manuscript accepted in AJHG: - 13 individuals from 8 families, loss of function variants (PTVs, one missense, one single AA del). - Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism and ophthalmological abnormalities. Sources: Other |
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| Mendeliome v0.10923 | RAB39B | Ain Roesley reviewed gene: RAB39B: Rating: GREEN; Mode of pathogenicity: None; Publications: 34761259, 20159109, 25434005, 27066548, 26399558, 27943471, 28851564, 28851564, 29152164, 33880059, 27448726, 32670181; Phenotypes: Intellectual developmental disorder, X-linked 72 MIM#300271, Waisman syndrome MIM#311510; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10923 | PTCHD1 | Ain Roesley reviewed gene: PTCHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33856728, 25131214; Phenotypes: intellectual disability MIM#300830; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10923 | PRSS12 | Ain Roesley reviewed gene: PRSS12: Rating: RED; Mode of pathogenicity: None; Publications: 12459588, 22090715, 23344636; Phenotypes: Intellectual disability, PRSS12 related MIM#249500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10923 | PPP3CA | Chern Lim reviewed gene: PPP3CA: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 29432562, 32593294; Phenotypes: Developmental and epileptic encephalopathy 91, MIM#617711, Arthrogryposis, cleft palate, craniosynostosis and impaired intellectual development, MIM#618265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10923 | PLP1 | Ain Roesley reviewed gene: PLP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301361; Phenotypes: Pelizaeus-Merzbacher disease MIM#312080, Spastic paraplegia 2, X-linked MIM#312920; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10923 | LDB3 | Ain Roesley reviewed gene: LDB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26419279, 16427346, 14660611, 14662268, 27546599, 25911362; Phenotypes: Cardiomyopathy, dilated, 1C, with or without LVNC MIM#601493, Cardiomyopathy, hypertrophic, 24 MIM#601493, Left ventricular noncompaction 3 MIM#601493, Myopathy, myofibrillar, 4 MIM#609452; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10907 | ARR3 |
Bryony Thompson gene: ARR3 was added gene: ARR3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARR3 was set to Other Publications for gene: ARR3 were set to 27829781; 35001458 Phenotypes for gene: ARR3 were set to Myopia 26, X-linked, female-limited MIM#301010 Review for gene: ARR3 was set to GREEN Added comment: At least 6 multi-generational families with female-limited early-onset high myopia. Only female carriers are affected and hemizygous males are unaffected. Authors hypothesise the mode of inheritance might be explained by metabolic interference due to X-inactivation. Sources: Literature |
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| Mendeliome v0.10863 | MVD | Paul De Fazio reviewed gene: MVD: Rating: RED; Mode of pathogenicity: None; Publications: 34135477; Phenotypes: Nonsyndromic genetic hearing loss MONDO:0019497, MVD-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10853 | MPDZ | Paul De Fazio reviewed gene: MPDZ: Rating: AMBER; Mode of pathogenicity: None; Publications: 34135477, 29026089; Phenotypes: Nonsyndromic genetic hearing loss MONDO:0019497, MPDZ-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10850 | DHDDS | Chern Lim reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34382076; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10849 | ITSN1 | Ee Ming Wong reviewed gene: ITSN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34707297; Phenotypes: neurodevelopmental disorder MONDO:0700092, ITSN1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10849 | SEZ6 |
Paul De Fazio gene: SEZ6 was added gene: SEZ6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEZ6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEZ6 were set to 34135477 Phenotypes for gene: SEZ6 were set to Nonsyndromic genetic hearing loss MONDO:0019497, SEZ6-related Review for gene: SEZ6 was set to RED gene: SEZ6 was marked as current diagnostic Added comment: Homozygous missense variant p.(Val698Ile) identified in 4 affected individuals from a single consanguineous Pakistani family by WES. 5 other genotyped unaffected individuals were heterozygous or homozygous wild-type. Variant is in gnomad (36 hets, 0 hom). RNA expression studies show the gene is expressed in the mouse inner ear, but no functional studies were performed on the variant (in silico analysis only). Sources: Literature |
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| Mendeliome v0.10847 | OBSCN | Ee Ming Wong reviewed gene: OBSCN: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34957489; Phenotypes: Rhabdomyolysis MONDO:0005290, OBSCN-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10846 | ADAMTS1 |
Paul De Fazio gene: ADAMTS1 was added gene: ADAMTS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ADAMTS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAMTS1 were set to 34135477 Phenotypes for gene: ADAMTS1 were set to Nonsyndromic genetic hearing loss MONDO:0019497, ADAMTS1-related Review for gene: ADAMTS1 was set to RED gene: ADAMTS1 was marked as current diagnostic Added comment: Homozygous missense variant p.(Ser135Ala) identified in 3 affected siblings from a single consanguineous Pakistani family by WES. A fourth unaffected sibling was homozygous wild type. Variant is in gnomad (26 hets, 1 hom). RNA expression studies show the gene is expressed in the mouse inner ear, but no functional studies were performed on the variant (in silico analysis only). Sources: Literature |
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| Mendeliome v0.10844 | ATP5O |
Ain Roesley gene: ATP5O was added gene: ATP5O was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP5O was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATP5O were set to 34954817 Phenotypes for gene: ATP5O were set to mitochondrial disease, ATP5F1E-related MONDO:0044970 Penetrance for gene: ATP5O were set to Complete Review for gene: ATP5O was set to RED gene: ATP5O was marked as current diagnostic Added comment: Now known as ATP5PO (HGNC) 1 compound het individual with dev delay, muscular hypotonia, ID, dystonia, seizures and neurologic regression Sources: Literature |
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| Mendeliome v0.10844 | ATP5E | Ain Roesley reviewed gene: ATP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 MIM#614053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10836 | TMEM53 |
Lucy Spencer gene: TMEM53 was added gene: TMEM53 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM53 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM53 were set to PMID: 33824347 Phenotypes for gene: TMEM53 were set to Sclerosing bone disorder, macrocephaly, impaired vision, short stature Review for gene: TMEM53 was set to GREEN Added comment: PMID: 33824347- Previously unknown type of sclerosing bone disorder in 4 independent families, bi-allelic LOF variants in TMEM53. 5 individuals from 4 families, all have proportional or short limbed stature, not identifiable at birth. Head deformities (macrocephaly, dolichocephaly, prominent forehead), epicanthic folds, thick vermilion of upper and lower lips. Vision diminished after early childhood due to optic nerve compression. 3 of 4 families confirmed consanguineous, and all affected members from all 4 families have homozygous variants inherited from heterozygous parents. 3 families have the same splicing variant proven to cause exon 2 skipping and an NMD frameshift by RT-PCR. The other family has a an NMD frameshift variant. So 4 families but only 2 variants. Sources: Literature |
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| Mendeliome v0.10836 | SLC38A3 |
Ain Roesley gene: SLC38A3 was added gene: SLC38A3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC38A3 were set to 34605855 Phenotypes for gene: SLC38A3 were set to developmental epileptic encephalopathy, SLC38A3-related MONDO:0100062 Review for gene: SLC38A3 was set to GREEN gene: SLC38A3 was marked as current diagnostic Added comment: 7 families 6 of whom are consanguineous but unique variants in all of them Acquired microcephaly noted (8/10 with <-2 SD, 5/10 <-3 SD) 10/10 with axial hopotonia, absent speech, GDD/ID 9/10 with visual impairment 8/10 with seizures 8/10 with peripheral hypertonia Sources: Literature |
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| Mendeliome v0.10835 | MAN2C1 |
Michelle Torres gene: MAN2C1 was added gene: MAN2C1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAN2C1 were set to 35045343 Phenotypes for gene: MAN2C1 were set to neurodevelopmental disorder MONDO:0700092 MAN2C1-related Review for gene: MAN2C1 was set to GREEN Added comment: Six individuals from four different families, including two fetuses, exhibiting dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Variants include PTC and missense. Sources: Literature |
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| Mendeliome v0.10835 | ARSK |
Paul De Fazio gene: ARSK was added gene: ARSK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARSK were set to 34916232; 32856704 Phenotypes for gene: ARSK were set to Mucopolysaccharidosis Review for gene: ARSK was set to GREEN gene: ARSK was marked as current diagnostic Added comment: 4 individuals from 2 unrelated consanguineous families (Turkish and Indian) reported with a homozygous missense and an NMD-predicted nonsense variant. Affected individuals had features of mucopolysaccharidosis such as short stature, coarse facial features and dysostosis multiplex. Urinary GAG excretion was normal by conventional methods, but LC-MS/MS in 2 individuals revealed an increase in specific dermatan sulfate-derived disaccharides. Functional studies showed reduced protein levels and reduced enzyme activity for the nonsense and missense variant respectively. A mouse model also shows a mucopolysaccharidosis phenotype, albeit milder. Rated green (2 families, functional evidence, mouse model). Sources: Literature |
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| Mendeliome v0.10826 | LRPPRC | Zornitza Stark Phenotypes for gene: LRPPRC were changed from to Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) MIM#220111 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10823 | LRPPRC | Zornitza Stark reviewed gene: LRPPRC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) MIM#220111; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10823 | PLCD1 | Paul De Fazio reviewed gene: PLCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21665001, 22458588, 21665001, 30003652, 33786625, 31082376, 32265483, 31049339; Phenotypes: Nail disorder, nonsyndromic congenital, 3, (leukonychia) MIM#151600, nonsyndromic congenital nail disorder 3 MONDO:0007900; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10823 | AKAP10 | Paul De Fazio reviewed gene: AKAP10: Rating: RED; Mode of pathogenicity: None; Publications: 12646697, 17485678; Phenotypes: {Cardiac conduction defect, susceptibility to} MIM#115080, sudden cardiac arrest MONDO:0007264; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10823 | HMCN1 | Paul De Fazio reviewed gene: HMCN1: Rating: RED; Mode of pathogenicity: None; Publications: 25986072, 16020313, 14570714, 27007659; Phenotypes: {Macular degeneration, age-related, 1} MIM#603075, age related macular degeneration 1 MONDO:0011285; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10823 | CCND1 | Paul De Fazio reviewed gene: CCND1: Rating: RED; Mode of pathogenicity: None; Publications: 12097293, 23502783, 21131975, 14657069, 23540573, 20633772; Phenotypes: {Colorectal cancer, susceptibility to} MIM#114500, {Multiple myeloma, susceptibility to} MIM#254500, {von Hippel-Lindau syndrome, modifier of} MIM#193300; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10823 | PADI4 | Paul De Fazio reviewed gene: PADI4: Rating: RED; Mode of pathogenicity: None; Publications: 16449362, 19470526, 26474773; Phenotypes: Susceptibility to rheumatoid arthritis; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10813 | PDSS2 | Ain Roesley reviewed gene: PDSS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29032433, 25349199, 17186472, 21723727, 10972372; Phenotypes: Coenzyme Q10 deficiency, primary, 3 MIM#614652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | PDHX | Ain Roesley reviewed gene: PDHX: Rating: ; Mode of pathogenicity: None; Publications: 20002125, 34873726, 33092611, 30981218, 25087164, 22766002; Phenotypes: Lacticacidemia due to PDX1 deficiency MIM#245349; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | NDUFV1 | Ain Roesley reviewed gene: NDUFV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34807224; Phenotypes: Mitochondrial complex I deficiency, nuclear type 4 MIM#618225; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | NDUFS8 | Ain Roesley reviewed gene: NDUFS8: Rating: GREEN; Mode of pathogenicity: None; Publications: 23430795, 9837812, 15159508, 22499348, 20818383, 20819849; Phenotypes: Mitochondrial complex I deficiency, nuclear type 2 MIM#618222; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | NDUFS7 | Ain Roesley reviewed gene: NDUFS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 17604671, 17275378, 10360771; Phenotypes: Mitochondrial complex I deficiency, nuclear type 3 MIM#618224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | NDUFAF5 | Ain Roesley reviewed gene: NDUFAF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 34797029; Phenotypes: Mitochondrial complex I deficiency, nuclear type 3 MIM#618224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | NDUFS7 | Ain Roesley reviewed gene: NDUFS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 34797029; Phenotypes: Mitochondrial complex I deficiency, nuclear type 3 MIM#618224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | NDUFA1 | Ain Roesley reviewed gene: NDUFA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29506883, 19185523, 17262856, 21596602; Phenotypes: Mitochondrial complex I deficiency, nuclear type 12 MIM#301020; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | MYO5A | Ain Roesley reviewed gene: MYO5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32275080, 22711375, 25283056; Phenotypes: Griscelli syndrome, type 1 MIM#214450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | LRPPRC | Ain Roesley reviewed gene: LRPPRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32972427, 26510951, 21266382; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) MIM#220111; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10812 | LEMD3 | Ain Roesley reviewed gene: LEMD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34098227, 33598273, 32519343, 32151766, 32151766; Phenotypes: Buschke-Ollendorff syndrome MIM#166700, Osteopoikilosis with or without melorheostosis MIM#166700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10795 | ACP5 | Alison Yeung reviewed gene: ACP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 26854080, 26951490, 21217755, 26789720, 2363422, 21217752; Phenotypes: spondyloenchondrodysplasia with immune dysregulation, OMIM# 607944; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10793 | CHP1 |
Zornitza Stark gene: CHP1 was added gene: CHP1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CHP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHP1 were set to 29379881; 32787936 Phenotypes for gene: CHP1 were set to Spastic ataxia 9, autosomal recessive, MIM #618438 Review for gene: CHP1 was set to GREEN Added comment: 2 different consanguineous families with 2 affected siblings with ataxia (1 paediatric onset, 1 adult onset). 3 of the patients had cerebellar atrophy. WES identified homozygous variants in CHP1 gene in both families (K19del and Arg91Cys), which segregated with the disorder in the family. Decreased CHP1 protein on IHC of cerebellar tissue in family with Arg91Cys variant. In vitro functional expression studies in HEK293 cells showed that the K19del mutation resulted in decreased protein expression, with normal levels of transcript, suggesting defects in protein stability. The mutant protein formed massive protein aggregates in transfected neuronal cell bodies and neurite-like projections, whereas the wildtype protein showed a more uniform distribution. The mutant protein altered CHP1 association into functional complexes and impaired membrane localization of the Na+/H+ transporter NHE1. The findings indicated that the CHP1 mutation likely causes ataxia in an NHE1-dependent manner, resembling the mechanism observed in the Chp1 vacillator mutant mouse. Sources: Expert Review |
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| Mendeliome v0.10760 | AGR2 |
Zornitza Stark gene: AGR2 was added gene: AGR2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AGR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGR2 were set to 34952832 Phenotypes for gene: AGR2 were set to CF-like disorder Review for gene: AGR2 was set to GREEN Added comment: 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. Sources: Literature |
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| Mendeliome v0.10759 | HPGD | Ain Roesley reviewed gene: HPGD: Rating: GREEN; Mode of pathogenicity: None; Publications: 20406614, 32282352, 31878983, 29282707; Phenotypes: Hypertrophic osteoarthropathy, primary, autosomal recessive 1 MIM#259100, Cranioosteoarthropathy MIM#259100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10754 | GLMN | Ain Roesley reviewed gene: GLMN: Rating: GREEN; Mode of pathogenicity: None; Publications: 11845407, 24961656, 32538359; Phenotypes: Glomuvenous malformations MIM#138000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10754 | GDI1 | Ain Roesley reviewed gene: GDI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28863211, 22002931, 9620768, 9668174; Phenotypes: Intellectual developmental disorder, X-linked 41 MIM#300849; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10751 | ANGPT2 | Zornitza Stark edited their review of gene: ANGPT2: Added comment: Bi-allelic disease PMID 34876502: single family reported with four fetuses with hydrops fetalis homozygous for ANGPT2 NM_001147.2:c.557A>G. The consanguineous parents and surviving sibblings (a girl and a boy), were heterozygous for this variant. This variant is predicted to create a cryptic exonic splice site, resulting in a r.557_566del and nonsense-mediated mRNA decay. This prediction was supported by the lack of a transcript from this allele in the parents.; Changed publications: 32908006, 34876502; Changed phenotypes: Lymphatic malformation-10, MIM#619369, Primary lymphoedema, Hydrops; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10749 | NMNAT2 | Ain Roesley reviewed gene: NMNAT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31136762; Phenotypes: Hydrops fetalis and multiple fetal anomalies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10749 | NECTIN1 | Ain Roesley reviewed gene: NECTIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25913853, 10932188; Phenotypes: Cleft lip/palate-ectodermal dysplasia syndrome MIM#225060, Zlotogora-Ogur syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10741 | UQCRC2 | Zornitza Stark edited their review of gene: UQCRC2: Added comment: Third family with different variant reported, together with functional data.; Changed rating: GREEN; Changed publications: 28275242, 23281071, 33865955 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10680 | OTUD6B | Zornitza Stark changed review comment from: IDDFSDA is a severe multisystem disorder characterized by global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. In 2017, 12 patients from 6 unrelated families with IDDFSDA identified with 4 homozygous mutations in the OTUD6B gene (WES and Sanger, and segregated with the disorder in the families). Other cases reported since. Suitable for fetal anomalies panel.; to: IDDFSDA is a severe multisystem disorder characterized by global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. In 2017, 12 patients from 6 unrelated families with IDDFSDA identified with 4 homozygous mutations in the OTUD6B gene (WES and Sanger, and segregated with the disorder in the families). Other cases reported since. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10660 | WNT7A | Seb Lunke reviewed gene: WNT7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21344627, 20949531, 16826533; Phenotypes: Fuhrmann syndrome, MIM# 228930, Ulna and fibula, absence of, with severe limb deficiency, MIM# 276820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10643 | ILK | Paul De Fazio reviewed gene: ILK: Rating: AMBER; Mode of pathogenicity: None; Publications: 17646580, 27886618, 25163546; Phenotypes: Dilated cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10643 | FAM46A | Belinda Chong reviewed gene: FAM46A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29358272; Phenotypes: Osteogenesis imperfecta, type XVIII MIM#617952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10640 | MYPN | Ain Roesley reviewed gene: MYPN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Nemaline myopathy 11, autosomal recessive MIM#617336 AR, cardiomyopathy MIM#615248 AD; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10640 | MYL9 |
Ain Roesley edited their review of gene: MYL9: Added comment: PMID:32621347; 3rd family with non-consanguineous parents and 3 TOPs. 2 were genotyped and found to be hom for the same deletion of exon 4 as reported by PMID: 29453416 Possibly 4th proband in PMID: 33264186 but specifics including genotype were lacking and overlapping institute/hospital as PMID: 33031641; Changed publications: 32621347, 33264186 |
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| Mendeliome v0.10640 | MYL9 | Ain Roesley reviewed gene: MYL9: Rating: GREEN; Mode of pathogenicity: None; Publications: 33264186; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome, MIM#619365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10640 | MSTO1 | Ain Roesley reviewed gene: MSTO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28554942, 28544275, 31604776, 31463572, 31130378, 30684668, 29339779; Phenotypes: Myopathy, mitochondrial, and ataxia, MIM# 617675; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10640 | MDH2 | Ain Roesley reviewed gene: MDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34766628, 27989324; Phenotypes: Developmental and epileptic encephalopathy 51 MIM#617339; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10640 | MBOAT7 | Ain Roesley reviewed gene: MBOAT7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33335874, 32645526, 32744787, 31852446, 31282596, 30701556; Phenotypes: intellectual disability MIM#617188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10627 | ICAM1 | Ain Roesley reviewed gene: ICAM1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10627 | IRAK3 | Ain Roesley reviewed gene: IRAK3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10627 | CAPN10 | Ain Roesley reviewed gene: CAPN10: Rating: RED; Mode of pathogenicity: None; Publications: 31791003, 31292430; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10587 | ITPKC |
Ain Roesley changed review comment from: Currently no mendelian gene-disease assocation. Best known for polymorphisms associated with Kawasaki disease susceptibility. KO mouse models looking at protein expression and effect on multiciliary beating frequency and spermatozoa, no significant defects in both; to: Currently no mendelian gene-disease association. Best known for polymorphisms associated with Kawasaki disease susceptibility. KO mouse models looking at tissue protein expression and effect on multiciliary beating frequency and spermatozoa, no significant defects in both |
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| Mendeliome v0.10587 | ITPKC | Ain Roesley reviewed gene: ITPKC: Rating: RED; Mode of pathogenicity: None; Publications: 32283413, 29098351, 27036498; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10573 | INPP5K | Ain Roesley reviewed gene: INPP5K: Rating: GREEN; Mode of pathogenicity: None; Publications: 28190456, 28190459, 28940338, 31630891, 33193651, 33792664; Phenotypes: Muscular dystrophy, congenital, with cataracts and intellectual disability MIM#617404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10573 | IGFBP7 | Ain Roesley reviewed gene: IGFBP7: Rating: RED; Mode of pathogenicity: None; Publications: 34519236, 31730227, 32429784; Phenotypes: Retinal arterial macroaneurysm with supravalvular pulmonic stenosis MIM#614224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10570 | IDH1 | Ain Roesley reviewed gene: IDH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34393643, 34588213, 34624834, 34720940, 32727816; Phenotypes: Ollier disease MONDO:0008145, Maffucci syndromeMONDO:0013808; Mode of inheritance: Other; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10570 | HNRNPH2 | Ain Roesley reviewed gene: HNRNPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34907471, 33728377, 31670473, 31236915, 30887513; Phenotypes: Intellectual developmental disorder, X-linked, syndromic, Bain type MIM#300986; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10563 | ATP5A1 | Naomi Baker edited their review of gene: ATP5A1: Added comment: PMID: 34954817 reports three individuals with de novo monoallelic missense variants. One of these is the recurrent p.(Arg207His) variant while the other two variants are different substitutions. The three patients presented with a variable phenotypes: (1) a 14-year-old girl who presented during the first few months of life with developmental delay, failure-to-thrive, and lactic acidosis. She recovered and had no persistent neurologic phenotype; (2) a 17-year-old boy with psychomotor delay, intellectual disability, ataxia, spastic paraparesis, and dystonia; (3) a 12-year-old girl with psychomotor retardation, spastic tetraparesis, generalized dystonia, absent speech, swallowing problems, and increased blood lactate concentrations. Enzymatic investigations of muscle tissue from patient 1 showed a decrease in ATPase activity.; Changed publications: PMID: 34954817 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10556 | PRKAR1B | Paul De Fazio reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome MIM#619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10556 | NAA10 |
Ain Roesley edited their review of gene: NAA10: Added comment: For Ogden association: lethal X-linked. 9 males from 3 families with recurrent Ser37Pro All presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias For non-lethal syndromic ID: reported in 10 males and (mostly de novo) in 37 females variants causing this are missense located along the protein and 1 truncating For syndromic microopththamia: variants are in the UTR; Changed mode of inheritance: Other |
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| Mendeliome v0.10554 | MYH1 | Seb Lunke Phenotypes for gene: MYH1 were changed from recurrent rhabdomyolysis to rhabdomyolysis, MONDO:0005290 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10552 | NAA10 | Ain Roesley reviewed gene: NAA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 34075687, 21700266; Phenotypes: Ogden syndrome MIM#300855; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10552 | PI4KA | Paul De Fazio reviewed gene: PI4KA: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415310; Phenotypes: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis MIM#616531, Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis MONDO:0014679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10552 | SLC35F1 |
Ain Roesley gene: SLC35F1 was added gene: SLC35F1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC35F1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SLC35F1 were set to 33821533 Phenotypes for gene: SLC35F1 were set to Rett-like syndrome Penetrance for gene: SLC35F1 were set to unknown Review for gene: SLC35F1 was set to RED gene: SLC35F1 was marked as current diagnostic Added comment: WES found a de novo heterozygous c.1037T>C; p.(I346T) (absent in gnomad v2 and v3) in a female described to have Rett-like syndrome. Global developmental delay, generalized tonic andtonic–clonic seizure, never acquired independent walking and developed spastictetraplegia in adulthood and limited speech no protein functional work was performed Sources: Literature |
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| Mendeliome v0.10552 | CRACR2A |
Dean Phelan gene: CRACR2A was added gene: CRACR2A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CRACR2A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRACR2A were set to PMID:34908525 Phenotypes for gene: CRACR2A were set to Late onset combined immunodeficiency Review for gene: CRACR2A was set to AMBER Added comment: PMID:34908525 - one patient compound het (missense and PTC) with late onset combined immunodeficiency (current chest infections, panhypogammaglobulinemia and CD4+T cell lymphopenia). Functional studies showed defective JNK phosphorylation, defective SOCE and impaired cytokine production. Further search did not identify any additional publications. Sources: Literature |
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| Mendeliome v0.10552 | MYH1 |
Ain Roesley gene: MYH1 was added gene: MYH1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MYH1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYH1 were set to 33755318 Phenotypes for gene: MYH1 were set to recurrent rhabdomyolysis Penetrance for gene: MYH1 were set to unknown Review for gene: MYH1 was set to RED gene: MYH1 was marked as current diagnostic Added comment: 18 yr old male from a consaguineous family. WES was performed and a homozygous c.1295A>C:p.K432T was found. Only 1 het in gnomad v2 and v3. no protein functional work was done Sources: Literature |
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| Mendeliome v0.10550 | PAK2 |
Arina Puzriakova gene: PAK2 was added gene: PAK2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAK2 were set to 33693784 Phenotypes for gene: PAK2 were set to Knobloch 2 syndrome Review for gene: PAK2 was set to RED Added comment: Antonarakis et al., 2021 (PMID: 33693784) reported two affected siblings from a non-consanguineous New Zealand family. Both had retinal detachment and interstitial parenchymal pulmonary changes on chest X-rays, but only one child had additional significant features such as cataract, posterior encephalocele, severe DD/ID with ASD, and epilepsy. WES revealed a heterozygous PAK2 variant (c.1303 G>A, p.Glu435Lys) in both individuals that apparently occurred de novo indicating parental germ-line mosaicism; however, mosaicism could not be detected by deep sequencing of blood parental DNA. Functional studies showed that the variant, located in the kinase domain, results in a partial loss of the kinase activity. Sources: Literature |
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| Mendeliome v0.10542 | TBX2 |
Krithika Murali changed review comment from: Liu et al. (2018) reported 4 affected individuals from 2 unrelated families with congenital cardiac defects (ASD, PDA, double outlet right ventricle, pulmonary stenosis), skeletal abnormalities (camptodactyly, congenital fusion thoracic spine, hemivertebrae ).Thymus aplasia/hypoplasia, cleft palate also noted. Other associated features include - facial dysmorphisms, variable developmental delay, and endocrine system disorders (e.g. autoimmune hypothyroidism, hypoparathyroidism). PMID23727221 and PMID30223900 - TBX2 gene and TBX2 gene promoter sequencing in congenital heart disease cohorts versus controls - not enough supportive evidence for variant pathogenicity, including no segregation data. Variants prevalent in population databases also included as likely pathogenic. PMID 20635360 - de novo dup 17q23.2 encompassing TBX2 gene in boy with cognitive impairment, multiple congenital defects and prenatal onset growth restriction. Part of BCAS3 gene (associated with autosomal recessive Hengel-Maroofian-Schols syndrome) also included in duplication. No supportive evidence of TBX2 gene function impairment in the patient provided.; to: Liu et al. (2018) reported 4 affected individuals from 2 unrelated families with congenital cardiac defects (ASD, PDA, double outlet right ventricle, pulmonary stenosis), skeletal abnormalities (camptodactyly, congenital fusion thoracic spine, hemivertebrae ).Thymus aplasia/hypoplasia, cleft palate also noted. Other associated features include - facial dysmorphisms, variable developmental delay, and endocrine system disorders (e.g. autoimmune hypothyroidism, hypoparathyroidism). PMID23727221 and PMID30223900 - TBX2 gene and TBX2 gene promoter sequencing in congenital heart disease cohorts versus controls - not enough supportive evidence for variant pathogenicity, including no segregation data. Variants prevalent in population databases also included as potentially disease causing. PMID 20635360 - de novo dup 17q23.2 encompassing TBX2 gene in boy with cognitive impairment, multiple congenital defects and prenatal onset growth restriction. Part of BCAS3 gene (associated with autosomal recessive Hengel-Maroofian-Schols syndrome) also included in duplication. No supportive evidence of TBX2 gene function impairment in the patient provided. |
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| Mendeliome v0.10527 | SLC25A24 | Seb Lunke reviewed gene: SLC25A24: Rating: ; Mode of pathogenicity: None; Publications: 29100093, 29100094, 29100094, 31775791, 32732226, 32860237; Phenotypes: Fontaine progeroid syndrome, MIM#612289; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10510 | NAA20 |
Zornitza Stark gene: NAA20 was added gene: NAA20 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAA20 were set to 34230638 Phenotypes for gene: NAA20 were set to Intellectual disability; Microcephaly; Neurodevelopmental disorder MONDO:0700092 Review for gene: NAA20 was set to GREEN Added comment: 2 consanguineous families with 5 affected individuals with developmental delay, intellectual disability, and microcephaly (-2-4SD). Exome and genome sequencing identified 2 different homozygous variants in NAA20 gene (p.Met54Val and p.Ala80Val), and segregated with affected individuals. N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Sources: Literature |
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| Mendeliome v0.10493 | PLA2G7 | Paul De Fazio reviewed gene: PLA2G7: Rating: RED; Mode of pathogenicity: None; Publications: 3198761, 10733466, 25587968, 28406212; Phenotypes: Platelet-activating factor acetylhydrolase deficiency MIM#614278; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10493 | DSG1 | Belinda Chong reviewed gene: DSG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19558595, 29315490, 31192455, 23974871, 29229434, 33666035; Phenotypes: Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgE, AR (MIM#615508), Keratosis palmoplantaris striata I, AD (MIM# 148700); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10491 | KCNC1 |
Zornitza Stark changed review comment from: Additional individuals reported with different variants, causing a broad range of neurological phenotypes including ID and movement disorders.; to: Additional individuals reported with different variants, causing a broad range of neurological phenotypes including ID and movement disorders. Likely reflects different mechanisms (LoF vs GoF). |
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| Mendeliome v0.10483 | DPF2 | Belinda Chong reviewed gene: DPF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29429572, 31706665; Phenotypes: Coffin-Siris syndrome 7 MIM#618027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10483 | FREM1 | Zornitza Stark Phenotypes for gene: FREM1 were changed from to Manitoba oculotrichoanal syndrome 248450; Bifid nose with or without anorectal and renal anomalies, MIM# 608980; Trigonocephaly 2, MIM# 614485 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10480 | FREM1 | Zornitza Stark reviewed gene: FREM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32016392, 21931569, 21507892, 19732862, 20301721, 28111185; Phenotypes: Manitoba oculotrichoanal syndrome 248450, Bifid nose with or without anorectal and renal anomalies, MIM# 608980, Trigonocephaly 2, MIM# 614485; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10477 | DNAJC19 | Belinda Chong reviewed gene: DNAJC19: Rating: GREEN; Mode of pathogenicity: None; Publications: 16055927, 17244376, 22797137; Phenotypes: 3-methylglutaconic aciduria, type V MIM#610198; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10469 | MMP3 | Paul De Fazio reviewed gene: MMP3: Rating: RED; Mode of pathogenicity: None; Publications: 12750310, 10351963; Phenotypes: {Coronary heart disease, susceptibility to, 6} 614466; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10449 | GRM1 | Ain Roesley reviewed gene: GRM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901947, 26308914, 31319223; Phenotypes: Spinocerebellar ataxia 44 MIM#617691, Spinocerebellar ataxia, autosomal recessive 13 MIM#614831; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10449 | GRHL2 | Ain Roesley reviewed gene: GRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27612988, 19415813; Phenotypes: Ectodermal dysplasia/short stature syndrome MIM#616029; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10448 | GPX4 | Ain Roesley reviewed gene: GPX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24706940, 32827718; Phenotypes: Spondylometaphyseal dysplasia, Sedaghatian type MIM#250220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10448 | GPKOW |
Ain Roesley gene: GPKOW was added gene: GPKOW was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GPKOW was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: GPKOW were set to 28612833 Phenotypes for gene: GPKOW were set to male-lethal microcephaly with intrauterine growth restriction Penetrance for gene: GPKOW were set to unknown Review for gene: GPKOW was set to RED gene: GPKOW was marked as current diagnostic Added comment: - multi-generational family with 5 deceased males (only 1 genotyped) - X-exome sequencing identified NM_015698.4:c.331+5G>A, which segregated through the obligate carriers - RNA from female carriers confirmed splicing defects, which leads to NMD no additional reports since Sources: Literature |
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| Mendeliome v0.10448 | GNA11 | Ain Roesley reviewed gene: GNA11: Rating: GREEN; Mode of pathogenicity: Other; Publications: 23802536, 23802516, 24823460, 26818911, 27334330; Phenotypes: Hypocalcemia, autosomal dominant 2 MIM#615361, Hypocalciuric hypercalcemia, type II MIM#145981; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10440 | SIX5 | Zornitza Stark changed review comment from: Multiple families reported.; to: Multiple families reported. However, association between SIX5 variants and BOR is DISPUTED by ClinGen: Association has been reported in at least 6 probands in 2 publications (17357085, 24429398), however the reported variants are high in frequency in population databases, have no evidence of pathogenicity, and/or an alternate cause of disease has later been reported (21280147). This gene-disease association is supported by protein interaction and biochemical function studies (14704431, 17357085, 11950062). While EYA1 and SIX1 gene inactivation in mice leads to ear and kidney abnormalities, two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668). In summary, there is convincing evidence disputing the association between SIX5 and autosomal dominant branchio-oto-renal syndrome. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10440 | SIX5 | Zornitza Stark Phenotypes for gene: SIX5 were changed from Branchiootorenal syndrome 2, MIM# 610896 to Branchiootorenal syndrome 2, MIM# 610896 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10439 | SIX5 | Zornitza Stark Phenotypes for gene: SIX5 were changed from to Branchiootorenal syndrome 2, MIM# 610896 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10436 | SIX5 | Zornitza Stark reviewed gene: SIX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 17357085, 33624842, 20301554, 24730701, 22447252; Phenotypes: Branchiootorenal syndrome 2, MIM# 610896; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10433 | SKI | Seb Lunke reviewed gene: SKI: Rating: GREEN; Mode of pathogenicity: None; Publications: 15884042, 23023332; Phenotypes: Shprintzen-Goldberg syndrome, MIM#182212; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10427 | TECRL |
Zornitza Stark gene: TECRL was added gene: TECRL was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: TECRL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TECRL were set to 17666061; 27861123; 30790670; 33367594 Phenotypes for gene: TECRL were set to Ventricular tachycardia, catecholaminergic polymorphic, 3, MIM# 614021 Review for gene: TECRL was set to GREEN Added comment: DEFINITIVE by ClinGen Homozygous or cpd heterozygous pathogenic variants in TECRL have been identified in patients with CPVT in at least 3 families in the literature with functional evidence. - 17666061 one consanguineous family with 4 affected relatives (siblings or 1stcousins) - 27861123 consanguineous family with 8 affected relatives (siblings or 1stcousins) - 30790670 reported in a single family with one child with features of CPVT -A multi-centre review published in 2020 provided an update on these cases and described two additional CPVT cases (homozygous p.Tyr197Ter nonsense variant and homozygous exon 2 deletion) and a family with three children with sudden cardiac death, where one was homozygous for the c.331+1G>A splice donor variant, PMID 33367594 Sources: Expert Review |
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| Mendeliome v0.10426 | KEL | Ain Roesley reviewed gene: KEL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10389 | ATP8B1 | Zornitza Stark edited their review of gene: ATP8B1: Changed phenotypes: Cholestasis, progressive familial intrahepatic 1, MIM# 211600, Cholestasis, benign recurrent intrahepatic, MIM# 243300, Cholestasis, intrahepatic, of pregnancy, 1, MIM# 147480 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10388 | ATP8B1 | Zornitza Stark Phenotypes for gene: ATP8B1 were changed from Cholestasis, progressive familial intrahepatic 1, MIM# 211600; Cholestasis, benign recurrent intrahepatic, MIM# 243300 to Cholestasis, progressive familial intrahepatic 1, MIM# 211600; Cholestasis, benign recurrent intrahepatic, MIM# 243300; Cholestasis, intrahepatic, of pregnancy, 1, MIM# 147480 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10386 | ATP8B1 | Zornitza Stark Phenotypes for gene: ATP8B1 were changed from to Cholestasis, progressive familial intrahepatic 1, MIM# 211600; Cholestasis, benign recurrent intrahepatic, MIM# 243300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10369 | RNF213 | Ain Roesley reviewed gene: RNF213: Rating: GREEN; Mode of pathogenicity: None; Publications: 28635953; Phenotypes: usceptibility to Moyamoya disease 2, (MIM# 607151); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10369 | DRD5 | Ain Roesley reviewed gene: DRD5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10369 | AXIN1 | Ain Roesley reviewed gene: AXIN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10312 | FAM126A | Belinda Chong reviewed gene: FAM126A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21911699, 17928815, 17683097, 16951682; Phenotypes: Leukodystrophy, hypomyelinating, 5 MIM#610532; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10312 | GM2A | Ain Roesley reviewed gene: GM2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28417072, 28192816, 27402091, 33819415; Phenotypes: GM2-gangliosidosis, AB variant MIM#272750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10312 | GLI1 |
Ain Roesley gene: GLI1 was added gene: GLI1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GLI1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: GLI1 were set to 34721536; 31621941; 31549748; 30620395 Phenotypes for gene: GLI1 were set to Polydactyly, postaxial, type A8 MIM#618123; Polydactyly, preaxial I MIM#174400 Penetrance for gene: GLI1 were set to unknown Review for gene: GLI1 was set to GREEN gene: GLI1 was marked as current diagnostic Added comment: >10 unrelated probands reported, both AD and AR reported Sources: Literature |
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| Mendeliome v0.10312 | GFRA1 | Ain Roesley reviewed gene: GFRA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34737117; Phenotypes: renal agenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10298 | CTU2 | Zornitza Stark Phenotypes for gene: CTU2 were changed from to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10295 | CTU2 | Zornitza Stark reviewed gene: CTU2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27480277, 26633546, 31301155; Phenotypes: Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10253 | REL | Zornitza Stark Phenotypes for gene: REL were changed from Combined immunodeficiency; T cells: normal, decreased memory CD4, poor proliferation; B cells: low, mostly naive, few switched memory B cells, impaired proliferation; Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms; Defective innate immunity to Immunodeficiency 92, MIM# 619652; Combined immunodeficiency; T cells: normal, decreased memory CD4, poor proliferation; B cells: low, mostly naive, few switched memory B cells, impaired proliferation; Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms; Defective innate immunity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10250 | REL |
Zornitza Stark changed review comment from: Second unrelated individual reported, homozygous splice site variant. Immunodeficiency-92 (IMD92) is an autosomal recessive primary immunodeficiency characterized by the onset of recurrent infections in infancy or early childhood. Infectious agents are broad, including bacterial, viral, fungal, and parasitic, including Cryptosporidium and Mycobacteria. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets.; to: Second unrelated individual reported, with a different homozygous splice site variant. Immunodeficiency-92 (IMD92) is an autosomal recessive primary immunodeficiency characterized by the onset of recurrent infections in infancy or early childhood. Infectious agents are broad, including bacterial, viral, fungal, and parasitic, including Cryptosporidium and Mycobacteria. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets. |
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| Mendeliome v0.10250 | REL |
Zornitza Stark edited their review of gene: REL: Added comment: Second unrelated individual reported, homozygous splice site variant. Immunodeficiency-92 (IMD92) is an autosomal recessive primary immunodeficiency characterized by the onset of recurrent infections in infancy or early childhood. Infectious agents are broad, including bacterial, viral, fungal, and parasitic, including Cryptosporidium and Mycobacteria. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets.; Changed rating: AMBER; Changed publications: 31103457, 34623332; Changed phenotypes: Immunodeficiency 92, MIM# 619652, Combined immunodeficiency, T cells: normal, decreased memory CD4, poor proliferation, B cells: low, mostly naive, few switched memory B cells, impaired proliferation, Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms, Defective innate immunity |
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| Mendeliome v0.10250 | ABO | Paul De Fazio reviewed gene: ABO: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Blood group, ABO system] MIM#616093; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10250 | TLR1 | Paul De Fazio reviewed gene: TLR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leprosy, protection against} {Leprosy, susceptibility to, 5} MIM#613223; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10244 | SEMA7A | Paul De Fazio reviewed gene: SEMA7A: Rating: RED; Mode of pathogenicity: None; Publications: 16372136, 31650878, 34585848; Phenotypes: Decreased bone mineral density, Kallmann syndrome, progressive familial intrahepatic cholestasis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10230 | EYA1 | Zornitza Stark Phenotypes for gene: EYA1 were changed from to Anterior segment anomalies with or without cataract MIM#602588; Branchiootic syndrome 1 MIM#602588; Branchiootorenal syndrome 1, with or without cataracts MIM#113650 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10227 | EYA1 | Zornitza Stark reviewed gene: EYA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9359046, 13269867; Phenotypes: Anterior segment anomalies with or without cataract MIM#602588, Branchiootic syndrome 1 MIM#602588, Branchiootorenal syndrome 1, with or without cataracts MIM#113650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10213 | ERCC6 | Belinda Chong reviewed gene: ERCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301516 20456449 9443879 8566949; Phenotypes: Cockayne syndrome, type B, MIM#133540, Cerebrooculofacioskeletal syndrome 1, MIM#214150, De Sanctis-Cacchione syndrome, MIM#278800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10207 | FAT4 | Ain Roesley reviewed gene: FAT4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29681106; Phenotypes: Hennekam lymphangiectasia-lymphedema syndrome 2 MIM#616006, Van Maldergem syndrome 2 MIM#615546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10207 | FBXL4 | Ain Roesley reviewed gene: FBXL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940506; Phenotypes: Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) MIM#615471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10206 | FOXRED1 | Ain Roesley reviewed gene: FOXRED1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33613441; Phenotypes: Mitochondrial complex I deficiency, nuclear type 19 MIM#618241; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10206 | FREM2 | Ain Roesley reviewed gene: FREM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15838507, 18203166, 29688405, 33082983; Phenotypes: Cryptophthalmos, unilateral or bilateral, isolated MIM#123570, Fraser syndrome 2 MIM#617666; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10204 | GATA4 | Ain Roesley reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12845333, 18055909, 15689439, 33413087, 30455927; Phenotypes: Atrial septal defect 2 MIM#607941, Atrioventricular septal defect 4 MIM#614430, Ventricular septal defect 1 MIM#614429; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10204 | NPC1 |
Daniel Flanagan gene: NPC1 was added gene: NPC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPC1 were set to 12408188; 9211849 Phenotypes for gene: NPC1 were set to Niemann-Pick disease, type C1/ type D (MIM#257220) Review for gene: NPC1 was set to GREEN Added comment: Biallelic NPC1 variants cause Niemann-Pick disease, type C1/ type D. Prenatal manifestation: hydrops fetalis. Sources: Literature |
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| Mendeliome v0.10204 | COMT | Ain Roesley reviewed gene: COMT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10194 | CHRNA3 |
Zornitza Stark changed review comment from: Five individuals from three unrelated families.; to: Five individuals from three unrelated families. Onset is in utero or early childhood. Affected individuals have impaired neuronal bladder and ureteral innervation causing coordination defects that result in secondary structural defects of the renal system, including hydronephrosis, vesicoureteral reflux (VUR), and small kidneys, that may result in chronic kidney disease as well as recurrent urinary tract infections (UTIs). Surgical treatment of VUR is not effective. Most individuals also have additional autonomic features, most commonly impaired pupillary reflex and sometimes orthostatic hypotension. |
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| Mendeliome v0.10174 | RNF212 | Paul De Fazio reviewed gene: RNF212: Rating: RED; Mode of pathogenicity: None; Publications: 18239089, 29277047; Phenotypes: Recombination rate QTL 1 MIM#612042; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10116 | LACC1 |
Bryony Thompson changed review comment from: At least 43 cases with biallelic variants (7 different variants) from 17 consanguineous families reported. Sources: Literature; to: At least 43 cases with biallelic variants (7 different variants) from 17 mainly consanguineous families reported. Sources: Literature |
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| Mendeliome v0.10115 | LACC1 |
Bryony Thompson gene: LACC1 was added gene: LACC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LACC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LACC1 were set to 25220867; 27881174; 30872671; 33718577 Phenotypes for gene: LACC1 were set to Juvenile arthritis MIM#618795 Review for gene: LACC1 was set to GREEN Added comment: At least 43 cases with biallelic variants (7 different variants) from 17 consanguineous families reported. Sources: Literature |
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| Mendeliome v0.10103 | REC8 |
Bryony Thompson gene: REC8 was added gene: REC8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: REC8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: REC8 were set to 34794894; 15515002; 34707299 Phenotypes for gene: REC8 were set to Primary ovarian insufficiency Review for gene: REC8 was set to AMBER Added comment: PMID: 34707299 - a French POI case with compound het predicted loss of function variants PMID: 15515002 - Rec8-/- female mice demonstrated ovarian dysgenesis and lack of ovarian follicles at reproductive maturity. PMID: 27603904 - 2 sisters with POI segregating a missense in REC8 inherited from the unaffected mother (p.Gln154Arg) and a missense in GDF9 inherited from the father. Possible digenic inheritance. Sources: Literature |
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| Mendeliome v0.10101 | GDF6 | Ain Roesley reviewed gene: GDF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 30733656, 29130651, 26643732, 19129173, 23307924, 32737436; Phenotypes: Klippel-Feil syndrome 1, autosomal dominantMIM#118100, Leber congenital amaurosis 17 (MIM#615360), Microphthalmia, isolated 4 (MIM#613094), Multiple synostoses syndrome 4 (MIM#617898); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10100 | MSH5 |
Bryony Thompson changed review comment from: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature; to: 4 unrelated male azoospermia cases with 3 different homozygous frameshift/missense variants. A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.10100 | MSH5 |
Bryony Thompson changed review comment from: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature; to: 4 unrelated male azoospermia cases with 3 different homozygous frameshift/missense variants. A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.10089 | GFM1 | Ain Roesley reviewed gene: GFM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31680380, 25852744, 26937387; Phenotypes: Combined oxidative phosphorylation deficiency 1 MIM#609060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10089 | GJA3 | Ain Roesley reviewed gene: GJA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10205266, 15286166, 15448617, 21681855, 22312188, 22550389, 22876138; Phenotypes: Cataract 14, multiple types MIM#601885; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10089 | GJC2 | Ain Roesley reviewed gene: GJC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19056803, 31431325, 25059390, 20537300, 21266381; Phenotypes: Spastic paraplegia 44, autosomal recessive MIM#613206, Leukodystrophy, hypomyelinating, 2 MIM#608804, Lymphatic malformation 3 MIM#613480; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10087 | GLB1 | Ain Roesley reviewed gene: GLB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24156116; Phenotypes: GM1-gangliosidosis, type I MIM#230500, GM1-gangliosidosis, type II MIM# 230600, GM1-gangliosidosis, type III MIM#230650, Mucopolysaccharidosis type IVB (Morquio) MIM#253010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10085 | TRIM27 | Ain Roesley reviewed gene: TRIM27: Rating: RED; Mode of pathogenicity: None; Publications: 34419804; Phenotypes: parkinson's disease; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10079 | CR1 | Ain Roesley reviewed gene: CR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10068 | TMEM260 | Zornitza Stark changed review comment from: Seven unrelated families reported.; to: Seven unrelated families reported. Clinical features: ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12) in patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10044 | ECM1 |
Zornitza Stark changed review comment from: PMID: 11929856 - Hamada et al 2002 - looked at 6 different unrelated consanguineous families (from Saudi Arabia, Kuwait, Pakistan, The Netherlands, UK, and a group of South African families with a probable common ancestor) with a clinical diagnosis of Lipoid proteinosis (LP)/Urbach–Wiethe disease. They performed a genome-wide linkage analysis and identified a region and then looked at the expression of candidate genes in fibroblasts from patients compared to controls. ECM1 was found to have lower expression levels. 6 homozygous deletion variants were identified in the patients. In one family they established that the parents were heterozygous for the variant. PMID: 28720532 - Afifi et al 2017 - studied 12 patients from 10 unrelated consanguineous Egyptian families with a clinical diagnosis of lipoid proteinosis. The patients reported progressive hoarseness of voice and easily damaged skin by minor trauma or friction. Homozygous ECM1 variants were detected in affected members in all families: 1 family had a missense variant, 5 families had splice site variants and 4 families had indels predicted to cause frameshifts. Parents were found to be heterozygous for the variants. PMID: 33159951 - Zhu et al 2021 - a novel homozygous three-nucleotide duplication (c.506_508dupCTG) in ECM in two siblings affected with LP from a consanguineous Chinese family.; to: Lipoid proteinosis of Urbach and Wiethe is a rare autosomal recessive disorder typified by generalized thickening of skin, mucosae, and certain viscera. Classic features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. The disorder is clinically heterogeneous, with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurologic abnormalities such as temporal lobe epilepsy. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane PMID: 11929856 - Hamada et al 2002 - looked at 6 different unrelated consanguineous families (from Saudi Arabia, Kuwait, Pakistan, The Netherlands, UK, and a group of South African families with a probable common ancestor) with a clinical diagnosis of Lipoid proteinosis (LP)/Urbach–Wiethe disease. They performed a genome-wide linkage analysis and identified a region and then looked at the expression of candidate genes in fibroblasts from patients compared to controls. ECM1 was found to have lower expression levels. 6 homozygous deletion variants were identified in the patients. In one family they established that the parents were heterozygous for the variant. PMID: 28720532 - Afifi et al 2017 - studied 12 patients from 10 unrelated consanguineous Egyptian families with a clinical diagnosis of lipoid proteinosis. The patients reported progressive hoarseness of voice and easily damaged skin by minor trauma or friction. Homozygous ECM1 variants were detected in affected members in all families: 1 family had a missense variant, 5 families had splice site variants and 4 families had indels predicted to cause frameshifts. Parents were found to be heterozygous for the variants. PMID: 33159951 - Zhu et al 2021 - a novel homozygous three-nucleotide duplication (c.506_508dupCTG) in ECM in two siblings affected with LP from a consanguineous Chinese family. |
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| Mendeliome v0.10041 | SMPX | Zornitza Stark edited their review of gene: SMPX: Added comment: PMID 33974137: Four different missense variants were identified in ten patients from nine families in five different countries. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. Clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.; Changed publications: 21549342, 21549336, 21893181, 22911656, 28542515, 33974137; Changed phenotypes: Deafness, X-linked 4, MIM# 300066, Distal myopathy, adult-onset | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10017 | FOXR1 |
Paul De Fazio gene: FOXR1 was added gene: FOXR1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FOXR1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FOXR1 were set to 34723967 Phenotypes for gene: FOXR1 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay Review for gene: FOXR1 was set to AMBER gene: FOXR1 was marked as current diagnostic Added comment: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnornmalities, and dysmorphic features. In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation). A mouse knockout has comparable phenotypes, and a severe survival deficit. Rated amber (1 patient, functional evidence, mouse model). Sources: Literature |
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| Mendeliome v0.10017 | TAB2 | Chern Lim reviewed gene: TAB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34456334; Phenotypes: Mitral valve disease, cardiomyopathy, short stature and hypermobility, Congenital heart defects, nonsyndromic, 2 (MIM#614980); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10017 | FAAH2 |
Ain Roesley changed review comment from: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomoad Sources: Literature; to: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomAD Sources: Literature |
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| Mendeliome v0.10017 | FAAH2 |
Ain Roesley gene: FAAH2 was added gene: FAAH2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAAH2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: FAAH2 were set to PMID: 34645488 Penetrance for gene: FAAH2 were set to unknown Review for gene: FAAH2 was set to RED gene: FAAH2 was marked as current diagnostic Added comment: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomoad Sources: Literature |
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| Mendeliome v0.10013 | ARPC4 |
Bryony Thompson gene: ARPC4 was added gene: ARPC4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARPC4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARPC4 were set to DOI:https://doi.org/10.1016/j.xhgg.2021.100072 Phenotypes for gene: ARPC4 were set to Microcephaly; mild motor delays; significant speech impairment Review for gene: ARPC4 was set to GREEN Added comment: 7 affected individuals from 6 families (gonadal mosaicism was confirmed in the mother of the 2 affected siblings) with a recurrent missense variant (NM_005718.4:c.472C>T; p.R158C). The variant was associated with a decreased amount of F-actin in cells from two affected individuals. Sources: Literature |
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| Mendeliome v0.9984 | CARD10 |
Zornitza Stark gene: CARD10 was added gene: CARD10 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CARD10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CARD10 were set to 32238915 Phenotypes for gene: CARD10 were set to Immunodeficiency 89 and autoimmunity, MIM# 619632 Review for gene: CARD10 was set to RED Added comment: A pair of siblings reported with adult onset of recurrent infections, allergies, microcytic anaemia, and Crohn disease. Homozygous missense variant. Sources: Expert list |
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| Mendeliome v0.9970 | EMD | Belinda Chong reviewed gene: EMD: Rating: GREEN; Mode of pathogenicity: None; Publications: 21697856 31802929; Phenotypes: Emery-Dreifuss muscular dystrophy 1, X-linked MIM#310300; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9952 | GNPTAB | Ain Roesley reviewed gene: GNPTAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301728; Phenotypes: Mucolipidosis II alpha/beta MIM#252500, Mucolipidosis III alpha/beta MIM#252600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9952 | NADSYN1 | Zornitza Stark Phenotypes for gene: NADSYN1 were changed from Multiple congenital abnormalities; absent kidneys; cardiac; limb; vertebral to Vertebral, cardiac, renal, and limb defects syndrome 3, MONDO:0030077; Vertebral, cardiac, renal, and limb defects syndrome 3, OMIM:618845 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9951 | NADSYN1 | Zornitza Stark edited their review of gene: NADSYN1: Changed phenotypes: Vertebral, cardiac, renal, and limb defects syndrome 3, MONDO:0030077, Vertebral, cardiac, renal, and limb defects syndrome 3, OMIM:618845 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9951 | GRHL3 | Ain Roesley reviewed gene: GRHL3: Rating: ; Mode of pathogenicity: None; Publications: 24360809, 29500247; Phenotypes: Van der Woude syndrome 2 MIM#606713; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9949 | GRIP1 | Ain Roesley reviewed gene: GRIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27859469, 31982235; Phenotypes: Fraser syndrome 3 MIM#617667; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9949 | GTPBP3 | Ain Roesley reviewed gene: GTPBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34276756, 25434004; Phenotypes: Combined oxidative phosphorylation deficiency 23 MIM#616198; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9929 | ACVR1 |
Zornitza Stark changed review comment from: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner. Multiple unrelated families reported. The R206H variant is recurrent.; to: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner. Multiple unrelated families reported. The R206H variant is recurrent. Note variants in this gene are also associated with congenital heart disease, PMID 29089047. |
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| Mendeliome v0.9912 | CYP11B1 | Zornitza Stark Phenotypes for gene: CYP11B1 were changed from to Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, MIM# 202010; Aldosteronism, glucocorticoid-remediable, MIM# 103900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9909 | CYP11B1 | Zornitza Stark reviewed gene: CYP11B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8768848, 1731223, 29703198; Phenotypes: Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, MIM# 202010, Aldosteronism, glucocorticoid-remediable, MIM# 103900; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9909 | CYP11A1 | Zornitza Stark Phenotypes for gene: CYP11A1 were changed from to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM# 613743 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9906 | CYP11A1 | Zornitza Stark reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12161514, 16705068, 18182448, 28425981; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM# 613743; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9846 | CALU | Ain Roesley reviewed gene: CALU: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9785 | IRF6 | Ain Roesley reviewed gene: IRF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301581; Phenotypes: Popliteal pterygium syndrome 1MIM#119500, van der Woude syndrome MIM#119300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9785 | INPPL1 | Ain Roesley reviewed gene: INPPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23273567, 34529350, 34094554; Phenotypes: Opsismodysplasia MIM#258480; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9779 | IHH | Ain Roesley reviewed gene: IHH: Rating: GREEN; Mode of pathogenicity: None; Publications: 34530144, 12632327, 32311039, 29155992; Phenotypes: Acrocapitofemoral dysplasia MIM#607778, Brachydactyly, type A1 MIM#112500; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9779 | KIAA1109 | Ain Roesley reviewed gene: KIAA1109: Rating: GREEN; Mode of pathogenicity: None; Publications: 29290337, 30906834; Phenotypes: Alkuraya-Kucinskas syndrome MIM#617822; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9779 | KCTD1 | Ain Roesley reviewed gene: KCTD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23541344, 31324836; Phenotypes: Scalp-ear-nipple syndrome MIM#181270; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9779 | KCNJ2 | Ain Roesley reviewed gene: KCNJ2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Andersen syndrome MIM#170390, Atrial fibrillation, familial, 9 MIM#613980, Short QT syndrome 3 MIM#609622; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9779 | KAT6A | Ain Roesley reviewed gene: KAT6A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30245513; Phenotypes: Arboleda-Tham syndrome MIM#616268; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9737 | IMPAD1 | Ain Roesley reviewed gene: IMPAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22887726, 21549340; Phenotypes: Chondrodysplasia with joint dislocations, GPAPP type MIM#614078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9737 | IL1RAPL1 | Ain Roesley reviewed gene: IL1RAPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34452636, 27470653, 21484992, 18801879, 18801879; Phenotypes: Intellectual developmental disorder, X-linked 21 MIM#300143; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9733 | IFITM5 | Ain Roesley reviewed gene: IFITM5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22863190, 22863195, 32383316, 24519609; Phenotypes: Osteogenesis imperfecta, type V MIM#610967; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9727 | CFTR | Zornitza Stark Phenotypes for gene: CFTR were changed from to Cystic fibrosis, MIM# 219700; Congenital bilateral absence of vas deferens, MIM# 277180 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9725 | CFTR | Zornitza Stark reviewed gene: CFTR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cystic fibrosis, MIM# 219700, Congenital bilateral absence of vas deferens, MIM# 277180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9725 | ASIP | Ain Roesley reviewed gene: ASIP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9713 | BSG | Paul De Fazio reviewed gene: BSG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Blood group, OK] MIM#111380; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9713 | TPCN2 | Paul De Fazio reviewed gene: TPCN2: Rating: RED; Mode of pathogenicity: None; Publications: 20197744, 26918892; Phenotypes: [Skin/hair/eye pigmentation 10, blond/brown hair] MIM#612267; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9713 | MYO9B | Paul De Fazio reviewed gene: MYO9B: Rating: RED; Mode of pathogenicity: None; Publications: 16720215, 16423886, 16282976; Phenotypes: {Celiac disease, susceptibility to, 4} MIM#609753; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9682 | BMPER |
Zornitza Stark commented on gene: BMPER: Perinatal lethal skeletal dysplasia. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases. At least 5 unrelated families reported. |
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| Mendeliome v0.9638 | HR | Ain Roesley reviewed gene: HR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alopecia universalis MIM#203655, Atrichia with papular lesions MIM#209500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9638 | HPSE2 | Ain Roesley reviewed gene: HPSE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25145936, 23313374, 33558177; Phenotypes: Urofacial syndrome 1 MIM#236730; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9638 | HNRNPK | Ain Roesley reviewed gene: HNRNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Au-Kline syndrome MIM#616580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9638 | HES7 | Ain Roesley reviewed gene: HES7: Rating: ; Mode of pathogenicity: None; Publications: 29459493, 23897666, 18775957, 20087400; Phenotypes: Spondylocostal dysostosis 4, autosomal recessive MIM#613686; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9635 | TOP2B | Zornitza Stark Phenotypes for gene: TOP2B were changed from Autosomal dominant deafness; Antibody deficiency, recurrent infections, facial dysmorphism, limb anomalies; Intellectual disability to Autosomal dominant deafness; B-cell immunodeficiency, distal limb anomalies, and urogenital malformations, MIM# 609296; Intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9581 | SIM1 |
Zornitza Stark edited their review of gene: SIM1: Added comment: At least 20 probands with reduced penetrance reported. PMID:33434169; 1x missense inherited from normal mother PMID:30926952; 2x unrelated - 1 missense 1 splice. Family history noted PMID:23778136; 4 children with clinical features of PWL syndrome, including severe obesity - all missense 1x inherited from normal father PMID:23778139; at least 13 families with segregation and reduced penetrance evidence - all missense In vitro luciferase done to show LoF NOTE: Individuals with Prader-Willi-like phenotype may have 6q16.2del instead, which encompasses SIM1; Changed rating: GREEN; Changed publications: 33434169, 30926952, 23778136, 23778139; Changed phenotypes: congenital obesity, Prader-Willi-like syndrome; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Mendeliome v0.9581 | POMC | Zornitza Stark Phenotypes for gene: POMC were changed from to Obesity, adrenal insufficiency, and red hair due to POMC deficiency MIM#609734 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9569 | KIAA0391 |
Lucy Spencer changed review comment from: Four unrelated families with multisystem disease associated with bi-allelic variants in PRORP. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. -1 consanguineous family with homozygous missense in 3 affected sisters, het parents unaffected. Siblings had profound bilateral SNHL in infancy. In teens developed primary amenorrhea/Perrault syndrome, and hypergonadotropic hypogonadism. -1 unrelated male with compound het missense, each inherited from an unaffected parent. Hearing loss noted at 3, diagnosed at 5. -1 unrelated male compound het for a missense and a frameshift. appendicular hypertonia in infancy, mild dysmorphism. Severe global dev delay at 20 months. Normal hearing at 18 months, but at 3 years had bilateral SNHL. -an affected mother and her 2 affected children (son and daughter), homozygous for a missense. Father is heterozygous and unaffected. Son has psychotic disorder, autistic traits. Sister had intrauterine growth retardation, global developmental delay, and seizures in the first years of life. Mother presented with retrobulbar optic neuritis and tonic pupil at 39 years of age, then with asthenia, myalgias, memory loss, and frequent headaches. All variants are in p.400s. Sources: Literature; to: Four unrelated families with multisystem disease associated with bi-allelic variants in PRORP. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. -1 consanguineous family with homozygous missense in 3 affected sisters, het parents unaffected. Siblings had profound bilateral SNHL in infancy. In teens developed primary amenorrhea/Perrault syndrome, and hypergonadotropic hypogonadism. -1 unrelated male with compound het missense, each inherited from an unaffected parent. Hearing loss noted at 3, diagnosed at 5. -1 unrelated male compound het for a missense and a frameshift. appendicular hypertonia in infancy, mild dysmorphism. Severe global dev delay at 20 months. Normal hearing at 18 months, but at 3 years had bilateral SNHL. -an affected mother and her 2 affected children (son and daughter), homozygous for a missense. Father is heterozygous and unaffected. Son has psychotic disorder, autistic traits. Sister had intrauterine growth retardation, global developmental delay, and seizures in the first years of life. Mother presented with retrobulbar optic neuritis and tonic pupil at 39 years of age, then with asthenia, myalgias, memory loss, and frequent headaches. All variants are in p.400s. Sources: Literature |
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| Mendeliome v0.9567 | KIAA0391 |
Lucy Spencer gene: KIAA0391 was added gene: KIAA0391 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA0391 were set to PMID: 34715011 Added comment: Four unrelated families with multisystem disease associated with bi-allelic variants in PRORP. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. -1 consanguineous family with homozygous missense in 3 affected sisters, het parents unaffected. Siblings had profound bilateral SNHL in infancy. In teens developed primary amenorrhea/Perrault syndrome, and hypergonadotropic hypogonadism. -1 unrelated male with compound het missense, each inherited from an unaffected parent. Hearing loss noted at 3, diagnosed at 5. -1 unrelated male compound het for a missense and a frameshift. appendicular hypertonia in infancy, mild dysmorphism. Severe global dev delay at 20 months. Normal hearing at 18 months, but at 3 years had bilateral SNHL. -an affected mother and her 2 affected children (son and daughter), homozygous for a missense. Father is heterozygous and unaffected. Son has psychotic disorder, autistic traits. Sister had intrauterine growth retardation, global developmental delay, and seizures in the first years of life. Mother presented with retrobulbar optic neuritis and tonic pupil at 39 years of age, then with asthenia, myalgias, memory loss, and frequent headaches. All variants are in p.400s. Sources: Literature |
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| Mendeliome v0.9564 | SPATA5L1 |
Paul De Fazio gene: SPATA5L1 was added gene: SPATA5L1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPATA5L1 were set to 34626583 Phenotypes for gene: SPATA5L1 were set to Intellectual disability; spastic-dystonic cerebral palsy; epilepsy; hearing loss Review for gene: SPATA5L1 was set to GREEN gene: SPATA5L1 was marked as current diagnostic Added comment: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly. Sources: Literature |
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| Mendeliome v0.9563 | SPRED2 |
Dean Phelan gene: SPRED2 was added gene: SPRED2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPRED2 were set to PMID: 34626534 Phenotypes for gene: SPRED2 were set to developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt Review for gene: SPRED2 was set to GREEN Added comment: PMID: 34626534 Homozygosity for three different variants c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95) were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behaviour. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. Sources: Literature |
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| Mendeliome v0.9563 | KPNA3 |
Ain Roesley gene: KPNA3 was added gene: KPNA3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KPNA3 were set to 34564892 Phenotypes for gene: KPNA3 were set to infantile onsetHereditary Spastic Paraplegia Penetrance for gene: KPNA3 were set to Complete Review for gene: KPNA3 was set to GREEN gene: KPNA3 was marked as current diagnostic Added comment: 8 affecteds from 5 families with infantile-onset pure HSP all missense variants, in vitro functional demonstrated reduced cargo binding Noted that 1 individual had 2 de novo missense in the gene and though 1 is less deleterious than the other in the functional assays, authors were not able to rule out either one as a VUS Sources: Literature |
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| Mendeliome v0.9562 | POMC | Zornitza Stark reviewed gene: POMC: Rating: GREEN; Mode of pathogenicity: None; Publications: 33666293; Phenotypes: Obesity, adrenal insufficiency, and red hair due to POMC deficiency MIM#609734; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9543 | EHBP1L1 |
Krithika Murali gene: EHBP1L1 was added gene: EHBP1L1 was added to Mendeliome. Sources: Expert list,Literature Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EHBP1L1 were set to 34645488; 26833786 Phenotypes for gene: EHBP1L1 were set to Non-immune hydrops fetalis Review for gene: EHBP1L1 was set to AMBER Added comment: No OMIM gene disease association. Biallelic EHBP1L1 variants identified in 2 consanguineous families from Saudi Arabia with non-immune hydrops fetalis resulting in recurrent fetal loss. Supportive mouse models for this phenotype also reported. Sources: Expert list, Literature |
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| Mendeliome v0.9529 | AGTR1 | Zornitza Stark Phenotypes for gene: AGTR1 were changed from to Renal tubular dysgenesis, MIM# 267430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9526 | AGTR1 | Zornitza Stark reviewed gene: AGTR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9526 | AGT | Zornitza Stark Phenotypes for gene: AGT were changed from to Renal tubular dysgenesis, MIM# 267430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9523 | AGT | Zornitza Stark reviewed gene: AGT: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 34234805, 33163725; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9516 | ACE | Zornitza Stark Phenotypes for gene: ACE were changed from to Renal tubular dysgenesis, MIM# 267430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9513 | ACE | Zornitza Stark reviewed gene: ACE: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 22095942; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9502 | ETHE1 | Zornitza Stark commented on gene: ETHE1: Severe metabolic disorder characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhoea. Brain MRI shows necrotic lesions in deep gray matter structures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9469 | BCL9L |
Krithika Murali gene: BCL9L was added gene: BCL9L was added to Mendeliome. Sources: Literature,Expert list,Other Mode of inheritance for gene: BCL9L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BCL9L were set to 23035047; 8757136 Phenotypes for gene: BCL9L were set to Heterotaxy; Congenital Heart Disease Review for gene: BCL9L was set to AMBER Added comment: Novel gene disease assocaition. Saunders et al., 2012 (PMID: 23035047) report biallelic BCL9L variants in 2 affected brothers with heterotaxy and congenital heart disease, heterozygous in unaffected parents. Functional evidence in zebrafish (PMID 8757136) Sources: Literature, Expert list, Other |
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| Mendeliome v0.9406 | CHRNA5 | Paul De Fazio reviewed gene: CHRNA5: Rating: RED; Mode of pathogenicity: None; Publications: 20643934, 18385676; Phenotypes: Lung cancer susceptibility 2 (MIM#612052), Nicotine dependence, susceptibility to (MIM#612052); Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9406 | STOX1 | Paul De Fazio reviewed gene: STOX1: Rating: RED; Mode of pathogenicity: None; Publications: 15806103, 17290274, 30548667, 33301424; Phenotypes: Preeclampsia/eclampsia 4 (MIM#609404); Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9392 | KCNC2 |
Daniel Flanagan gene: KCNC2 was added gene: KCNC2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: KCNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNC2 were set to PMID:32392612; 31972370 Phenotypes for gene: KCNC2 were set to epileptic encephalopathy; spastic tetraplegia; opisthotonos attacks; intellectual disability; West syndrome Review for gene: KCNC2 was set to AMBER Added comment: PMID: 31972370. De novo missense variant (p.Val471Leu) identified in a child with early severe developmental and epileptic encephalopathy, spastic tetraplegia, opisthotonos attacks. PMID: 32392612. De novo missense variant (p.Asp167Tyr) identified in a neurofibromatosis type 1 related West syndrome patient. Functional analysis showed a significant reduction of the mean potassium current and a shift in the voltage dependence of steady-state activation. Maternally inherited NF1 variant (p.T1951Nfs*5) also identified, the mother was "clinically unremarkable". Sources: Expert list |
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| Mendeliome v0.9384 | L3MBTL1 |
Zornitza Stark gene: L3MBTL1 was added gene: L3MBTL1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: L3MBTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) Publications for gene: L3MBTL1 were set to 23543057; 15123827; 30794780 Phenotypes for gene: L3MBTL1 were set to Affected tissue: myeloid lineages; Phenotype resulting from under expression: lymphoid malignancy Review for gene: L3MBTL1 was set to RED Added comment: Germline variation in this imprinted gene is not currently associated with disease. Somatic deletions of 20q are associated with chronic myeloid malignancies. Aziz et al showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis. Sources: Expert Review |
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| Mendeliome v0.9379 | OOEP |
Zornitza Stark gene: OOEP was added gene: OOEP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OOEP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OOEP were set to 29574422 Phenotypes for gene: OOEP were set to Multi locus imprinting disturbance in offspring Review for gene: OOEP was set to RED Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) and a transient neonatal diabetes mellitus phenotype. This gene encodes part of the subcortical maternal complex (SCMC). Other genes in this group act as 'maternal effect' genes and are associated with early embryonic arrest, recurrent hydatiform mole and MLID in offspring. As is the case for other genes encoding components of the SCMC, the pathogenicity of variants can be difficult to establish as reproductive outcomes are not recorded in genomic databases and variants may be listed in population databases as they are not classed as pathogenic in males or women with no reproductive history. Functional studies of genes encoding components of the SCMC are limited as their expression is restricted to the oocyte and early embryo. Sources: Literature |
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| Mendeliome v0.9378 | ZNF445 |
Zornitza Stark gene: ZNF445 was added gene: ZNF445 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF445 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF445 were set to 34039421; 30602440; 30846001 Phenotypes for gene: ZNF445 were set to Temple syndrome; Multi locus imprinting disturbance (MLID) Review for gene: ZNF445 was set to RED Added comment: Single report (Kagami 2021) of a child with Temple syndrome and MLID found to have a novel homozygous truncating variant in ZNF445. ZNF445 has been shown to play a critical role in the maintenance of postfertilisation methylation imprints (Takahashi 2019). Mechanism and parent of origin effects remain uncertain. Sources: Literature |
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| Mendeliome v0.9373 | ERGIC1 | Zornitza Stark edited their review of gene: ERGIC1: Added comment: Pehlivan et al. 2019 (PMID:31230720) identified the third case of arthrogryposis in a child who harboured a previously unreported homozygous variant (c.782G>A; p.Gly261Asp) in this gene. Parents were heterozygous carriers. Functional studies were not performed.; Changed rating: GREEN; Changed publications: 28317099, 34037256, 31230720 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9366 | NLRP5 |
Zornitza Stark edited their review of gene: NLRP5: Added comment: 'Maternal effect gene' Part of the subcortical maternal complex Report of five mothers carrying either monoallelic or biallelic variants in NLRP5, who had both unaffected offspring and offspring with BWS-MLID (Doherty 2015). Report of one family where the mother carried biallelic variants in NLRP5, had one offspring with BWS, one unaffected offspring and multiple miscarriages (Sparago 2019). Reports of at least three unrelated individuals with recurrent early embryonic arrest carrying biallelic variants in NLRP5. Functional work suggesting protein degradation in affected human cell lines (Mu 2019, Xu 2020).; Changed rating: GREEN; Changed publications: 32222962, 31829238, 30877238, 26323243, 34440388; Changed phenotypes: Early embryonic arrest, Multi locus imprinting disturbance in offspring; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.9355 | GYPC | Paul De Fazio reviewed gene: GYPC: Rating: RED; Mode of pathogenicity: None; Publications: 29469208; Phenotypes: [Blood group, Gerbich] MIM#616089; Mode of inheritance: Other; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9347 | USP48 |
Eleanor Williams gene: USP48 was added gene: USP48 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: USP48 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: USP48 were set to 34059922 Phenotypes for gene: USP48 were set to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497 Penetrance for gene: USP48 were set to Incomplete Review for gene: USP48 was set to GREEN Added comment: PMID: 34059922 - Bassani et al 2021 - 3 cases reported with variants in USP48 and non syndromic hearing loss. They first analysed 4-generation Italian family with 6 individuals with hearing loss. The only rare variant segregating with the disease was a missense variant in USP48 (NM_032234.7:c.1216G > A, NP_115612.4:p.(Gly406Arg)). The variant is present in GnomAD v2.1.1 with a minor allele frequency (MAF) of 6.7 × 10−5 (17 allele out of 251 304 with no homozygotes). They also observed one hearing individual in the family who was heterozygous for the variant, suggesting incomplete penetrance. In a Dutch family the found by exome sequencing a missense variant in USP48 (NM_032236.7:c.2215_2216delinsTT, NP_115612.4:p.(Thr739Leu)). The probands mother and uncle were also affected by no sequence data was available for analysis. In a French family a proband is reported with right profound sensorineural hearing impairment (at 12 months), but normal left hearing (at 6 years old). The patient is heterozygote for a de novo splice variant in USP48 (NM_032236.7:c.3058 + 2 T > C, NP_115612.4:p.?;) which is not found in GnomAD and is predicted to result in a frameshift resulting in either NMD or a truncated protein. In functional experiments they showed that the two missense variants found in the Italian and Dutch families, and a shortened protein as predicted for the variant found in the French variant, showed an impaired ability to cleave tetra-ubiquitin into tri-, di- and mono-ubiquitin. Using immunohistology, they show that the human USP48 protein is present in fetal inner ear specimens. In addition zebrafish lacking usp48 showed a significant decrease of auditory response in acoustic startle response assays at 600 and 800 Hz wavelengths. Sources: Literature |
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| Mendeliome v0.9344 | TTC26 | Zornitza Stark Phenotypes for gene: TTC26 were changed from Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations to Biliary, renal, neurologic, and skeletal syndrome, MIM# 619534; Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9343 | TTC26 | Zornitza Stark edited their review of gene: TTC26: Changed phenotypes: Biliary, renal, neurologic, and skeletal syndrome, MIM# 619534, Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9338 | AIP | Paul De Fazio reviewed gene: AIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16728643, 17360484, 26187128; Phenotypes: Pituitary adenoma predisposition MIM#102200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9303 | ZDHHC15 |
Krithika Murali changed review comment from: Lewis et al Neurology Genetics 2021 Functional analysis of 4 ZDHHC15 variants - x2 Jin et al, others identified through GeneMatcher Yeast cells expressing ZDHHC15 p.L13P (Jin et al, maternally inherited), p.K115R (maternally inherited) and p.S330p were indistinguishable from cells harboring the reference ZDHHC15 allele, however those expressing p.H158R (also reported in Jin et al, maternally inherited) disrupted normal protein function.; to: Lewis et al Neurology Genetics 2021 Functional analysis of 4 ZDHHC15 variants - x2 Jin et al Nat Genet 2020 PMID 32989326, others identified through GeneMatcher Yeast cells expressing ZDHHC15 p.L13P (Jin et al, maternally inherited), p.K115R (maternally inherited) and p.S330p were indistinguishable from cells harboring the reference ZDHHC15 allele, however those expressing p.H158R (also reported in Jin et al, maternally inherited) disrupted normal protein function. |
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| Mendeliome v0.9297 | ABHD16A |
Lucy Spencer gene: ABHD16A was added gene: ABHD16A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ABHD16A were set to PMID: 34587489 Phenotypes for gene: ABHD16A were set to Spastic paraplegia Review for gene: ABHD16A was set to GREEN Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls. In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian. 4 missense variants, 1 frameshift, 1 nonsense. From PMID: 34587489 Sources: Literature |
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| Mendeliome v0.9297 | WLS |
Teresa Zhao changed review comment from: - We identified homozygous mutations in 10 affected persons from 5 unrelated families. - Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. - The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Sources: Literature; to: - Homozygous mutations in 10 affected persons from 5 unrelated families. - Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. - The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Sources: Literature |
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| Mendeliome v0.9297 | WLS |
Teresa Zhao gene: WLS was added gene: WLS was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WLS were set to PMID: 34587386 Phenotypes for gene: WLS were set to Syndromic structural birth defects Review for gene: WLS was set to GREEN Added comment: - We identified homozygous mutations in 10 affected persons from 5 unrelated families. - Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. - The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Sources: Literature |
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| Mendeliome v0.9296 | SHQ1 |
Zornitza Stark gene: SHQ1 was added gene: SHQ1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHQ1 were set to 34542157; 29178645 Phenotypes for gene: SHQ1 were set to Dystonia; Neurodegeneration Review for gene: SHQ1 was set to AMBER Added comment: Three unrelated families reported. Family 1: isolated dystonia only; Family 2: dystonia, and neurodegeneration; Family 3: neurodegeneration. Rated Amber as phenotypes likely represent a continuum but currently unclear. Sources: Literature |
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| Mendeliome v0.9274 | CDH15 |
Zornitza Stark commented on gene: CDH15: PMID: 19012874 - 4 unrelated patients with missense variants and mild-severe ID. Only two genes checked. All variants are common in gnomAD (>20 hets each) and classified as VUS or likely benign in ClinVar (paper is from 2008, pre-dates gnomAD). Functional studies were performed showing a LOF effect, where cell adhesion was reduced. However NMD PTCs are present in gnomAD (many >=6 hets each) PMID: 12052883 - null mouse model were viable, showed no gross developmental defects. In particular, the skeletal musculature appeared essentially normal. In the cerebellum of M-cadherin-lacking mutants, typical contactus adherens junctions were present and similar in size and numbers to the equivalent junctions in wild-type animals. However, the adhesion plaques in the cerebellum of these mutants appeared to contain elevated levels of N-cadherin compared to wild-type animals. PMID: 28422132 - reviewed microdeletions spanning multiple genes including CDH15, suggests it may contribute to a more severe neurological phenotype, with particular regard to brain malformations. PMID: 26506440 - speculates low penetrance for PTCs in this gene. Acknowledges variants in ExAC, describes them as benign Note no P/LP variants in ClinVar |
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| Mendeliome v0.9244 | ARFGEF1 |
Zornitza Stark gene: ARFGEF1 was added gene: ARFGEF1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARFGEF1 were set to 34113008 Phenotypes for gene: ARFGEF1 were set to Intellectual disability; Epilepsy Review for gene: ARFGEF1 was set to GREEN Added comment: 13 individuals reported with variants in this gene and a neurodevelopmental disorder characterised by variable ID, seizures present in around half. Variants were inherited from mildly affected parents in 40% of families. Sources: Expert Review |
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| Mendeliome v0.9219 | IRGM | Paul De Fazio reviewed gene: IRGM: Rating: RED; Mode of pathogenicity: None; Publications: 17554261, 19299395, 18985712, 20106866, 21278745, 20360734; Phenotypes: {Inflammatory bowel disease (Crohn disease) 19} MIM#612278; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9218 | FMN1 |
Bryony Thompson gene: FMN1 was added gene: FMN1 was added to Mendeliome. Sources: Literature SV/CNV tags were added to gene: FMN1. Mode of inheritance for gene: FMN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FMN1 were set to 20610440; 19383632; 15202026 Phenotypes for gene: FMN1 were set to oligosyndactyly; radioulnar synostosis; hearing loss; renal defects Review for gene: FMN1 was set to AMBER Added comment: A 263 Kb homozygous deletion of FMN1 has been identified in a single case with oligosyndactyly, radioulnar synostosis, hearing loss and renal defects. Also, a supporting null mouse model with oligosyndactyly. Also, a large duplication including GREM1 reported in association with Cenani–Lenz syndrome. Sources: Literature |
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| Mendeliome v0.9203 | B9D1 |
Bryony Thompson changed review comment from: hNow N PMID: 34338422 - compound het missense and frameshift variant in a proband with anal atresia with vestibular fistula, ventricular septal defect, and right renal agenesis (VACTERL cohort) PMID: 21763481 - B9d1 -/- mouse displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction.; to: 3 unrelated cases with a syndromic phenotype and a supporting null mouse model PMID: 34338422 - compound het missense and frameshift variant in a proband with anal atresia with vestibular fistula, ventricular septal defect, and right renal agenesis (VACTERL cohort) PMID: 24886560 - 2 Joubert syndrome cases PMID: 21763481 - B9d1 -/- mouse displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction. |
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| Mendeliome v0.9197 | ZMYM2 | Zornitza Stark edited their review of gene: ZMYM2: Changed phenotypes: Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, MIM# 619522 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9180 | WNT9B | Zornitza Stark Phenotypes for gene: WNT9B were changed from to Renal agenesis/hypoplasia/dysplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9176 | WNT9B | Zornitza Stark reviewed gene: WNT9B: Rating: AMBER; Mode of pathogenicity: None; Publications: 34145744; Phenotypes: Renal agenesis/hypoplasia/dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9170 | ERGIC1 |
Zornitza Stark gene: ERGIC1 was added gene: ERGIC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ERGIC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERGIC1 were set to 28317099; 34037256 Phenotypes for gene: ERGIC1 were set to Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100 Review for gene: ERGIC1 was set to AMBER Added comment: Reinstein et al. (2018) used WES in a large consanguineous Israeli Arab kindred consisting of 16 patients affected with the neurogenic type of arthrogryposis multiplex congenita. They identified a homozygous missense (V98E) mutation in ERGIC1 gene, which segregated with the disorder in the kindred, and was not found in the ExAC database or in 212 ethnically matched controls. Functional studies of the variant and studies of patient cells were not performed. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi. Marconi et al (2021) used genome sequencing in a consanguineous family with 2 affected siblings presenting congenital arthrogryposis and some facial dysmorphism. They identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents. Sources: Literature |
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| Mendeliome v0.9162 | FCGR2B | Paul De Fazio reviewed gene: FCGR2B: Rating: RED; Mode of pathogenicity: None; Publications: 12115230, 15153543, 20385827; Phenotypes: {Systemic lupus erythematosus, susceptibility to} MIM#152700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9150 | SLC4A1 | Zornitza Stark Phenotypes for gene: SLC4A1 were changed from to Cryohydrocytosis MIM# 185020; Distal renal tubular acidosis 4 with haemolytic anaemia MIM# 611590; Ovalocytosis, SA type MIM# 166900; Spherocytosis, type 4 MIM# 612653; Distal renal tubular acidosis 1 MIM# 179800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9147 | FGFR2 | Chern Lim reviewed gene: FGFR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29848297, 32879300, 27323706; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9147 | SLC4A1 | Danielle Ariti reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16227998, 15211439, 7949112, 8640229, 16227998, 8640229, 16227998, 33881640, 32632909; Phenotypes: Cryohydrocytosis MIM# 185020, Distal renal tubular acidosis 4 with haemolytic anaemia MIM# 611590, Ovalocytosis, SA type MIM# 166900, Spherocytosis, type 4 MIM# 612653, Distal renal tubular acidosis 1 MIM# 179800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9131 | LPIN2 | Zornitza Stark Phenotypes for gene: LPIN2 were changed from to Majeed syndrome, MIM# 609628; Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9128 | LPIN2 | Zornitza Stark reviewed gene: LPIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15994876, 33993107, 33670882, 33314777, 31727123; Phenotypes: Majeed syndrome, MIM# 609628, Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9101 | UMPS |
Zornitza Stark edited their review of gene: UMPS: Added comment: 20 unrelated patients have been reported with biallelic missense variants; one mouse model Orotic aciduria is characterised by megaloblastic anaemia and orotic acid crystalluria, frequently associated with a degree of physical and intellectual disability. Other features include, congenital malformations (Atrial/ Ventricular septal defect) and immunodeficiencies (T-cell dysfunction, failure to thrive, recurrent infections). Haematology features - Megaloblastic anaemia - Low to normal reticulocyte count - Anisocytosis - Poikilocytosis - Hypochromia; Changed publications: 9042911, 33489760; Changed phenotypes: Orotic aciduria, MIM# 258900 |
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| Mendeliome v0.9091 | PDGFRL | Michelle Torres reviewed gene: PDGFRL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9088 | IFIH1 |
Sarah Pantaleo changed review comment from: Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007). In one case of neonatal-onset IBD, a homozygous truncating variant was identified. seven carriers of LoF variants (three of whom have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.; to: IFIH1 encodes MDA5, a key cystolic sensor for viral nucleic acids. Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007). In one case of neonatal-onset IBD, a homozygous truncating variant was identified. There were seven carriers of LoF variants identified (range of onset 6 months to 6 years of age). In three of these cases, a second hypomorphic missense variant was identified. Luciferase reporter assays were employed to assess MDA5 activity. In some cases, the second missense variant was either proven to not affect protein function or was in cis with the LoF variant. Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis. |
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| Mendeliome v0.9088 | IFIH1 |
Sarah Pantaleo changed review comment from: Rare, likely loss-of-functions IFIH1 variants identified in eight patients with Very Early Onset Inflammatory Bowel Disease (VEOIBD) with VEOIBD from a combined cohort of 42 children. One homozygous truncating variant in a neonate from a consanguineous family, seven carriers of LoF variants (three of whom also have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.; to: Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007). In one case of neonatal-onset IBD, a homozygous truncating variant was identified. seven carriers of LoF variants (three of whom have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant. |
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| Mendeliome v0.9075 | UBE2U |
Ee Ming Wong gene: UBE2U was added gene: UBE2U was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UBE2U were set to PMID: 33776059 Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay Penetrance for gene: UBE2U were set to Complete Review for gene: UBE2U was set to RED gene: UBE2U was marked as current diagnostic Added comment: - one missense UBE2U variant identified in one family with four other affected individuals (includes proband) - in silico analyses predicts the UBE2U variant to be damaging - no functional - another STUM missense variant identified in the same family predicted to be benign - additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome Sources: Literature |
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| Mendeliome v0.9068 | CACNA1I |
Kristin Rigbye gene: CACNA1I was added gene: CACNA1I was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CACNA1I were set to 33704440 Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder Mode of pathogenicity for gene: CACNA1I was set to Other Review for gene: CACNA1I was set to GREEN Added comment: 4 different missense variants identified and shown to result in a gain of function. 2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy. 1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases. Sources: Literature |
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| Mendeliome v0.9068 | ZNF668 |
Paul De Fazio changed review comment from: 5 individuals from 3 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature; to: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature |
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| Mendeliome v0.9067 | ZNF668 |
Paul De Fazio changed review comment from: 5 individuals from 3 consanguineous families reported with different truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature; to: 5 individuals from 3 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature |
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| Mendeliome v0.9067 | ZNF668 |
Paul De Fazio gene: ZNF668 was added gene: ZNF668 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF668 were set to 34313816; 26633546 Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism Review for gene: ZNF668 was set to GREEN gene: ZNF668 was marked as current diagnostic Added comment: 5 individuals from 3 consanguineous families reported with different truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature |
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| Mendeliome v0.9026 | TOM1 |
Zornitza Stark gene: TOM1 was added gene: TOM1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TOM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TOM1 were set to 31263572 Phenotypes for gene: TOM1 were set to Immunodeficiency 85 and autoimmunity, MIM# 619510 Review for gene: TOM1 was set to RED Added comment: Parent and child reported with onset of atopic eczema and recurrent respiratory infections in the first decade of life; autoimmune enteropathy with vomiting, diarrhoea, and poor overall growth. More variable features included autoimmune oligoarthritis, interstitial pneumonitis, and EBV viremia. Laboratory studies showed hypogammaglobulinaemia and abnormal T-cell function, consistent with a combined immunodeficiency. Missense variant in TOM1, with limited functional data. Sources: Expert list |
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| Mendeliome v0.9025 | GINS2 |
Arina Puzriakova gene: GINS2 was added gene: GINS2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GINS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GINS2 were set to 34353863 Phenotypes for gene: GINS2 were set to Meier-Gorlin syndrome with craniosynostosis Review for gene: GINS2 was set to RED Added comment: Sa et al., 2021 (PMID: 34353863) identified a patient presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. A homozygous missense variant (c.341G>T, p.Arg114Leu) in GINS2 was identified that was heterozygous in both unaffected parents. Some supportive functional data included. GINS2 is not currently not associated with any phenotype in OMIM or G2P and no additional cases have been identified to date. Sources: Literature |
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| Mendeliome v0.9019 | FGF20 |
Zornitza Stark gene: FGF20 was added gene: FGF20 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: FGF20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FGF20 were set to 22698282 Phenotypes for gene: FGF20 were set to Renal hypodysplasia/aplasia 2, MIM#615721 Review for gene: FGF20 was set to AMBER Added comment: Multiple affected fetuses in a consanguineous family; functional data. Sources: Expert Review |
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| Mendeliome v0.9018 | ITGA8 | Zornitza Stark Phenotypes for gene: ITGA8 were changed from to Renal hypodysplasia/aplasia 1, MIM# 191830 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9015 | ITGA8 | Zornitza Stark reviewed gene: ITGA8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24439109; Phenotypes: Renal hypodysplasia/aplasia 1, MIM# 191830; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8984 | PNPLA6 |
Zornitza Stark changed review comment from: Ataxia is part of the phenotype. Sources: Expert list; to: Variants in this gene are associated with multiple phenotypes. Oliver-McFarlane syndrome is a rare congenital disorder characterized by trichomegaly, severe chorioretinal atrophy and multiple pituitary hormone deficiencies, including growth hormone. At least 10 families reported. Laurence-Moon syndrome has a clinical presentation similar to that of Oliver-McFarlane syndrome, including chorioretinopathy and pituitary dysfunction, but with childhood onset of ataxia, peripheral neuropathy, and spastic paraplegia and without trichomegaly. Single family reported. |
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| Mendeliome v0.8984 | PNPLA6 | Zornitza Stark edited their review of gene: PNPLA6: Changed publications: 25480986, 33818269, 32758583, 30097146; Changed phenotypes: Oliver-McFarlane syndrome, MIM# 275400, Laurence-Moon syndrome, MIM# 245800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8969 | MYO1H |
Zornitza Stark gene: MYO1H was added gene: MYO1H was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYO1H were set to 28779001 Phenotypes for gene: MYO1H were set to Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction, MIM#619482 Review for gene: MYO1H was set to RED Added comment: Single family reported with three affected children, homozygous LoF variant. Sources: Literature |
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| Mendeliome v0.8965 | PRKDC | Zornitza Stark Phenotypes for gene: PRKDC were changed from to Immunodeficiency 26, with or without neurologic abnormalities MIM# 615966; Absent T and B cells; normal NK cells; SCID; recurrent respiratory infections; microcephaly; seizures; developmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8962 | PRKDC | Zornitza Stark reviewed gene: PRKDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 19075392, 23722905; Phenotypes: Immunodeficiency 26, with or without neurologic abnormalities MIM# 615966, Absent T and B cells, normal NK cells, SCID, recurrent respiratory infections, microcephaly, seizures, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8962 | TBX1 | Zornitza Stark Phenotypes for gene: TBX1 were changed from to DiGeorge syndrome MIM# 188400; Velocardiofacial syndrome MIM# 192430; Decreased T cells; Hypoparathyroidism; Conotruncal cardiac malformation; velopalatal insufficiency; abnormal facies (cleft palate, prominent tubular nose etc); intellectual disability; Immunodeficiency; thymic hypoplasia or aplasia with resultant T‐cell dysfunction; renal anomalies; autoimmunity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8959 | TBX1 | Zornitza Stark reviewed gene: TBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301696, 31830774, 16684884; Phenotypes: DiGeorge syndrome MIM# 188400, Velocardiofacial syndrome MIM# 192430, Decreased T cells, Hypoparathyroidism, Conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies (cleft palate, prominent tubular nose etc), intellectual disability, Immunodeficiency, thymic hypoplasia or aplasia with resultant T‐cell dysfunction, renal anomalies, autoimmunity; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8935 | MTHFD1 | Danielle Ariti reviewed gene: MTHFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780, Decreased Ig levels, poor antibody responses to conjugated polysaccharide antigens, low B/T/NK cells, Recurrent bacterial infection, megaloblastic anaemia, failure to thrive, neutropenia, seizures, intellectual disability, folate-responsive, Lymphopaenia; Phenotypes: 32414565, 19033438; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8889 | ZNF699 |
Zornitza Stark gene: ZNF699 was added gene: ZNF699 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF699 were set to 33875846 Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488 Review for gene: ZNF699 was set to GREEN Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections. 12 unrelated families reported, 5 different homozygous frameshift variants. Sources: Literature |
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| Mendeliome v0.8853 | PLAG1 |
Zornitza Stark edited their review of gene: PLAG1: Added comment: Additional families reported, upgrade to Green. Silver-Russell syndrome-4 (SRS4) is characterised by intrauterine growth retardation followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face and prominent forehead, and relative macrocephaly at birth may be observed. So far 4 families have been reported with some functional studies of the role of the gene in the growth pathway. Abi Habib et al. (2018) reported 1 family (child, sister and mother) patient with Silver-Russell syndrome (with normal methylation on chromosomes 7, 11, and 14, and exclusion of maternal UPD and chromosomal rearrangements). Using WES they identified a heterozygous 1-bp deletion in the PLAG1 gene. The variant segregated with disease, and was not present in polymorphism databases or ExAC. They also reported another patient with a different heterozygous 1-bp deletion in the PLAG1 gene. This was not found in her unaffected twin brother, older brother, or parents. Experiments in Hep3b cells demonstrated that PLAG1 positively regulates expression of the IGF2 promoter P3, independently and via the HMGA2-PLAG1-IGF2 pathway. Disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects (SRS1; 180860), except for body asymmetry, which is not expected to occur since the molecular defects are present in all cells of the body, unlike the mosaic epigenetic changes at the 11p15.5 locus. Inoue et al. (2020) reported 1 family with 2 affected people with Silver-Russell syndrome with a nonsense variant in the PLAG1 gene, which segregated with disease. Vado et al. (2020) reported 1 family with multiple affected people with Silver-Russell syndrome with a frameshift variant in the PLAG1 gene, which segregated with disease.; Changed rating: GREEN; Changed publications: 28796236, 29913240, 33291420, 32546215 |
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| Mendeliome v0.8851 | WIPF1 | Zornitza Stark Phenotypes for gene: WIPF1 were changed from to Wiskott-Aldrich syndrome 2 MIM# 614493; Reduced T cells; defective lymphocyte responses to anti-CD3; high IgE; Thrombocytopenia with or without small platelets; recurrent bacterial and viral Infections; eczema; bloody diarrhoea; gastrointestinal bleeding; WAS protein absent | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8844 | TAP2 | Zornitza Stark Phenotypes for gene: TAP2 were changed from to Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8841 | TAP1 | Zornitza Stark Phenotypes for gene: TAP1 were changed from to Bare lymphocyte syndrome, type I MIM#604571; Low CD8; absent MHC I on lymphocytes; vasculitis; pyoderma gangrenosum; skin lesions; recurrent respiratory tract infections; bronchiectasis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8836 | WIPF1 | Danielle Ariti reviewed gene: WIPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22231303, 27742395, 11869681, 14757742; Phenotypes: Wiskott-Aldrich syndrome 2 MIM# 614493, Reduced T cells, defective lymphocyte responses to anti-CD3, high IgE, Thrombocytopenia with or without small platelets, recurrent bacterial and viral Infections, eczema, bloody diarrhoea, gastrointestinal bleeding, WAS protein absent; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8835 | TAP2 | Danielle Ariti reviewed gene: TAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7517574, 9232449, 10560675, 27861817; Phenotypes: Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571, Low CD8, absent MHC I on lymphocytes, Vasculitis, pyoderma gangrenosum, recurrent bacterial/viral respiratory infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8835 | TAP1 | Danielle Ariti reviewed gene: TAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28161407, 10074494, 1473153; Phenotypes: Bare lymphocyte syndrome, type I MIM#604571, Low CD8, absent MHC I on lymphocytes, vasculitis, pyoderma gangrenosum, skin lesions, recurrent respiratory tract infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8834 | RNF220 |
Zornitza Stark gene: RNF220 was added gene: RNF220 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF220 were set to 33964137; 10881263 Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum Review for gene: RNF220 was set to GREEN Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal. Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9). The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263). Extensive segregation analyses were carried out including several affected and unaffected members. RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc : *RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS) *The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions. *Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome. *Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2). *RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1. *Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt. *Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies. Sources: Literature |
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| Mendeliome v0.8829 | ARF3 |
Zornitza Stark gene: ARF3 was added gene: ARF3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARF3 were set to 34346499 Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system Review for gene: ARF3 was set to AMBER Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality. Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu. Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both. ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively. Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons. There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185). In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val). This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia. Evidence to support the effect of each variant include: Arg99Leu: Had identical Golgi localization to that of wt Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF) In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF). In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu) Asp67Val: Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant) Displayed decreased protein stability In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF) In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye. There is no associated phenotype in OMIM, G2P or SysID. Sources: Literature |
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| Mendeliome v0.8824 | PLXNA2 |
Zornitza Stark gene: PLXNA2 was added gene: PLXNA2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLXNA2 were set to 34327814 Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology Review for gene: PLXNA2 was set to AMBER Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants. The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members. Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)). Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed). The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed). Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved. Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele. As the authors discuss: *PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration. *Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch. *Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD. *Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus. Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg: - Cyanotic heart disease explaining discordance in cognitive outcome among sibs - Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or - Additional pathogenic variants possibly explaining the CHD in the first subject. There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes. Sources: Literature |
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| Mendeliome v0.8779 | STAT3 | Zornitza Stark Phenotypes for gene: STAT3 were changed from to Hyper-IgE recurrent infection syndrome MIM# 147060; Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8776 | STAT3 | Zornitza Stark reviewed gene: STAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17881745, 14566054, 25349174, 25038750, 25359994; Phenotypes: Hyper-IgE recurrent infection syndrome MIM# 147060, Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8776 | STK4 | Zornitza Stark Phenotypes for gene: STK4 were changed from to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868; CD4/CD8 lymphopaenia; cardiac malformations; reduced naïve T cells; increased TEM and TEMRA cells; poor T cell Proliferation; Reduced memory B cells; Reduced IgM, increased IgG, IgA, IgE; impaired antibody responses; intermittent neutropaenia; bacterial/ viral/ fungal infections; autoimmune cytopaenias; mucocutaneous candidiasis; cutaneous warts | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8770 | SMARCAL1 | Zornitza Stark Phenotypes for gene: SMARCAL1 were changed from to Schimke immune-osseous dysplasia MIM# 242900; T cell deficiency; Short stature; spondyloepiphyseal dysplasia; renal dysfunction; lymphocytopaenia; nephropathy; bacterial/viral/fungal infections; may present as SCID; bone marrow failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8767 | STK4 | Danielle Ariti reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22294732, 26117625, 22174160, 22952854; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868, CD4/CD8 lymphopaenia, cardiac malformations, reduced naïve T cells, increased TEM and TEMRA cells, poor T cell Proliferation, Reduced memory B cells, Reduced IgM, increased IgG, IgA, IgE, impaired antibody responses, intermittent neutropaenia, bacterial/ viral/ fungal infections, autoimmune cytopaenias, mucocutaneous candidiasis, cutaneous warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8767 | SMARCAL1 | Danielle Ariti reviewed gene: SMARCAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301550, 17089404, 20036229; Phenotypes: Schimke immune-osseous dysplasia MIM# 242900, T cell deficiency, Short stature, spondyloepiphyseal dysplasia, renal dysfunction, lymphocytopaenia, nephropathy, bacterial/viral/fungal infections, may present as SCID, bone marrow failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8758 | FAM20A | Zornitza Stark Phenotypes for gene: FAM20A were changed from to Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8755 | FAM20A | Zornitza Stark reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23434854, 23697977, 23468644, 24756937, 21549343, 24259279, 24196488, 26502894, 25827751, 21990045; Phenotypes: Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8741 | TCF7L2 |
Zornitza Stark changed review comment from: 2 reviews Konstantinos Varvagiannis (Other) I don't know Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants. Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11). One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury. TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts. Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development. Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1]. The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA). No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism. There are no variant or other studies performed, nor any animal models discussed. In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs). Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm. There is no other associated phenotype (notably NDD) in OMIM. G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF). SysID includes this gene within the autism candidate genes and current primary ID genes.; to: Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants. Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11). One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury. TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts. Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development. Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1]. The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA). No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism. There are no variant or other studies performed, nor any animal models discussed. In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs). Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm. There is no other associated phenotype (notably NDD) in OMIM. G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF). SysID includes this gene within the autism candidate genes and current primary ID genes. |
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| Mendeliome v0.8736 | PIDD1 |
Zornitza Stark gene: PIDD1 was added gene: PIDD1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010 Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum Review for gene: PIDD1 was set to GREEN Added comment: There is enough evidence to include this gene in the current panel with green rating. Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested. The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families]. Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants. Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder. PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage. There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation. Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants. Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26 Evidence so far provided includes: - Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern. - Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability. - Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp] - Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain. - Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD. Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects. There is currently no associated phenotype in OMIM. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes. Sources: Expert Review |
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| Mendeliome v0.8734 | COLGALT1 |
Bryony Thompson gene: COLGALT1 was added gene: COLGALT1 was added to Mendeliome. Sources: Other Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980 Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3 MIM#618360 Review for gene: COLGALT1 was set to GREEN Added comment: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos. Sources: Other |
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| Mendeliome v0.8716 | RBCK1 | Zornitza Stark Phenotypes for gene: RBCK1 were changed from to Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895; muscular weakness; cardiomyopathy; recurrent bacterial/viral infections; autoinflammation; immunodeficiency; Poor antibody responses to polysaccharides; failure to thrive; fever; pneumonia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8713 | RBCK1 | Danielle Ariti reviewed gene: RBCK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29260357, 29695863; Phenotypes: Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895, muscular weakness, cardiomyopathy, recurrent bacterial/viral infections, autoinflammation, immunodeficiency, Poor antibody responses to polysaccharides, failure to thrive, fever, pneumonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8703 | ACTL6A |
Zornitza Stark changed review comment from: Two individuals from unrelated families reported with missense variants in this gene. Part of the BAF complex. Only one confirmed de novo.; to: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain. PMID 31994175: fourth individual reported, recurrent de novo p.Arg377Trp |
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| Mendeliome v0.8671 | RGS10 |
Zornitza Stark gene: RGS10 was added gene: RGS10 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RGS10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RGS10 were set to 34315806; 34339853 Phenotypes for gene: RGS10 were set to Immunodeficiency; short stature Review for gene: RGS10 was set to RED Added comment: Three affected siblings with short stature and immunodeficiency and segregating biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals had recurrent infections, hypergammaglobulinaemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Limited functional data presented. Further experimental data linking RGS10 to immune function presented in PMID 34339853. Sources: Literature |
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| Mendeliome v0.8669 | MAST3 |
Zornitza Stark gene: MAST3 was added gene: MAST3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAST3 were set to 34185323 Phenotypes for gene: MAST3 were set to Developmental and epileptic encephalopathy Review for gene: MAST3 was set to GREEN Added comment: Eleven individuals reported with de novo missense variants in the STK domain, including two recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. Limited functional data. Sources: Literature |
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| Mendeliome v0.8657 | ACAN |
Zornitza Stark edited their review of gene: ACAN: Added comment: Patients with SSOAD exhibit a broad phenotypic spectrum involving short stature associated with advanced bone maturation and early-onset osteoarthritis (OA), as well as mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disc disease and osteochondritis dissecans, which is characterized by separation of articular cartilage and subchondral bone from the articular surface. Phenotypes are highly variable even among patients within the same family, and there are no apparent genotype-phenotype correlations. Well established gene-disease association, multiple families reported. Note fewer families reported with bi-allelic variants in this gene and extreme short stature.; Changed publications: 24762113, 27870580, 19110214, 30124491, 28331218, 20137779; Changed phenotypes: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800, Spondyloepimetaphyseal dysplasia, aggrecan type 612813 |
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| Mendeliome v0.8657 | NFKBIA | Zornitza Stark Phenotypes for gene: NFKBIA were changed from to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132; Ectodermal dysplasia; TCR/ BCR activation impaired; low memory and isotype switched B cells; decreased IgG and IgA; elevated IgM; poor specific antibody responses; diarrhoea; agammaglobulinaemia; ectodermal dysplasia; recurrent respiratory and gastrointestinal infections; colitis; variable defects of skin, hair and teeth | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8654 | NFKB2 | Zornitza Stark Phenotypes for gene: NFKB2 were changed from to Immunodeficiency, common variable, 10 MIM# 615577; Low serum IgG, IgA, IgM; low B cell numbers; low switched memory B cells; Recurrent sinopulmonary infections, Alopecia; endocrinopathies; ACTH deficiency | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8651 | NFKB1 | Zornitza Stark Phenotypes for gene: NFKB1 were changed from to Immunodeficiency, common variable, 12 MIM# 616576; Normal-low IgG, IgA, IgM; low-normal B cells; low switched memory B cells; hypogammaglobulinaemia; recurrent respiratory and gastrointestinal infections; Chronic obstructive pulmonary disease COPD; EBV proliferation; autoimmunity; alopecia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8648 | MCM4 | Zornitza Stark Phenotypes for gene: MCM4 were changed from to Immunodeficiency 54 MIM# 609981; Decreased NK cell number and function; Viral infections (EBV, HSV, VZV); Short stature; B cell lymphoma; Adrenal failure; Failure to thrive; Microcephaly; Increased chromosomal breakage; Hyperpigmentation; Lymphadenopathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8644 | MCM4 | Zornitza Stark reviewed gene: MCM4: Rating: AMBER; Mode of pathogenicity: None; Publications: 22354167, 22354170, 22499342; Phenotypes: Immunodeficiency 54 MIM# 609981, Decreased NK cell number and function, Viral infections (EBV, HSV, VZV), Short stature, B cell lymphoma, Adrenal failure, Failure to thrive, Microcephaly, Increased chromosomal breakage, Hyperpigmentation, Lymphadenopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8644 | MAP3K14 | Zornitza Stark Phenotypes for gene: MAP3K14 were changed from to NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8641 | MAP3K14 | Zornitza Stark reviewed gene: MAP3K14: Rating: GREEN; Mode of pathogenicity: None; Publications: 10319865, 11238593, 12352969; Phenotypes: NIK deficiency, Poor T cell proliferation to antigen, Low B-cell numbers, Low NK number and function, recurrent bacterial/viral/ cryptosporidium infections, hypogammaglobulinaemia, decreased immunoglobulin levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8641 | LRBA | Zornitza Stark Phenotypes for gene: LRBA were changed from to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700; Normal-decreased CD4 numbers; T cell dysregulation; Low-normal B cells; Reduced IgG and IgA; Recurrent infections; chronic diarrhoea; inflammatory bowel disease; hypogammaglobulinaemia; pneumonitis; autoimmune disorders; thrombocytopaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | LRBA | Zornitza Stark reviewed gene: LRBA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22608502, 22721650, 25468195, 26206937, 33155142; Phenotypes: Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700, Normal-decreased CD4 numbers, T cell dysregulation, Low-normal B cells, Reduced IgG and IgA, Recurrent infections, chronic diarrhoea, inflammatory bowel disease, hypogammaglobulinaemia, pneumonitis, autoimmune disorders, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | NFKBIA | Danielle Ariti reviewed gene: NFKBIA: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 28597146, 23864385, 23708964; Phenotypes: Ectodermal dysplasia and immunodeficiency 2 MIM# 612132, Ectodermal dysplasia, TCR/ BCR activation impaired, low memory and isotype switched B cells, decreased IgG and IgA, elevated IgM, poor specific antibody responses, diarrhoea, agammaglobulinaemia, ectodermal dysplasia, recurrent respiratory and gastrointestinal infections, colitis, variable defects of skin, hair and teeth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | NFKB2 | Danielle Ariti reviewed gene: NFKB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140114, 24888602, 25524009, 31417880; Phenotypes: Immunodeficiency, common variable, 10 MIM# 615577, Low serum IgG, IgA, IgM, low B cell numbers, low switched memory B cells, Recurrent sinopulmonary infections, Alopecia, endocrinopathies, ACTH deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | NFKB1 | Danielle Ariti reviewed gene: NFKB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26279205, 32278790, 27022143, 7834752; Phenotypes: Immunodeficiency, common variable, 12 MIM# 616576, Normal-low IgG, IgA, IgM, low-normal B cells, low switched memory B cells, hypogammaglobulinaemia, recurrent respiratory and gastrointestinal infections, Chronic obstructive pulmonary disease COPD, EBV proliferation, autoimmunity, alopecia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8632 | GIMAP5 |
Zornitza Stark gene: GIMAP5 was added gene: GIMAP5 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: GIMAP5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GIMAP5 were set to 33956074 Phenotypes for gene: GIMAP5 were set to Portal hypertension, noncirrhotic, 2, MIM# 619463 Review for gene: GIMAP5 was set to GREEN Added comment: 8 individuals from 4 unrelated families reported with onset of disease in the first decade of life. Clinical features included jaundice, hyperbilirubinaemia, pancytopaenia, including neutropaenia, lymphopaenia, and thrombocytopaenia, hepatosplenomegaly, and oesophageal varices. Some individuals had recurrent infections or features suggestive of an immunodeficiency. Liver biopsy was notable for the absence of cirrhosis and the presence of nodular regeneration. Sources: Expert list |
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| Mendeliome v0.8629 | IL7R | Zornitza Stark Phenotypes for gene: IL7R were changed from to Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971; fever; rash; failure to thrive; recurrent respiratory and gastric infections; diarrhoea; lymphadenopathy; pneumonitis; Pancytopaenia; low T-cell numbers; decreased immunoglobulins; normal-high B/NK-cell numbers. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8626 | MALT1 | Zornitza Stark Phenotypes for gene: MALT1 were changed from to Immunodeficiency 12 MIM# 615468; poor T-cell proliferation; normal T/B cell numbers; poor specific antibody response; recurrent bacterial/fungal/viral infections; bronchiectasis; failure to thrive | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8623 | IL2RG | Zornitza Stark Phenotypes for gene: IL2RG were changed from to Combined immunodeficiency, X-linked, moderate MIM# 312863; Severe combined immunodeficiency, X-linked MIM# 300400; recurrent viral/fungal/bacterial infections; Low T/NK cells; Low Ig levels; lymphocytopaenia; hypogammaglobulinaemia; failure to thrive; diarrhoea; Pneumonia; Thymic hypoplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8620 | IL2RG | Zornitza Stark reviewed gene: IL2RG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301584, 8462096, 8401490, 7883965, 9399950; Phenotypes: Combined immunodeficiency, X-linked, moderate MIM# 312863, Severe combined immunodeficiency, X-linked MIM# 300400, recurrent viral/fungal/bacterial infections, Low T/NK cells, Low Ig levels, lymphocytopaenia, hypogammaglobulinaemia, failure to thrive, diarrhoea, Pneumonia, Thymic hypoplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8620 | IKZF1 | Zornitza Stark Phenotypes for gene: IKZF1 were changed from to Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8617 | IKZF1 | Zornitza Stark reviewed gene: IKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317; Phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8617 | ITK | Zornitza Stark Phenotypes for gene: ITK were changed from to Lymphoproliferative syndrome 1 MIM# 613011; Lymphadenopathy; Recurrent infections; Hypogammaglobulinaemia; Evidence of EBV infection; EBV associated B cell Lymphoproliferation; High EBV viral load; Normal-low serum Ig; Depleted CD4+ T cells; Anaemia; Thrombocytopaenia; Hepatosplenomegaly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8614 | MALT1 |
Danielle Ariti edited their review of gene: MALT1: Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency. Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains. All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation.; Changed rating: GREEN |
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| Mendeliome v0.8614 | IL7R | Danielle Ariti reviewed gene: IL7R: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843216, 19890784, 26123418, 11023514, 7964471; Phenotypes: Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971, fever, rash, failure to thrive, recurrent respiratory and gastric infections, diarrhoea, lymphadenopathy, pneumonitis, Pancytopaenia, low T-cell numbers, decreased immunoglobulins, normal-high B/NK-cell numbers.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8614 | ITK | Danielle Ariti reviewed gene: ITK: Rating: GREEN; Mode of pathogenicity: None; Publications: 19425169, 22289921, 25061172, 26056787, 9311799, 10213685; Phenotypes: Lymphoproliferative syndrome 1 MIM# 613011, Lymphadenopathy, Recurrent infections, Hypogammaglobulinaemia, Evidence of EBV infection, EBV associated B cell Lymphoproliferation, High EBV viral load, Normal-low serum Ig, Depleted CD4+ T cells, Anaemia, Thrombocytopaenia, Hepatosplenomegaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8614 | MALT1 | Danielle Ariti reviewed gene: MALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23727036, 24332264, 14576442, 31037583; Phenotypes: Immunodeficiency 12 MIM# 615468, poor T-cell proliferation, normal T/B cell numbers, poor specific antibody response, recurrent bacterial/fungal/viral infections, bronchiectasis, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8601 | CLCN3 |
Kristin Rigbye gene: CLCN3 was added gene: CLCN3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CLCN3 were set to PMID: 34186028 Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder Mode of pathogenicity for gene: CLCN3 was set to Other Review for gene: CLCN3 was set to GREEN Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available. The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities: - Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures. - Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants. - Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals. - Six have mood or behavioural disorders, particularly anxiety (3/6). - Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia. The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal. Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers. Both loss and gain of function in this gene resulted in the same phenotype. Sources: Literature |
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| Mendeliome v0.8591 | UBA2 |
Ain Roesley changed review comment from: 2x unrelated probands with isolated split hand malformation. fs variants - 1x de novo and 1x inherited from apparent unaffected mother (no radiographs of her hand available) 1x proband with unilateral split-hand malformation. Her daughter and grandson reported to have ectrofactyly but were unavailable for testing; to: 2x unrelated probands with isolated split hand malformation. fs variants - 1x de novo and 1x inherited from apparent unaffected mother (no radiographs of her hand available) 1x proband with unilateral split-hand malformation (missense). Her daughter and grandson reported to have ectrofactyly but were unavailable for testing |
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| Mendeliome v0.8586 | TP73 | Ee Ming Wong reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34077761; Phenotypes: chronic airway disease, brain malformation, lissencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8586 | EDEM3 |
Michelle Torres gene: EDEM3 was added gene: EDEM3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EDEM3 were set to 34143952 Phenotypes for gene: EDEM3 were set to EDEM3-congenital disorder of glycosylation Review for gene: EDEM3 was set to GREEN Added comment: PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional show LoF of EDEM3 enzymatic activity. Sources: Literature |
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| Mendeliome v0.8550 | HOGA1 | Paul De Fazio reviewed gene: HOGA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20797690, 21896830, 22391140; Phenotypes: Hyperoxaluria, primary, type III MIM#613616; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8542 | IKZF3 |
Zornitza Stark gene: IKZF3 was added gene: IKZF3 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: IKZF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IKZF3 were set to 34155405 Phenotypes for gene: IKZF3 were set to Immunodeficiency 84, MIM# 619437 Review for gene: IKZF3 was set to AMBER Added comment: Single family reported where heterozygous missense variant in this gene segregated with immunodeficiency in a mother and two children. Findings included low levels of B cells and impaired early B-cell development, variable T-cell abnormalities, hypogammaglobulinaemia, increased susceptibility to infection with Epstein-Barr virus (EBV). One individual developed lymphoma in adulthood. Mouse model recapitulated phenotype. Sources: Expert Review |
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| Mendeliome v0.8538 | LCK | Zornitza Stark Phenotypes for gene: LCK were changed from to Immunodeficiency 22 MIM# 615758; Recurrent infections; Immune dysregulation; autoimmunity; Low CD4+; low CD8+; restricted T cell repertoire; poor TCR signaling; Normal IgG/IgA; high IgM; failure to thrive; diarrhoea; lymphopaenia; hypogammaglobulinaemia; anaemia; thrombocytopaenia; CD4+ T-cell lymphopaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8533 | LCK | Zornitza Stark reviewed gene: LCK: Rating: AMBER; Mode of pathogenicity: None; Publications: 22985903, 1579166, 11021796; Phenotypes: Immunodeficiency 22 MIM# 615758, Recurrent infections, Immune dysregulation, autoimmunity, Low CD4+, low CD8+, restricted T cell repertoire, poor TCR signaling, Normal IgG/IgA, high IgM, failure to thrive, diarrhoea, lymphopenia, hypogammaglobulinemia, anaemia, thrombocytopaenia, CD4+ T-cell lymphopenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8533 | DOCK8 | Zornitza Stark Phenotypes for gene: DOCK8 were changed from to Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700; T cell Lymphopaenia; decraese T/B/NK cells; Eosinophilia; low IgM; elevated IgE; recurrent cutaneous/ viral/ bacterial/ fungal/ infections; severe atopy/allergic disease; autoimmune haemolytic anaemia; eczema; cancer diathesis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8527 | DOCK8 | Danielle Ariti reviewed gene: DOCK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 19776401, 20622910, 21931011, 26659092, 19898472, 25422492; Phenotypes: Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700, T cell Lymphopaenia, decraese T/B/NK cells, Eosinophilia, low IgM, elevated IgE, recurrent cutaneous/ viral/ bacterial/ fungal/ infections, severe atopy/allergic disease, autoimmune haemolytic anaemia, eczema, cancer diathesisc; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8527 | DNMT3B | Zornitza Stark Phenotypes for gene: DNMT3B were changed from to Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860; facial dysmorphic features; flat nasal bridge; developmental delay; macroglossia; bacterial/opportunistic infections (recurrent); malabsorption; cytopaenia; malignancies; multiradial configurations of chromosomes 1, 9, 16; Hypogammaglobulinaemia; agammaglobulinaemia; variable antibody deficiency; decreased immunoglobulin production; low T/B/NK cells | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8524 | DNMT3B | Zornitza Stark reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20587527, 10555141, 17359920, 9718351, 10647011, 11102980, 12239717; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860, facial dysmorphic features, flat nasal bridge, developmental delay, macroglossia, bacterial/opportunistic infections (recurrent), malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia, agammaglobulinaemia, variable antibody deficiency, decreased immunoglobulin production, low T/B/NK cells; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8522 | SYNCRIP |
Zornitza Stark gene: SYNCRIP was added gene: SYNCRIP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937 Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology Review for gene: SYNCRIP was set to GREEN Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases. Features included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals. The 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence. Variants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance. Overall the variants reported to date include [NM_006372.5]: 1 - c.858_859del p.(Gly287Leufs*5) 2 - c.854dupA p.(Asn285Lysfs*8) 3 - c.734T>C p.(Leu245Pro) 4 - chr6:85605276-85683190 deletion (GRCh38) 5 - c.629T>C p.(Phe210Ser) 6 - c.1573_1574delinsTT p.(Gln525Leu) 7 - c.1247_1250del p.(Arg416Lysfs*145) 8 - c.1518_1519insC p.(Ala507Argfs*14) [P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1] SYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation. Mutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD. The missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2. There are no additional studies performed. Overall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%] Animal models are not discussed. There is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes. Sources: Literature |
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| Mendeliome v0.8511 | CAMK4 |
Zornitza Stark gene: CAMK4 was added gene: CAMK4 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350 Phenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus Review for gene: CAMK4 was set to GREEN Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant. Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms. CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018). The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below]. Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function. Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported. Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below). Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function. Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID. --- The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy. Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one. Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein. Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect. To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV. Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect. ---- Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20]. ---- Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*). Sources: Expert Review |
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| Mendeliome v0.8481 | CIITA | Zornitza Stark Phenotypes for gene: CIITA were changed from to Bare Lymphocyte Syndrome, type II, complementation group A MIM# 209920; varied ID; bronchiolitis; pneumonia; severe autoimmune cytopaenia; CD4 T-cell lymphopaenia; hypogammaglobulinemia; absence of antigen-induced immune response; chronic diarrhoea; recurrent respiratory infections; recurrent gastroenteritis; failure to thrive; liver/biliary tract disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8478 | CIITA | Zornitza Stark reviewed gene: CIITA: Rating: GREEN; Mode of pathogenicity: None; Publications: 8402893, 9099848, 11862382, 28676232, 24789686, 20197681, 11466404, 15821736, 12910265; Phenotypes: Bare Lymphocyte Syndrome, type II, complementation group A MIM# 209920, varied ID, bronchiolitis, pneumonia, severe autoimmune cytopaenia, CD4 T-cell lymphopaenia, hypogammaglobulinemia, absence of antigen-induced immune response, chronic diarrhoea, recurrent respiratory infections, recurrent gastroenteritis, failure to thrive, liver/biliary tract disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8478 | CD40LG | Zornitza Stark Phenotypes for gene: CD40LG were changed from to Immunodeficiency, X-linked, with hyper-IgM MIM# 308230; Severe opportunistic infections (recurrent), idiopathic neutropaenia; dysgammaglobulinaemia hepatitis; cholangitis; cholangiocarcinoma; autoimmune blood cytopenias; haemolytic anaemia; thrombocytopaenia; diarrhoea; peripheral neuroectodermal tumours | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8475 | CD3G | Zornitza Stark Phenotypes for gene: CD3G were changed from to Immunodeficiency 17, CD3 gamma deficient MIM# 615607; immune deficiency; autoimmunity; failure to thrive; recurrent gastrointestinal infections; recurrent respiratory infections; autoimmune haemolytic anaemia; bronchiolitis obliterans; low CD3 complex; partial T lymphocytopenia; intractable diarrhoea. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8468 | CD40LG | Danielle Ariti reviewed gene: CD40LG: Rating: GREEN; Mode of pathogenicity: None; Publications: 7679801, 7679206, 8094231, 9933119, 15358621, 15997875, 7678782, 7915248, 15367912, 7518839, 16311023, 9933119, 12402041, 7882172, 33475257; Phenotypes: mmunodeficiency, X-linked, with hyper-IgM MIM# 308230, Severe opportunistic infections (recurrent), idiopathic neutropaenia, dysgammaglobulinaemia hepatitis, cholangitis, cholangiocarcinoma, autoimmune blood cytopenias, haemolytic anaemia, thrombocytopaenia, diarrhoea, peripheral neuroectodermal tumours; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8468 | CD3G | Danielle Ariti reviewed gene: CD3G: Rating: GREEN; Mode of pathogenicity: None; Publications: 2872416, 1635567, 17277165, 23590417, 24910257, 18482219, 31921117, 11160319; Phenotypes: Immunodeficiency 17, CD3 gamma deficient MIM# 615607, immune deficiency, autoimmunity, failure to thrive, recurrent gastrointestinal infections, recurrent respiratory infections, autoimmune haemolytic anaemia, bronchiolitis obliterans, low CD3 complex, partial T lymphocytopenia, intractable diarrhoea.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8468 | WDR26 | Paul De Fazio reviewed gene: WDR26: Rating: GREEN; Mode of pathogenicity: None; Publications: 28686853, 33506510, 33675273; Phenotypes: Skraban-Deardorff syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8464 | ABCD1 | Zornitza Stark Phenotypes for gene: ABCD1 were changed from to Adrenoleukodystrophy MIM#300100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8449 | ZNF148 |
Natalie Tan gene: ZNF148 was added gene: ZNF148 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF148 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZNF148 were set to PMID: 27964749 Phenotypes for gene: ZNF148 were set to Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies; MIM#617260 Review for gene: ZNF148 was set to GREEN Added comment: Four unrelated individuals with de novo heterozygous nonsense or frameshift mutations (all resulting in premature termination codons in the last exon of ZNF148, predicted to escape nonsense-mediated mRNA decay and result in expression of a truncated protein). Phenotype characterised by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. No functional studies to date. Sources: Literature |
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| Mendeliome v0.8387 | ATP6V0A4 | Zornitza Stark Phenotypes for gene: ATP6V0A4 were changed from to Renal tubular acidosis, distal, autosomal recessive, MIM#602722 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8384 | ATP6V0A4 | Zornitza Stark reviewed gene: ATP6V0A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12414817, 10973252; Phenotypes: Renal tubular acidosis, distal, autosomal recessive, MIM#602722; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8381 | HNF1B | Zornitza Stark Phenotypes for gene: HNF1B were changed from to Renal cysts and diabetes syndrome, MIM# 137920 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8376 | GDF1 | Zornitza Stark edited their review of gene: GDF1: Added comment: PMID: 32144877 - founder PTC in Arab population causing congenital heart detects AND right isomerism in 3 (unrelated?) families. Reviews other publications and reports additional chet (two PTC) or homozygous (missense) families with situs inversus and/or heart defects. No apparent genotype-phenotype correlation btw dominant and recessive disease.; Changed rating: GREEN; Changed publications: 32144877; Changed phenotypes: Congenital heart defects, multiple types, 6 613854, Right atrial isomerism (Ivemark) 208530; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8367 | DCDC2 | Zornitza Stark changed review comment from: Only a single case with nephronophthisis, most reports are for cholangitis, though zebrafish model has renal cysts.; to: At least 5 families reported with cholangitis, and two with nephronophthisis, though zebrafish model has renal cysts. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8361 | CRB2 |
Zornitza Stark changed review comment from: More than 7 unrelated families reported, mouse model. Some have presented predominantly with proteinuria, and some more with a multi-system ciliopathy phenotype, and yet others with RP.; to: VM with renal disease: More than 7 unrelated families reported, mouse model. Some have presented predominantly with proteinuria, and some more with a multi-system ciliopathy phenotype, and yet others with RP. FSGS: at least 4 families and animal model. |
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| Mendeliome v0.8361 | CEP55 | Zornitza Stark Phenotypes for gene: CEP55 were changed from to Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, MIM# 236500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8358 | CEP55 | Zornitza Stark reviewed gene: CEP55: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, MIM# 236500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8326 | AK2 |
Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. PMID: 19043417 (2009). 6 affected individuals from 5 unrelated families (3 of the families showed evidence of consanguinity). Homozygous (5 individuals) and compound heterozygous (1 individual) variants in the AK2 gene. Variants included missense, deletion and inframe indel, resulting in protein LoF. Available parents were sequenced and found heterozygous for the variants, supporting bi-allelic inheritance. PMID: 19043416 (2009). 7 affected individuals from 6 unrelated families (2 separate consanguineous & 4 non-consanguineous families). Homozygous and compound heterozygous variants detected (missense, deletion, inframe indel), resulting in protein LoF. Reticular dysgenesis phenotype including Leukopenia, lymphopenia and agranulocytosis in all affected individuals and sensorineural deafness in 7 individuals. |
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| Mendeliome v0.8312 | C2orf69 |
Zornitza Stark gene: C2orf69 was added gene: C2orf69 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C2orf69 were set to 34038740; 33945503 Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency-53 (COXPD53), MIM#619423 Review for gene: C2orf69 was set to GREEN Added comment: PMID 34038740: 20 affected children from 8 unrelated families reported, presenting with fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. Endogenous C2ORF69 was found to be (1) loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. Zebrafish model. PMID 33945503: 8 individuals from 5 families reported with muscle hypotonia, developmental delay, progressive microcephaly, and brain MRI abnormalities. Age at onset ranged from birth to 6 months of age. Six patients had vision impairment, liver abnormalities, inflammation/inflammatory arthritis, and 5 patients had seizures. Sources: Literature |
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| Mendeliome v0.8306 | NYNRIN |
Laura Raiti gene: NYNRIN was added gene: NYNRIN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NYNRIN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NYNRIN were set to PMID: 30885698 Review for gene: NYNRIN was set to AMBER Added comment: 3 individuals with Wilms Tumour reported (2 children from 1 family, the 3rd child from a second family). Biallelic truncating mutations in NYNRIN in three children with Wilms Tumour from two families, each parent was heterozygous for one of the mutations. One of the affected children had an inguinal hernia and another had epilepsy, hypothyroidism, and intellectual disability. Sources: Literature |
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| Mendeliome v0.8293 | CXCR2 |
Zornitza Stark gene: CXCR2 was added gene: CXCR2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CXCR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CXCR2 were set to 24777453 Phenotypes for gene: CXCR2 were set to WHIM syndrome 2, 619407 Review for gene: CXCR2 was set to RED Added comment: 2 sisters with neutropaenia, myelokathexis, and recurrent bacterial infections and homozygous frameshift variant in this gene. Sources: Expert list |
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| Mendeliome v0.8292 | RING1 |
Eleanor Williams gene: RING1 was added gene: RING1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RING1 were set to 29386386 Phenotypes for gene: RING1 were set to microcephaly; intellectual disability Review for gene: RING1 was set to RED Added comment: Not associated with any phenotype in OMIM. PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Early motor and language development were normal but were delayed after the first year of life. Cognitive testing showed a verbal IQ of 55 and a visual performance IQ of 63. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance. Sources: Literature |
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| Mendeliome v0.8292 | RNF2 |
Eleanor Williams gene: RNF2 was added gene: RNF2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RNF2 were set to 33864376 Phenotypes for gene: RNF2 were set to epilepsy; intellectual disability; intrauterine growth retardation Review for gene: RNF2 was set to AMBER Added comment: Not associated with any phenotype in OMIM. PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles. Sources: Literature |
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| Mendeliome v0.8263 | EPHA7 |
Zornitza Stark gene: EPHA7 was added gene: EPHA7 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: EPHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EPHA7 were set to 34176129 Phenotypes for gene: EPHA7 were set to Intellectual disability Review for gene: EPHA7 was set to AMBER Added comment: Lévy et al (2021 - PMID: 34176129) provide evidence that haploinssuficiency of EPHA7 results in a neurodevelopmental disorder. The authors report on 12 individuals belonging to 9 unrelated families, all harboring with 6q microdeletions spanning EPHA7. Overlapping features included DD (13/13), ID (10/10 - mild in most cases, individuals with larger CNVs/additional variants had more severe phenotype), speech delay and behavioral disorders. Variable other features incl. hypotonia (70%), non specific facial features, eye abnormalities (40%) and cardiac defects (25%). The CNVs ranged from 152 kb to few Mb in size but in 4 subjects (P5-8) were only minimal, involving only EPHA7. 9 out of 12 individuals had inherited the deletion (5 subjects paternal, 4 maternal), in 1 subject (P12) this occured de novo, while for 2 others inheritance was not specified. Most deletions were inherited from an unaffected parent (in 6/7 families), with unclear contribution in a further one. The authors discuss on previous studies suggesting an important role for EphA7 in brain development (modulation of cell-cell adhesion and repulsion, regulation of dendrite morphogenesis in early corticogenesis, role in dendritic spine formation later in development. EphA7 has also been proposed to drive neuronal maturation and synaptic function). Haploinsufficiency for other ephrins or ephrin receptors has been implicated in other NDDs. Overall Lévy et al promote incomplete penetrance and variable expressivity with haploinsufficiency of this gene being a risk factor for NDD. [The gene has also an %HI of 2.76% and a pLI of 1]. Sources: Expert Review |
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| Mendeliome v0.8229 | ATP9A |
Arina Puzriakova gene: ATP9A was added gene: ATP9A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843 Phenotypes for gene: ATP9A were set to Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms Review for gene: ATP9A was set to AMBER Added comment: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree (2 mild, 1 severe), postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3. Sources: Literature |
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| Mendeliome v0.8229 | ATP2C2 |
Eleanor Williams gene: ATP2C2 was added gene: ATP2C2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP2C2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATP2C2 were set to 33864365; 28440294 Phenotypes for gene: ATP2C2 were set to language impairment, HP:0002463 Review for gene: ATP2C2 was set to RED Added comment: PMID: 33864365 - Martinelli et al 2021 - report a family with a missense variant NM_001286527.2:c.304G>A, p.(Val102Met) in ATP2C2 in a father and two siblings with specific language impairment. However two other affected siblings did not have this variant. This variant was also reported by Chen et al. They found that the variant had a higher frequency in language cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). They postulate that variant is not sufficient on its own to cause a disorder but is a susceptibility factor which increases the risk for language impairment. PMID: 28440294 - Chen et al 2017 - report 2 probands with severe learning impairment, and missense variants in ATP2C2 (NM_001286527: c.G304A:p.V102M and NM_001291454:exon21: c.C1936T:p.R646W). Sources: Literature |
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| Mendeliome v0.8223 | XDH | Ain Roesley reviewed gene: XDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 32071838; Phenotypes: Xanthinuria, type I (MIM#278300); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8201 | KIF1B | Paul De Fazio reviewed gene: KIF1B: Rating: RED; Mode of pathogenicity: None; Publications: 33710394; Phenotypes: Hypotonia, coloboma, hypoplasia of the corpus callosum, severe neurodevelopmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8201 | HEATR5B |
Teresa Zhao gene: HEATR5B was added gene: HEATR5B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HEATR5B were set to PMID: 33824466 Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia Review for gene: HEATR5B was set to AMBER Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay. Two homozygous splice variants were reported ((c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. Homozygous knockout mice were not viable. *NOTE: gene (and alias) not found in OMIM Sources: Literature |
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| Mendeliome v0.8201 | NEK8 | Zornitza Stark Phenotypes for gene: NEK8 were changed from to Renal-hepatic-pancreatic dysplasia 2, MIM# 615415; MONDO:0014174 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8198 | NEK8 | Zornitza Stark reviewed gene: NEK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 33131162, 23418306, 26862157, 26697755, 26967905, 23274954, 31633649; Phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415, MONDO:0014174; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8185 | TTC26 |
Zornitza Stark gene: TTC26 was added gene: TTC26 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TTC26 were set to 34177428; 32617964; 31595528; 24596149; 22718903 Phenotypes for gene: TTC26 were set to Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations Review for gene: TTC26 was set to GREEN Added comment: Three unrelated families and functional data including zebrafish model. Sources: Literature |
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| Mendeliome v0.8165 | RNU12 |
Bryony Thompson gene: RNU12 was added gene: RNU12 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNU12 were set to 34085356; 27863452 Phenotypes for gene: RNU12 were set to CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations Review for gene: RNU12 was set to GREEN Added comment: 5 CDAGS syndrome families with biallelic variants all including NC_000022.10:g.43011402C>T and another variant on the second allele. Whole transcriptome sequencing analysis of patient lymphoblastoid cells identified differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events. Also, limited evidence for an association with cerebellar ataxia with a single large consanguineous family reported with a homozygous variant. Sources: Literature |
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| Mendeliome v0.8159 | KCNJ16 |
Zornitza Stark gene: KCNJ16 was added gene: KCNJ16 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KCNJ16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KCNJ16 were set to 33811157; 33840812 Phenotypes for gene: KCNJ16 were set to Renal tubulopathy; deafness Review for gene: KCNJ16 was set to GREEN Added comment: 8 unrelated families reported. Sources: Literature |
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| Mendeliome v0.8145 | KLHL7 | Ain Roesley reviewed gene: KLHL7: Rating: GREEN; Mode of pathogenicity: None; Publications: 31953236, 30300710, 31856884; Phenotypes: PERCHING syndrome (MIM#617055), Retinitis pigmentosa 42 (MIM#612943); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8100 | PPP2R1A | Elena Savva reviewed gene: PPP2R1A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 26168268, 33106617; Phenotypes: Mental retardation, autosomal dominant 36 MIM#616362; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8011 | ADA2 | Zornitza Stark commented on gene: ADA2: Vasculitis, autoinflammation, immunodeficiency, and haematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits. Some affected individuals have immunodeficiency. At least 10 unrelated families reported, the p.Gly47Arg variant is a common founder variant in the Jewish population. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7994 | SURF1 | Elena Savva reviewed gene: SURF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24027061; Phenotypes: Charcot-Marie-Tooth disease, type 4K MIM#616684, Mitochondrial complex IV deficiency, nuclear type 1 MIM#220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7986 | RELN |
Ee Ming Wong edited their review of gene: RELN: Added comment: - Six affected individuals carrying missense variants in RELN including 1. Two individuals with compound heterozygous variants - One of the variants has 26 homozygotes in gnomAD and therefore pathogenicity of this variant is in question - LoF demonstrated for three of the variants (reduced RELN secretion), except for p.Y1821H which demonstrated an apparently increased RELN secretion (GoF) 2. Two brothers carrying the maternally inherited variant (mother apparently healthy) - LoF demonstrated for these variants 3. Two individuals de novo for RELN variants - Dominant negative demonstrated for these variants where secretion of WT-RELN was impaired when co-transfected with mutant constructs in HEK293T cells; Changed rating: AMBER; Changed publications: Riva et al bioRxiv (pre-print, not peer-reviewed); Changed phenotypes: Pachygyria, Polymicrogyria, Heterotopia; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.7949 | SASH3 |
Zornitza Stark gene: SASH3 was added gene: SASH3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SASH3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SASH3 were set to 33876203 Phenotypes for gene: SASH3 were set to Combined immunodeficiency; immune dysregulation Review for gene: SASH3 was set to GREEN Added comment: Four unrelated males reported presenting with combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopaenias. One missense variant, rest were nonsense. Sources: Literature |
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| Mendeliome v0.7938 | WDR91 | Zornitza Stark commented on gene: WDR91: PMID 32732226: Novel candidate gene identified in a fetus with hygroma and hydrocephaly detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma, macrocephaly, abnormal ears, unilateral simian crease, hydrocephaly, cerebellar hypoplasia, and interventricular communication. A homozygous truncating variant was found by exome sequencing with concordant segregation among 4 affected fetus, 2 healthy sibs and both parents. Mouse models support role in brain development. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7932 | EIF2AK2 | Zornitza Stark edited their review of gene: EIF2AK2: Added comment: Four unrelated families reported with dystonia, recurrent variant, (p.Gly130Arg); Changed publications: 32197074, 33866603; Changed phenotypes: Intellectual disability, white matter abnormalities, ataxia, regression with febrile illness, Dystonia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7911 | MYOF |
Zornitza Stark gene: MYOF was added gene: MYOF was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MYOF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYOF were set to 32542751 Phenotypes for gene: MYOF were set to Hereditary angioedema-7 (HAE7), MIM#619366 Review for gene: MYOF was set to RED Added comment: Three individuals from one family reported, onset of recurrent episodic swelling of the face, lips, and oral mucosa was in the second decade. Variant was also present in another unaffected family member. Some functional data. Sources: Expert list |
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| Mendeliome v0.7905 | PLG |
Zornitza Stark changed review comment from: Association between mono-allelic variants and HAE: Over 20 families reported with a recurrent variant, p.Lys330Glu. Single family reported with a different variant. Note bi-allelic variants are associated with a separate disorder. Bi-allelic variants and plasminogen deficiency: congenital plasminogen deficiency is characterised clinically by chronic mucosal pseudomembranous lesions consisting of subepithelial fibrin deposition and inflammation. The most common clinical manifestation is ligneous ('wood-like') conjunctivitis, a redness and subsequent formation of pseudomembranes mostly on the palpebral surfaces of the eye that progress to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. The lesions may be triggered by local injury and/or infection and often recur after local excision. Pseudomembranous lesions of other mucous membranes often occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children also have congenital occlusive hydrocephalus. At least 3 unrelated families reported.; to: Association between mono-allelic variants and HAE: Over 20 families reported with a recurrent variant, p.Lys330Glu. Single family reported with a different variant. Note bi-allelic variants are associated with a separate disorder. Bi-allelic variants and plasminogen deficiency: congenital plasminogen deficiency is characterised clinically by chronic mucosal pseudomembranous lesions consisting of subepithelial fibrin deposition and inflammation. The most common clinical manifestation is ligneous ('wood-like') conjunctivitis, a redness and subsequent formation of pseudomembranes mostly on the palpebral surfaces of the eye that progress to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. The lesions may be triggered by local injury and/or infection and often recur after local excision. Pseudomembranous lesions of other mucous membranes often occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children also have congenital occlusive hydrocephalus. Over 20 unrelated families reported. |
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| Mendeliome v0.7891 | RELN | Ee Ming Wong reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25648840; Phenotypes: Myoclonus dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7891 | PGM2L1 | Chern Lim reviewed gene: PGM2L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33979636; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7891 | LTBP1 |
Chern Lim gene: LTBP1 was added gene: LTBP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LTBP1 were set to 33991472 Phenotypes for gene: LTBP1 were set to cutis laxa syndrome Review for gene: LTBP1 was set to GREEN gene: LTBP1 was marked as current diagnostic Added comment: PMID:33991472 - Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families. - Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). - Functional studies done on patient fibroblasts and zebrafish models. Sources: Literature |
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| Mendeliome v0.7891 | SLC30A5 |
Melanie Marty gene: SLC30A5 was added gene: SLC30A5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC30A5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC30A5 were set to 33547425; 12095919 Phenotypes for gene: SLC30A5 were set to Perinatal lethal cardiomyopathy Review for gene: SLC30A5 was set to AMBER Added comment: Four affected children from two unrelated families with cardiomyopathy, hydrops fetalis, or cystic hygroma that all deceased perinatally. 2 different homozygous PTCs variants found. Knockout of SLC30A5 in mouse models showed reduced body growth and reduced bone density. About 60% of the mice died due to bradyarrhythmia. Sources: Literature |
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| Mendeliome v0.7891 | SRCAP | Paul De Fazio reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Floating-Harbor syndrome MIM#136140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7891 | BCAS3 | Paul De Fazio reviewed gene: BCAS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34022130; Phenotypes: Syndromic neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7891 | PGM2L1 |
Chern Lim gene: PGM2L1 was added gene: PGM2L1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PGM2L1 were set to 33979636 Phenotypes for gene: PGM2L1 were set to severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris Review for gene: PGM2L1 was set to GREEN gene: PGM2L1 was marked as current diagnostic Added comment: PMID: 33979636: - Hom/chet PTVs in 4 unrelated individuals. All four affected individuals had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. - Studies on patient fibroblasts and cell lines indicated that PGM2L1 deficiency causes a decrease, but not a disappearance, of the sugar bisphosphates needed for the formation of NDP-sugars and that there is no evidence that this leads to a glycosylation defect. Sources: Literature |
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| Mendeliome v0.7749 | MCM7 |
Arina Puzriakova gene: MCM7 was added gene: MCM7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCM7 were set to 33654309; 34059554 Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability; Lipodystrophy; Adrenal insufficiency Review for gene: MCM7 was set to AMBER Added comment: MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. MCM7 is not associated with any phenotype in OMIM or G2P at present. ------ Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (see below). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families. - PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment. Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression. - PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7. Sources: Literature |
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| Mendeliome v0.7725 | HSD11B2 | Zornitza Stark Phenotypes for gene: HSD11B2 were changed from to Apparent mineralocorticoid excess, MIM# 218030; MONDO:0009025 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7722 | HSD11B2 | Zornitza Stark reviewed gene: HSD11B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7670488, 9683587, 17314322; Phenotypes: Apparent mineralocorticoid excess, MIM# 218030, MONDO:0009025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7706 | RAB11B | Zornitza Stark commented on gene: RAB11B: NDAGSCW is a neurodevelopmental disorder characterized by severely delayed psychomotor development apparent from infancy. Affected individuals have delayed and difficulty walking, intellectual disability, absent speech, and variable additional features, including hip dysplasia, tapering fingers, and seizures. Brain imaging shows decreased cortical white matter, often with decreased cerebellar white matter, thin corpus callosum, and thin brainstem. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7700 | UFSP2 |
Zornitza Stark changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Hip dysplasia: single 8 generation family reported. Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Additional cases identified through the 100,000 Genomes project. Hip dysplasia: single 8 generation family reported. Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported. |
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| Mendeliome v0.7670 | UFSP2 |
Zornitza Stark changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Hip dysplasia: single 8 generation family reported. Spondyloepimetaphyseal dysplasia, Di Rocco type: single 3-generation family reported.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Hip dysplasia: single 8 generation family reported. Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported. |
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| Mendeliome v0.7637 | THOC2 | Paul De Fazio changed review comment from: Multiple (>10) individuals with neurodevelopmental phenotypes reported with missense, splice, and exon deletion variants. Variants are reported de novo or inherited from a carrier mother. Note that null (whole gene deletion or NMD) variants have not been reported in affected individuals. Arg77Cys appears to be recurrent (reported in multiple individuals).; to: Multiple (>10) males with neurodevelopmental phenotypes reported with missense, splice, and exon deletion variants. Variants are reported de novo or inherited from a carrier mother. Note that null (whole gene deletion or NMD) variants have not been reported in affected individuals. Arg77Cys appears to be recurrent (reported in multiple individuals). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7637 | THOC2 | Paul De Fazio reviewed gene: THOC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26166480, 32116545, 29851191, 32960281; Phenotypes: Mental retardation, X-linked 12/35 MIM#300957; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7637 | FGA | Chern Lim reviewed gene: FGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31064749, 17295221, 19073821, 11739173; Phenotypes: Afibrinogenemia, congenital (MIM#202400), AR, Amyloidosis, familial visceral (MIM#105200), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7621 | SMARCA5 |
Zornitza Stark gene: SMARCA5 was added gene: SMARCA5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMARCA5 were set to 33980485 Phenotypes for gene: SMARCA5 were set to Neurodevelopmental disorder; microcephaly; dysmorphic features Review for gene: SMARCA5 was set to GREEN Added comment: 12 individuals reported with either de novo or appropriately segregating variants in this gene and mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Functional data supports gene-disease association. Sources: Literature |
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| Mendeliome v0.7618 | LEMD2 |
Zornitza Stark changed review comment from: Recurrent de novo variant in both individuals; to: Recurrent de novo variant in both individuals p.Ser479Phe. |
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| Mendeliome v0.7615 | SEPT9 | Zornitza Stark edited their review of gene: SEPT9: Added comment: Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant form of recurrent focal neuropathy characterized clinically by acute, recurrent episodes of brachial plexus neuropathy with muscle weakness and atrophy preceded by severe pain in the affected arm. Multiple founder variants, including p.Arg88Trp. Also note intragenic duplication and 5'UTR variant reported, which may not be detectable by all NGS assays.; Changed publications: 16186812, 19451530, 19939853, 19139049 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7506 | POLR3K |
Zornitza Stark gene: POLR3K was added gene: POLR3K was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR3K were set to 30584594; 33659930 Phenotypes for gene: POLR3K were set to Hypomyelinating leukodystrophy-21, MIM#619310 Review for gene: POLR3K was set to AMBER Added comment: Two individuals from same ethnic background reported with a common homozygous missense variant in this gene, suggestive of founder effect. Some functional evidence, and note other gene family members are linked to similar phenotypes. Neurodegenerative phenotype: global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life. Sources: Expert Review |
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| Mendeliome v0.7495 | APOL1 | Zornitza Stark Phenotypes for gene: APOL1 were changed from {Glomerulosclerosis, focal segmental, 4, susceptibility to} 612551 to {Glomerulosclerosis, focal segmental, 4, susceptibility to} 612551; {End-stage renal disease, nondiabetic, susceptibility to} OMIM:612551 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7488 | OCRL |
Eleanor Williams changed review comment from: PMID: 33517444 - Ramadesikan et al 2021 - studied the cellular effect of 7 OCRL1 (OCRL) variants identified in Lowe Syndrome patients in kidney epithelial cells. Differences in cell spreading, ciliogenesis, protein localization and degree of Golgi apparatus fragmentation were observed. The results help provide a framework to explains symptom heterogeneity and may help stratify patients.; to: Genotype/Phenotype information: PMID: 33517444 - Ramadesikan et al 2021 - studied the cellular effect of 7 OCRL1 (OCRL) variants identified in Lowe Syndrome patients in kidney epithelial cells. Differences in cell spreading, ciliogenesis, protein localization and degree of Golgi apparatus fragmentation were observed. The results help provide a framework to explains symptom heterogeneity and may help stratify patients. |
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| Mendeliome v0.7488 | APOL1 | Eleanor Williams reviewed gene: APOL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33517446; Phenotypes: {Focal Segmental Glomerulosclerosis 4, Susceptibility to} OMIM:612551, {End-stage renal disease, nondiabetic, susceptibility to} OMIM:612551; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7464 | ANKRD17 | Paul De Fazio reviewed gene: ANKRD17: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909992; Phenotypes: Intellectual disability, speech delay, and dysmorphism; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7464 | DPYSL5 |
Michelle Torres gene: DPYSL5 was added gene: DPYSL5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DPYSL5 were set to 33894126 Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities Review for gene: DPYSL5 was set to GREEN Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development Sources: Literature |
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| Mendeliome v0.7464 | SCD |
Elena Savva gene: SCD was added gene: SCD was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SCD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCD were set to PMID: 33690217; 10899171 Phenotypes for gene: SCD were set to Adrenoleukodystrophy Review for gene: SCD was set to RED Added comment: PMID: 33690217 zebrafish K/O mimics the motor phenotype of ALD zebrafish PMID: 10899171 null mouse was deficient in hepatic cholesterol esters and triglycerides despite the presence of normal activities of acyl-CoA, very low levels of triglycerides Sources: Literature |
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| Mendeliome v0.7360 | HNRNPDL |
Bryony Thompson gene: HNRNPDL was added gene: HNRNPDL was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: HNRNPDL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HNRNPDL were set to 24647604; 31267206; 31995753; 32407983; 32904822; 32367994 Phenotypes for gene: HNRNPDL were set to Muscular dystrophy, limb-girdle, autosomal dominant 3 MIM#609115 Review for gene: HNRNPDL was set to GREEN gene: HNRNPDL was marked as current diagnostic Added comment: At least 5 families reported with either D378H/N, and supporting functional assays demonstrating that these variants affect protein function. No other pathogenic variants have been reported. A VUS has been reported (along with another SETX variant) in an individual with a multi-system disorder, including a metabolic myopathy. Sources: Expert list |
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| Mendeliome v0.7249 | NDUFB11 |
Kristin Rigbye changed review comment from: Variable syndromic features have been observed in affected individuals, however anaemia and cardiomyopathy appear to be consistent features in males and females, respectively (PMID: 28050600, PMID: 30423443, PMID: 27488349). Affected females have previously been reported with inherited pathogenic variants from their unaffected mothers. It has been suggested that this may be due to patterns of somatic X-chromosome inactivation, mosaicism or additional genetic or external factors (PMID: 28050600). Affected females have been reported with null alleles, whereas affected males have only been identified with missense variants or a recurrent single residue in-frame deletion, suggesting that some residual enzyme activity is required for males to be viable, whereas complete loss of function variants may be lethal when hemizygous (PMID: 30423443). Note: female carriers of missense variants have not been reported as clinically affected. Western blots from cells of male patients with the recurrent F93del variant showed reduced protein levels, and recombinant cells demonstrated a proliferation defect, consistent with the anaemia phenotype (PMID: 27488349).; to: Variable syndromic features have been observed in affected individuals, however anaemia and cardiomyopathy appear to be consistent features in males and females, respectively (PMID: 28050600, PMID: 30423443, PMID: 27488349). It has been suggested that heterozygous females do not display the severe phenotype associated with mitochondrial complex 1 deficiency due to highly skewed XCI favouring expression of the wild type allele, whereas these null variants result in a severe lethal disorder in hemizygous males (PMID: 25772934). Affected females have previously been reported with inherited pathogenic variants from their unaffected mothers. It has been suggested that this may be due to patterns of somatic X-chromosome inactivation, mosaicism or additional genetic or external factors (PMID: 28050600). Affected females have been reported with null alleles, whereas affected males have only been identified with missense variants or a recurrent single residue in-frame deletion, suggesting that some residual enzyme activity is required for males to be viable, whereas complete loss of function variants may be lethal when hemizygous (PMID: 30423443). Note: female carriers of missense variants have not been reported as clinically affected. Western blots from cells of male patients with the recurrent F93del variant showed reduced protein levels, and recombinant cells demonstrated a proliferation defect, consistent with the anaemia phenotype (PMID: 27488349). |
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| Mendeliome v0.7212 | ERCC1 | Zornitza Stark changed review comment from: Three unrelated families reported, variable severity reported from a Cockayne phenotype with congenital onset and early mortality, through to adolescent presentation with short stature, photosensitivity and progressive liver and renal dysfunction.; to: More than three unrelated families reported, variable severity reported from a Cockayne phenotype with congenital onset and early mortality, through to adolescent presentation with short stature, photosensitivity and progressive liver and renal dysfunction. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7203 | GREB1L | Zornitza Stark Phenotypes for gene: GREB1L were changed from Renal hypodysplasia/aplasia 3, OMIM# 617805 to Renal hypodysplasia/aplasia 3, OMIM# 617805; Deafness, autosomal dominant 80, MIM# 619274 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7201 | GREB1L | Zornitza Stark edited their review of gene: GREB1L: Added comment: DFNA80 is characterized by nonsyndromic congenital deafness associated with absent or malformed cochleae and eighth cranial nerves. Four unrelated families reported, no comment on a renal phenotype. Note variants in this gene are also associated with renal agenesis.; Changed publications: 29100091, 29955957, 32585897; Changed phenotypes: Renal hypodysplasia/aplasia 3, OMIM# 617805, Deafness, autosomal dominant 80, MIM# 619274 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7199 | EMC10 | Zornitza Stark edited their review of gene: EMC10: Added comment: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect (but different to the previously reported family).; Changed rating: GREEN; Changed publications: 32869858, 33531666; Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7192 | ADCY6 |
Zornitza Stark changed review comment from: Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies. Sources: Literature; to: - PMID: 33820833 (2021) - Further 2 sibs reported with a homozygous c.3346C>T:p.Arg1116Cys variant in the ADCY6 gene. The family was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and IUGR were detected prenatally. Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies. Sources: Literature |
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| Mendeliome v0.7191 | UNC50 |
Arina Puzriakova gene: UNC50 was added gene: UNC50 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UNC50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNC50 were set to 29016857; 33820833 Phenotypes for gene: UNC50 were set to Arthrogryposis multiplex congenita Review for gene: UNC50 was set to AMBER Added comment: UNC50 is currently not associated with any phenotype in OMIM (last edited on 02/01/2018) or Gene2Phenotype. - PMID: 29016857 (2017) - Homozygosity mapping of disease loci combined with WES in a single male from a consanguineous family presenting with lethal AMC revealed a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4). Functional studies in C. elegans showed the variant caused loss of acetylcholine receptor expression in the muscle. - PMID: 33820833 (2021) - Single individual reported with the same homozygous c.750_751del:p.Cys251Phefs*4 variant in UNC50 as previously described. The case was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and tetra ventricular dilation were detected prenatally. -- Note: it isn't definitively clear whether these are different individuals. Both are singleton males born to consanguineous parents, with the same variant and similar phenotype. Also both infants died at 28 w.g. However, the 2021 paper (PMID:33820833) states their patient was selected from a cohort of cases without a molecular diagnosis and indicate the UNC50 gene had already previously been identified in relation to this phenotype, highlighting the earlier paper (PMID:29016857). There is also no mention of tetra ventricular dilation in the first case, so it is likely that these do represent distinct individuals. Additional cases needed to provide clarity. Sources: Literature |
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| Mendeliome v0.7191 | PLCH1 |
Arina Puzriakova gene: PLCH1 was added gene: PLCH1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLCH1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLCH1 were set to 33820834 Phenotypes for gene: PLCH1 were set to Holoprosencephaly spectrum; Severe developmental delay; Brain malformations Review for gene: PLCH1 was set to AMBER Added comment: PLCH1 is currently not associated with any phenotype in OMIM (last edited on 16/06/2009) or Gene2Phenotype. - PMID: 33820834 (2021) - Two sibling pairs from two unrelated families with a holoprosencephaly spectrum phenotype and different homozygous PLCH1 variants (c.2065C>T, p.Arg689* and c.4235delA, p.Cys1079ValfsTer16, respectively). One family presented with congenital hydrocephalus, epilepsy, significant developmental delay and a monoventricle or fused thalami; while sibs from the second family had alobar holoprosencephaly and cyclopia. 3/4 individuals also displayed a cleft palate and congenital heart disease. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome. Sources: Literature |
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| Mendeliome v0.7187 | PDIA6 |
Zornitza Stark gene: PDIA6 was added gene: PDIA6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PDIA6 were set to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes Review for gene: PDIA6 was set to AMBER Added comment: Amber in view of the good quality functional data. 1 case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the previously reported mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. The phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. Sources: Literature |
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| Mendeliome v0.7186 | EXOSC1 |
Zornitza Stark gene: EXOSC1 was added gene: EXOSC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EXOSC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOSC1 were set to 33463720 Phenotypes for gene: EXOSC1 were set to Pontocerebellar hypoplasia Review for gene: EXOSC1 was set to RED Added comment: An 8‐months‐old male with developmental delay, microcephaly, subtle dysmorphism, hypotonia, pontocerebellar hypoplasia and delayed myelination. Similarly affected elder sibling succumbed at the age of 4‐years 6‐months. Exome sequencing revealed a homozygous missense variant (c.104C >T, p.Ser35Leu) in EXOSC1. In silico mutagenesis revealed loss of a polar contact with neighbouring Leu37 residue. Quantitative real‐time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. Of note, bi‐allelic variants in other exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively. Sources: Literature |
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| Mendeliome v0.7185 | CACNA1H | Paul De Fazio reviewed gene: CACNA1H: Rating: GREEN; Mode of pathogenicity: None; Publications: 27729216, 25907736, 31126930; Phenotypes: Hyperaldosteronism, familial, type IV MIM#617027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7182 | UBE4A |
Zornitza Stark gene: UBE4A was added gene: UBE4A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UBE4A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UBE4A were set to 33420346 Phenotypes for gene: UBE4A were set to Intellectual disability and global developmental delay Review for gene: UBE4A was set to GREEN Added comment: 8 individuals, from 4 unrelated families, with syndromic intellectual disability and global developmental delay (other clinical features included hypotonia, short stature, seizures, and behaviour disorder. Exome sequencing identified biallelic loss-of-function variants in UBE4A in the 4 families, with variants segregating with disease and parents carriers. They demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioural abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals. Sources: Literature |
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| Mendeliome v0.7180 | MAPKAPK5 |
Zornitza Stark gene: MAPKAPK5 was added gene: MAPKAPK5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAPKAPK5 were set to 3344202 Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic Review for gene: MAPKAPK5 was set to GREEN Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization. Sources: Literature |
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| Mendeliome v0.7127 | VWA1 |
Melanie Marty gene: VWA1 was added gene: VWA1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VWA1 were set to 33459760; 33693694; 33559681 Phenotypes for gene: VWA1 were set to Hereditary motor neuropathy Review for gene: VWA1 was set to GREEN Added comment: Six different truncating variants identified in 15 affected individuals from six families (biallelic inheritance). Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. An additional 17 individuals from 15 families with hereditary motor neuropathy were identified. A 10-bp repeat expansion at the end of exon 1 was observed in 14 families and was homozygous in 10 of them. This mutation, c.62_71dup [p.Gly25Argfs*74], leads to a frameshift that results in a reduction in VWA1 transcript levels via nonsense-mediated decay. Sources: Literature |
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| Mendeliome v0.7121 | CLDN11 |
Melanie Marty gene: CLDN11 was added gene: CLDN11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CLDN11 were set to 33313762 Phenotypes for gene: CLDN11 were set to Hypomyelinating leukodystrophy Review for gene: CLDN11 was set to GREEN Added comment: In three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia, 2 different heterozygous de novo stop-loss variants were identified. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Sources: Literature |
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| Mendeliome v0.7121 | SYK |
Paul De Fazio gene: SYK was added gene: SYK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SYK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SYK were set to 33782605 Phenotypes for gene: SYK were set to Immune dysregulation and systemic inflammation Mode of pathogenicity for gene: SYK was set to Other Review for gene: SYK was set to GREEN gene: SYK was marked as current diagnostic Added comment: 5 unrelated patients with monoallelic missense variants in SYK with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. 2 patients were confirmed de novo, others were undetermined. Variants exhibited a GoF effect in functional studies. A knock-in mouse model of a patient variant recapitulated aspects of the human disease. Sources: Literature |
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| Mendeliome v0.7121 | NCDN |
Ain Roesley gene: NCDN was added gene: NCDN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NCDN were set to 33711248 Phenotypes for gene: NCDN were set to neurodevelopmental delay, intellectual disability, and epilepsy Penetrance for gene: NCDN were set to unknown Review for gene: NCDN was set to GREEN Added comment: 4x families all missense and de novo except for 1 consag family where 3 affecteds were homozygous and carrier parents unaffected ID ranged from mild to severe 3/4 probands had seizures only 3 affecteds had MRI done, with 1 delayed myelination in vitro studies were done Sources: Literature |
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| Mendeliome v0.7091 | CHD7 | Elena Savva reviewed gene: CHD7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26411921; Phenotypes: Hypogonadotropic hypogonadism 5 with or without anosmia MIM#612370, CHARGE syndrome MIM#214800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7084 | FBN2 |
Zornitza Stark edited their review of gene: FBN2: Added comment: The association between mono-allelic variants in FBN2 and CCA is well established. Recent report of bi-allelic variants, Kloth (2021): biallelic FBN2 variants (PTC/missense) in a teenager with severe CCA, including cardiac defects, mild scoliosis and muscular involvement. Carrier parents both "healthy/unaffected". Phenotype matches mouse K/O. Authors performed a lit review and identified an additional 2 homozygous patients (both missense variants) with - fetal akinesia, brain ischemia and neonatal death - severe muscle weakness with bilateral clubfeet, a pronounced gait disturbance, recurrent patellar dislocations, flexion contractures, camptodactyly, widespread striae and an unusual myofibrillar disorganization, variation in fiber size and atrophic fibers in muscle biopsy. Evidence for association with Macular degeneration, early-onset MIM#616118 is limited. One family reported, plus some rare variants reported in cohort studies. The familial variant p.Glu1144Lys is present in 11 hets in gnomad and has benign in silicos. The second variant reported in the paper, p.Met1247Thr is present in >20 hets.; Changed rating: GREEN; Changed publications: 33571691; Changed phenotypes: Contractural arachnodactyly, congenital MIM#121050, Macular degeneration, early-onset MIM#616118; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.7081 | MMP20 | Bryony Thompson reviewed gene: MMP20: Rating: GREEN; Mode of pathogenicity: None; Publications: 15744043, 33600052; Phenotypes: Amelogenesis imperfecta, type IIA2 MIM#612529; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7075 | CELA3B |
Bryony Thompson gene: CELA3B was added gene: CELA3B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CELA3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CELA3B were set to 31369399; 33565216 Phenotypes for gene: CELA3B were set to Chronic pancreatitis Mode of pathogenicity for gene: CELA3B was set to Other Review for gene: CELA3B was set to AMBER Added comment: PMID: 33565216 - p.Arg90Cys (c.268C>T) identified in a chronic pancreatitis (also diabetes and pancreatic adenocarcinoma present in some individuals) pedigree. Variant was present in 2 affected individuals and not present in 7 healthy relatives. Also, supporting in vitro functional assays demonstrating gain of function mechanism for R90C and R90L, and supporting mouse model. PMID: 31369399 - p.Arg90Leu (c.269G>T) identified in 4 French chronic pancreatitis cases and 0 controls. However, there are 229 hets in gnomAD v2.1 with this variant. Sources: Literature |
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| Mendeliome v0.7073 | SLC10A1 |
Zornitza Stark gene: SLC10A1 was added gene: SLC10A1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SLC10A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC10A1 were set to 24867799; 27882152; 28835676; 29290974; 31201272 Phenotypes for gene: SLC10A1 were set to Familial hypercholanemia-2, MIM#619256 Review for gene: SLC10A1 was set to GREEN Added comment: IEM characterised by persistently increased plasma levels of conjugated bile salts apparent from infancy. Most patients are asymptomatic and have no liver dysfunction, although some neonates may have transient jaundice or transiently elevated liver enzymes. These abnormalities improve with age. The bile acid defect can result in impaired absorption of fat-soluble vitamins, including D and K, causing decreased bone mineral density or prolonged prothrobin time (PT). Some variants are recurrent (founder effect likely) but at least 3 different variants reported, mouse model. Sources: Expert list |
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| Mendeliome v0.7056 | CCDC88C | Paul De Fazio reviewed gene: CCDC88C: Rating: GREEN; Mode of pathogenicity: None; Publications: 33602173; Phenotypes: Eearly-onset pure hereditary spastic paraplegia; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6901 | SPINT2 | Zornitza Stark changed review comment from: More than 15 unrelated families reported.; to: Well established gene-disease association. PMID 30445423 reviews 34 patients from 26 families: 13 different variants in SPINT2 were seen, including 3 premature termination codons, 2 start codon removals, and 3 canonical splice site variants, supporting loss of function as the pathogenic mechanism. The most commonly observed variant was Y163C, observed in 40 (59%) of 68 disease alleles. Seven unrelated patients with the Y163C mutation had a shared haplotype, suggesting that it is a founder mutation. Choanal atresia (20/34) and keratitis of infantile onset (26/34) were the most common findings. All patients presented with intractable diarrhoea, with onset typically in the first 2 weeks of life. Episodes of intestinal pseudoobstruction sometimes preceded the onset of diarrhoea. Characteristic epithelial tufts on intestinal histology were seen in 13 of the 34 patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6876 | POLR3A | Elena Savva reviewed gene: POLR3A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31637490; Phenotypes: Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism MIM#607694, Wiedemann-Rautenstrauch syndrome MIM#264090, POLR3A-related spastic ataxia; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6876 | FLII | Elena Savva reviewed gene: FLII: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32870709, 11971982, 32980309; Phenotypes: Dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6870 | COL4A6 | Paul De Fazio reviewed gene: COL4A6: Rating: RED; Mode of pathogenicity: None; Publications: 23714752, 12784310; Phenotypes: ?Deafness, X-linked 6 MIM#300914; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6808 | SATB1 | Zornitza Stark commented on gene: SATB1: Developmental delay with dysmorphic facies and dental anomalies (DEFDA) is characterized by generally mild global developmental delay with variably impaired intellectual development, walking by 2 to 3 years, and slow language acquisition. The severity of the disorder ranges from moderate cognitive deficits to mild learning difficulties or behavioral abnormalities. Most patients have dysmorphic facial features, often with abnormal dentition and nonspecific visual defects, such as myopia, astigmatism, and strabismus. Although rare, involvement of other systems, such as skeletal, cardiac, and gastrointestinal, may be present. 12 individuals from 11 families reported (one inherited variant, affected parent). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6793 | MPEG1 |
Zornitza Stark gene: MPEG1 was added gene: MPEG1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MPEG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MPEG1 were set to 33224153; 33692780; 28422754 Phenotypes for gene: MPEG1 were set to Immunodeficiency 77, MIM# 619223 Review for gene: MPEG1 was set to GREEN Added comment: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus. Four individuals reported, functional data, including animal model. Sources: Expert list |
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| Mendeliome v0.6769 | ALDH1L2 |
Naomi Baker gene: ALDH1L2 was added gene: ALDH1L2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ALDH1L2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ALDH1L2 were set to PMID: 31341639; 33168096 Phenotypes for gene: ALDH1L2 were set to pruritic ichthyosis, severe diffuse hypomyelination seen on MRI, and abnormal lipid peaks Review for gene: ALDH1L2 was set to RED Added comment: Individual reported with bialleleic ALDH1L2 variants (non-canonical splice and a frameshift mutation), who also has a de novo hemizygous RPS6KA3 frameshift mutation. Authors state that not all features of the individual could be explained by the RPS6KA3 variant, and that consideration of Coffin-Lowry sysndrome was only made after identification of the RPS6KA3 variant. Therefore individual has there is a blended phenotype of Coffin–Lowry syndrome and Sjögren–Larsson syndrome. From functional studies authors propose that the ALDH1L2 loss induces mitochondrial dysfunction due to reduced NADPH and increased oxidative stress (PMID: 31341639). Knockout mouse model was viable and did not show an apparent phenotype, however metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Authors therefore postulate that the role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous disease. Sources: Literature |
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| Mendeliome v0.6755 | INVS | Paul De Fazio reviewed gene: INVS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872123, 19177160; Phenotypes: Nephronophthisis 2, infantile, (MIM#602088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6742 | UBAP1 |
Zornitza Stark changed review comment from: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex.; to: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex. PMID 32934340: additional 7 families. Median age of onset 10yrs. |
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| Mendeliome v0.6736 | DOCK7 | Paul De Fazio reviewed gene: DOCK7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24814191, 30771731, 30807358; Phenotypes: Developmental and epileptic encephalopathy 23 MIM#615859; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6699 | KIDINS220 | Zornitza Stark edited their review of gene: KIDINS220: Added comment: Note additional family with severe prenatal phenotype and bi-allelic variants reported in PMID 32909676, so total of 3 unrelated families for bi-allelic fetal phenotype.; Changed publications: 27005418, 32909676 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6668 | WBP11 | Zornitza Stark Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, MIM# 619227; malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6667 | WBP11 | Zornitza Stark reviewed gene: WBP11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vertebral, cardiac, tracheoesophageal, renal, and limb defects, MIM# 619227; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6556 | ACSL5 |
Zornitza Stark gene: ACSL5 was added gene: ACSL5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ACSL5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACSL5 were set to 33191500 Phenotypes for gene: ACSL5 were set to severe FTT (no OMIM #) Review for gene: ACSL5 was set to RED Added comment: 6 individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Autozygosity mapping and WES identified homozygous variant (c.1358C>A:p.(Thr453Lys) in ACSL5. Segregated with affected individuals. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss‐of‐function mutation without any remaining activity. Affected individuals were treated with total parenteral nutrition or medium‐chain triglyceride‐based formula restricted in long‐chain triglycerides. They responded well and follow up suggests that treatment is only required during early life. Sources: Literature |
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| Mendeliome v0.6501 | PCBD1 |
Michelle Torres edited their review of gene: PCBD1: Added comment: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; Changed phenotypes: MODY, Hyperphenylalaninemia, BH4-deficient, D 264070 |
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| Mendeliome v0.6495 | SPEN | Chern Lim reviewed gene: SPEN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33596411; Phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6494 | PCBD1 |
Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY |
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| Mendeliome v0.6490 | PCBD1 |
Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY |
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| Mendeliome v0.6486 | MED27 |
Alison Yeung gene: MED27 was added gene: MED27 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED27 were set to 33443317 Phenotypes for gene: MED27 were set to Intellectual disability; cerebellar hypoplasia; dystonia Review for gene: MED27 was set to GREEN gene: MED27 was marked as current diagnostic Added comment: 16 patients from 11 families with balletic variants Sources: Literature |
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| Mendeliome v0.6463 | CLTCL1 |
Bryony Thompson changed review comment from: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature; to: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system. Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature |
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| Mendeliome v0.6463 | CLTCL1 |
Bryony Thompson gene: CLTCL1 was added gene: CLTCL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLTCL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLTCL1 were set to 26068709; 29402896; 22511880; 31354784 Phenotypes for gene: CLTCL1 were set to Congenital insensitivity to pain Review for gene: CLTCL1 was set to AMBER Added comment: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature |
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| Mendeliome v0.6462 | KIF22 | Elena Savva reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22152677, 22152678; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 MIM#603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6462 | GLI3 | Elena Savva reviewed gene: GLI3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32591344, 18000979, 24736735; Phenotypes: Polydactyly, postaxial, types A1 and B, MIM#174200, Greig cephalopolysyndactyly syndrome MIM#175700, Polydactyly, preaxial, type IV MIM#174700, Pallister-Hall syndrome MIM#146510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6418 | HS2ST1 | Zornitza Stark Phenotypes for gene: HS2ST1 were changed from Intellectual disability; dysmorphic features; congenital anomalies to Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Intellectual disability; dysmorphic features; congenital anomalies | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6417 | HS2ST1 | Zornitza Stark reviewed gene: HS2ST1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6407 | CRYM | Paul De Fazio reviewed gene: CRYM: Rating: GREEN; Mode of pathogenicity: None; Publications: 32742378, 12471561, 16740909, 18448257, 24676347, 26915689; Phenotypes: Deafness, autosomal dominant 40 MIM#616357; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6321 | FCHO1 | Zornitza Stark Phenotypes for gene: FCHO1 were changed from Combined immunodeficiency; T cells: low, poor proliferation; B cells: normal number; Recurrent infections (viral, mycobacteria, bacterial, fungal); lymphoproliferation; Failure to thrive; Increased activation-induced T-cell death; Defective clathrin-mediated endocytosis to Immunodeficiency 76, MIM# 619164; Combined immunodeficiency; T cells: low, poor proliferation; B cells: normal number; Recurrent infections (viral, mycobacteria, bacterial, fungal); lymphoproliferation; Failure to thrive; Increased activation-induced T-cell death; Defective clathrin-mediated endocytosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6320 | FCHO1 | Zornitza Stark edited their review of gene: FCHO1: Changed phenotypes: Immunodeficiency 76, MIM# 619164, Combined immunodeficiency, T cells: low, poor proliferation, B cells: normal number, Recurrent infections (viral, mycobacteria, bacterial, fungal), lymphoproliferation, Failure to thrive, Increased activation-induced T-cell death, Defective clathrin-mediated endocytosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6320 | FSTL5 |
Eleanor Williams gene: FSTL5 was added gene: FSTL5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FSTL5 was set to Unknown Publications for gene: FSTL5 were set to 33105483 Phenotypes for gene: FSTL5 were set to isolated club-foot; iTEV; Talipes equinovarus Review for gene: FSTL5 was set to RED Added comment: PMID: 33105483 - Khanshour et al 20201 - GWAS study of isolated Talipes equinovarus (clubfoot, iTEV) identified an associated locus within FSTL5. They show that Fstl5 is expressed in the embryonic hindlimb in bats, chicks and mice. However, Fstl5 was expressed more highly in neural tissues in mice, and rats lacking Fstl5 showed no gross developmental malformations. Conditional overexpression of Fstl5 in osteochondroprogenitors resulted in sexually dimorphic differences in skeletal development in mice. Sources: Literature |
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| Mendeliome v0.6295 | PNLIP |
Bryony Thompson gene: PNLIP was added gene: PNLIP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PNLIP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PNLIP were set to 31977950; 25862608; 24262094; 27604308 Phenotypes for gene: PNLIP were set to Pancreatic lipase deficiency MIM#614338; disorders of lipid and lipoprotein metabolism Review for gene: PNLIP was set to GREEN Added comment: 4 cases from 2 unrelated families, with supporting biochemical assays in patient cells and cellular-based assays. The cases have decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health. Sources: Literature |
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| Mendeliome v0.6221 | DDX58 | Zornitza Stark edited their review of gene: DDX58: Added comment: Prasov et al. 2021 (PMID: 33495304) - A heterozygous DDX58 variant (c.1529A>T) was identified in 5 individuals from 2 unrelated families from different ethnic backgrounds. Phenotypes varied with some being severely affected by systemic features and others solely with glaucoma.Functional analysis demonstrated the variant confers a dominant gain-of-function effect on interferon activity.; Changed mode of pathogenicity: Other; Changed publications: 25620203, 33495304 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6207 | EGFR | Eleanor Williams changed review comment from: PMID: 33326033 - Akhavanfard et al 2020 - identified a heterozygous germline variant in EGFR (c.3238 G>A, p.Asp1080Asn) in a 21 year old female with metastatic bilateral Adrenocortical carcinoma (ACC). Then they analyzed germline exome data from 21 children, 32 adolescents and young adults (15-39y), and 60 adult participants with ACC. 3.5% of all 113 ACC cases had at least a highly prioritized VUS germline EGFR variant, compared to only 0.3% in a non-TCGA (The Cancer Genome Atlas) ExAC control group (P < 0.0001). No segregation data.; to: PMID: 33326033 - Akhavanfard et al 2020 - identified a heterozygous germline variant in EGFR (c.3238 G>A, p.Asp1080Asn) in a 21 year old female with metastatic bilateral Adrenocortical carcinoma (ACC). Then they analyzed germline exome data from 21 children, 32 adolescents and young adults (15-39y), and 60 adult participants with ACC. 3.5% of all 113 ACC cases had at least a highly prioritized VUS germline EGFR variant, compared to only 0.3% in a non-TCGA (The Cancer Genome Atlas) ExAC control group (P < 0.0001). In the adolescents and young adults group 6.2% had ECGR variants. No segregation data. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6207 | EGFR | Eleanor Williams reviewed gene: EGFR: Rating: AMBER; Mode of pathogenicity: None; Publications: 33326033; Phenotypes: Adrenocortical carcinoma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6207 | WBP11 |
Eleanor Williams gene: WBP11 was added gene: WBP11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WBP11 were set to 33276377 Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems Review for gene: WBP11 was set to GREEN Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies. Sources: Literature |
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| Mendeliome v0.6197 | CDCA8 |
Zornitza Stark gene: CDCA8 was added gene: CDCA8 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CDCA8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CDCA8 were set to 28025328; 29546359 Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, thyroid dysgenesis, no OMIM # Mode of pathogenicity for gene: CDCA8 was set to Other Review for gene: CDCA8 was set to GREEN Added comment: 4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants. GREEN for mono allelic, RED for biallelic. Sources: Expert Review |
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| Mendeliome v0.6195 | DNAJC30 |
Zornitza Stark gene: DNAJC30 was added gene: DNAJC30 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DNAJC30 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAJC30 were set to 33465056 Phenotypes for gene: DNAJC30 were set to Leber Hereditary Optic Neuropathy Review for gene: DNAJC30 was set to GREEN Added comment: 33 individuals from 29 families had homozygous DNAJC30 missense variants. Three different variants identified (one responsible for most cases). All three variants absent from gnomAD. Incomplete penetrance and male predominance in affected individuals both typical of LHON due to mtDNA mutations. All 3 variants in the J domain of the protein. Functional evidence. Sources: Literature |
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| Mendeliome v0.6193 | NFS1 | Zornitza Stark edited their review of gene: NFS1: Added comment: Second paper reporting another family (consanguineous) with three affected children and supportive functional data. Homozygous for the same missense variant as reported in the 2014 paper - this family of Christian Arab descent; the family in the previous report of Mennonite background. Suggests this is a mutation hotspot.; Changed rating: GREEN; Changed publications: 24498631, 33457206 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6190 | TLR8 |
Zornitza Stark gene: TLR8 was added gene: TLR8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TLR8 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: TLR8 were set to 33512449 Phenotypes for gene: TLR8 were set to Immunodeficiency; bone marrow failure Mode of pathogenicity for gene: TLR8 was set to Other Review for gene: TLR8 was set to GREEN Added comment: Six unrelated males reported with a phenotype comprising neutropaenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure. Three different variants reported, the variant was somatic in 5/6 individuals. GoF mechanism demonstrated. Sources: Literature |
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| Mendeliome v0.6187 | PIGF |
Paul De Fazio changed review comment from: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated. Rated Red as the two families are likely to be related (founder mutation?). Sources: Literature; to: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness - only one of the two had seizures (GTCS), the other was 14mo and noted to have tonic posturing. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated by flow cytometry and a rescue assay. Alkaline phosphatase in both individuals was normal. Rated Red as the two families are likely to be related (founder mutation?). Sources: Literature |
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| Mendeliome v0.6187 | PIGF |
Paul De Fazio changed review comment from: The same missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated. Rated Red as the two families are likely to be related (founder mutation?). Sources: Literature; to: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated. Rated Red as the two families are likely to be related (founder mutation?). Sources: Literature |
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| Mendeliome v0.6187 | PIGF |
Paul De Fazio changed review comment from: Identified in 2 individuals with a phenotype similar to DOORS (syndrome Sources: Literature; to: The same missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated. Rated Red as the two families are likely to be related (founder mutation?). Sources: Literature |
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| Mendeliome v0.6187 | PIGF |
Paul De Fazio gene: PIGF was added gene: PIGF was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PIGF was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGF were set to 33386993 Phenotypes for gene: PIGF were set to Glycosylphosphatidylinositol\ deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures Review for gene: PIGF was set to RED gene: PIGF was marked as current diagnostic Added comment: Identified in 2 individuals with a phenotype similar to DOORS (syndrome Sources: Literature |
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| Mendeliome v0.6187 | BRWD1 |
Paul De Fazio gene: BRWD1 was added gene: BRWD1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BRWD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BRWD1 were set to 33389130 Phenotypes for gene: BRWD1 were set to Asthenoteratozoospermia, likely primary ciliary dyskinesia Review for gene: BRWD1 was set to GREEN gene: BRWD1 was marked as current diagnostic Added comment: Biallelic missense variants reported in 3 unrelated individuals. Apart from asthenoteratozoospermia, all 3 had PCD or "PCD-likely" symptoms of re-occurring airway infections, bronchiectasis, and rhinosinusitis. One individual had situs inversus. Studies on cells from one indivdidual showed abnormal respiratory cilia structure. BRWD1 staining was absent from respiratory cilia in this individual (present in controls). Rated Green as there are three unrelated individuals reported. Sources: Literature |
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| Mendeliome v0.6184 | HIRA |
Paul De Fazio gene: HIRA was added gene: HIRA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HIRA were set to 33417013; 28135719; 25363760 Phenotypes for gene: HIRA were set to Neurodevelopmental disorder Review for gene: HIRA was set to GREEN gene: HIRA was marked as current diagnostic Added comment: Two unrelated patients with different de novo loss of function variants identified in PMID 33417013: Individual 1: intragenic deletion, phenotype included psychomotor retardation, ID, growth retardation, microcephaly, and facial features reminiscent of 22q deletion syndrome. Individual 2: canonical splice variant, phenotype mostly confined to ASD Another two de novo variants were identified in the literature by the authors of that paper, one stop-gain (DDD study, PMID 28135719) and one missense (large autism cohort, PMID 25363760). PMID 33417013 also showed that HIRA knockdown in mice results in neurodevelopmental abnormalities. Rated Green due to 4 unrelated individuals (albeit 2 in large cohort studies) and a mouse model. NB: HIRA is within the common 22q deletion region. Sources: Literature |
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| Mendeliome v0.6179 | EYA3 |
Paul De Fazio gene: EYA3 was added gene: EYA3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EYA3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: EYA3 were set to 33475861 Phenotypes for gene: EYA3 were set to Oculo-auriculo-vertebral spectrum (OAVS) Review for gene: EYA3 was set to RED gene: EYA3 was marked as current diagnostic Added comment: 3 individuals with OAVS from two unrelated families with the same missense variant, p.(Asn358Ser). Variant has 20 heterozygotes in gnomAD. Unaffected carriers in both families were also identified - unknown if incomplete penetrance or nonsegregation. Functional studies indicate the variant increases protein half life, and gene knockdown in zebrafish had an effect on craniofacial development. Rated Red due to both families sharing the variant and uncertainty about incomplete penetrance versus nonsegregation. Sources: Literature |
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| Mendeliome v0.6174 | OTUD5 |
Zornitza Stark gene: OTUD5 was added gene: OTUD5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: OTUD5 were set to 33131077 Phenotypes for gene: OTUD5 were set to X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality Review for gene: OTUD5 was set to RED Added comment: 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. No functional studies. Sources: Literature |
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| Mendeliome v0.6171 | CLRN2 |
Paul De Fazio gene: CLRN2 was added gene: CLRN2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLRN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLRN2 were set to 33496845 Phenotypes for gene: CLRN2 were set to Non-syndromic hearing loss Review for gene: CLRN2 was set to AMBER gene: CLRN2 was marked as current diagnostic Added comment: Missense variant segregates with non-syndromic hearing loss in 3 members of a consanguineous family, two from one nuclear family and one from another. The variant was also shown to result in some transcripts being abnormally spliced, resulting in a premature stop codon. Functional studies in zebrafish and mice show the gene plays an essential role in normal organization and maintenance of the auditory hair bundles, and for hearing function. Rated Amber due to supporting functional studies in mice. Sources: Literature |
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| Mendeliome v0.6171 | CFAP47 |
Hazel Phillimore gene: CFAP47 was added gene: CFAP47 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CFAP47 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: CFAP47 were set to PMID: 33472045 Phenotypes for gene: CFAP47 were set to asthenoteratozoospermia; morphological abnormalities of the flagella (MMAF) Review for gene: CFAP47 was set to AMBER Added comment: CFAP47 also known as CXorf22. 3 different missense variants in 3 unrelated Chinese individuals with asthenoteratozoospermia associated with morphological abnormalities of the flagella (MMAF). Immunoblotting and immunofluorescence showed reduced levels of CFAP47 in spermatozoa in all 3 men. A separate asthenoteratozoospermia cohort showed 1 individual with CNV including whole gene deletion of CFAP47. Mouse model (with frameshift variants generated (via CRISPR-Cas9 technology) were sterile and presented with reduced sperm motility and abnormal flagellar morphology. Sources: Literature |
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| Mendeliome v0.6166 | METAP1 |
Paul De Fazio gene: METAP1 was added gene: METAP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: METAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METAP1 were set to PMID: 32764695 Phenotypes for gene: METAP1 were set to Intellectual disability, aggression, neurodevelopmental delay Review for gene: METAP1 was set to RED gene: METAP1 was marked as current diagnostic Added comment: Biallelic nonsense (NMD-predicted) variant identified in 4 sibs in a consanguineous family with dev delay. One sib had bilateral clinodactyly of her toes and her left 3rd finger, other sibs were not dysmorphic. Rated red due to single consanguineous family. Sources: Literature |
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| Mendeliome v0.6164 | MYADML2 |
Paul De Fazio gene: MYADML2 was added gene: MYADML2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MYADML2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYADML2 were set to 32778762 Phenotypes for gene: MYADML2 were set to Cranial asymmetry, reduced bone maturation, multiple dislocations, lumbar lordosis, and prominent clavicles Review for gene: MYADML2 was set to RED gene: MYADML2 was marked as current diagnostic Added comment: 5 sibs from a consanguineous family identified to have biallelic deletion encompassing part of the PYCR1 gene and the coding region of the MYADML2 gene. According to the authors: "All five affected sibs had the most common features of ARCL (autosomal recessive cutis laxa) but not many of the less common ones. We attributed the anomalies not typical for ARCL to MYADML2 deficit, because no other genetic defect possibly a candidate to underlie the skeletal phenotype was found." Phenotype may still be explained by the PYCR1 deletion alone. Sources: Literature |
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| Mendeliome v0.6149 | NOS1AP |
Zornitza Stark edited their review of gene: NOS1AP: Added comment: Nephrotic syndrome type 22 (NPHS22) is an autosomal recessive renal disease characterized by onset of progressive kidney dysfunction in infancy. Affected individuals usually present with edema associated with hypoproteinemia, proteinuria, and microscopic hematuria. Renal biopsy shows effacement of the podocyte foot processes, glomerulosclerosis, and thickening of the glomerular basement membrane. The disease is steroid-resistant and progressive, resulting in end-stage renal disease usually necessitating kidney transplant. Two unrelated families and animal model. No PMID yet: https://advances.sciencemag.org/content/7/1/eabe1386; Changed rating: GREEN; Changed phenotypes: Nephrotic syndrome, type 22, MIM# 619155; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Mendeliome v0.6141 | NDUFC2 |
Zornitza Stark gene: NDUFC2 was added gene: NDUFC2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NDUFC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NDUFC2 were set to 32969598 Phenotypes for gene: NDUFC2 were set to Mitochondrial complex I deficiency, nuclear type 36, MIM# 619170 Review for gene: NDUFC2 was set to AMBER Added comment: Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome. Two unrelated families reported, some functional data. Sources: Expert list |
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| Mendeliome v0.6105 | GPIHBP1 |
Bryony Thompson gene: GPIHBP1 was added gene: GPIHBP1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GPIHBP1 were set to 17883852; 19304573; 20026666; 17403372 Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome Review for gene: GPIHBP1 was set to GREEN gene: GPIHBP1 was marked as current diagnostic Added comment: Well-established cause of familial chylomicronemia (see OMIM). Greater than 3 families reported and a supporting mouse model. Sources: Expert list |
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| Mendeliome v0.6095 | TMEM251 |
Bryony Thompson gene: TMEM251 was added gene: TMEM251 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM251 were set to 33252156 Phenotypes for gene: TMEM251 were set to Dysostosis multiplex‐like skeletal dysplasia; severe short stature Review for gene: TMEM251 was set to AMBER Added comment: Two unrelated consanguineous families with homozygous variants (c.133C>T; p.Arg45Trp and c.215dupA; p.Tyr72Ter), with co-segregation data in one family. Preliminary in vitro functional assays conducted - Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Sources: Literature |
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| Mendeliome v0.6035 | SCAMP5 | Zornitza Stark edited their review of gene: SCAMP5: Added comment: PMID 33390987: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.; Changed publications: 31439720, 33390987 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6026 | KAT6B | Elena Savva reviewed gene: KAT6B: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 22715153, 32424177; Phenotypes: SBBYSS syndrome MIM#603736, Genitopatellar syndrome MIM#606170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6019 | KRT10 | Elena Savva reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 26176760, 20798280, 31638346, 18219278, 16505000; Phenotypes: Epidermolytic hyperkeratosis, MIM#113800, Ichthyosis with confetti, MIM#609165, Ichthyosis, cyclic, with epidermolytic hyperkeratosis, MIM#607602; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6019 | BCS1L | Elena Savva reviewed gene: BCS1L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 17314340; Phenotypes: Bjornstad syndrome MIM#262000, GRACILE syndrome, MIM#603358, Mitochondrial complex III deficiency, nuclear type MIM#1124000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5914 | RNU7-1 |
Ee Ming Wong gene: RNU7-1 was added gene: RNU7-1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNU7-1 were set to PMID: 33230297 Phenotypes for gene: RNU7-1 were set to PMID: 33230297 Review for gene: RNU7-1 was set to GREEN gene: RNU7-1 was marked as current diagnostic Added comment: - 16 affected individuals from 11 families - - Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of replication-dependent histone (RDH) mRNAs Sources: Literature |
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| Mendeliome v0.5914 | LSM11 |
Ee Ming Wong gene: LSM11 was added gene: LSM11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LSM11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LSM11 were set to PMID: 33230297 Phenotypes for gene: LSM11 were set to type I interferonopathy Aicardi–Goutières syndrome Review for gene: LSM11 was set to AMBER gene: LSM11 was marked as current diagnostic Added comment: - Two affected siblings from a consanguineous family carrying a homozygous variant in LSM11 - Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of replication-dependent histone (RDH) mRNAs - Knockdown of LSM11 in THP-1 cells results in an increase in misprocessed RDH mRNA and interferon signaling Sources: Literature |
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| Mendeliome v0.5914 | DPH2 |
Paul De Fazio gene: DPH2 was added gene: DPH2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DPH2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DPH2 were set to 32576952; 27421267 Phenotypes for gene: DPH2 were set to Diphthamide-deficiency syndrome Review for gene: DPH2 was set to AMBER gene: DPH2 was marked as current diagnostic Added comment: One family reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency. Another family was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative. In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952. Sources: Literature |
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| Mendeliome v0.5914 | FBRSL1 |
Elena Savva gene: FBRSL1 was added gene: FBRSL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FBRSL1 were set to PMID: 32424618 Phenotypes for gene: FBRSL1 were set to Malformation and intellectual disability syndrome Review for gene: FBRSL1 was set to GREEN Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. 2/3 had heart defects, cleft palate and hearing impairement. Supported by Xenopus oocyte functional studies Sources: Literature |
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| Mendeliome v0.5888 | LPIN1 | Zornitza Stark Phenotypes for gene: LPIN1 were changed from to Myoglobinuria, acute recurrent, autosomal recessive, MIM# 268200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5885 | LPIN1 | Zornitza Stark reviewed gene: LPIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18817903, 32549891, 32522502, 32410653; Phenotypes: Myoglobinuria, acute recurrent, autosomal recessive, MIM# 268200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5807 | MAB21L2 | Zornitza Stark changed review comment from: More than 7 unrelated families reported with microphthalmia/anophthalmia/coloboma and rhizomelia. Two individuals with the c.151C > T (p.Arg51Cys) variant also had ID. One family reported with eye phenotype and bi-allelic missense variants, LIMITED evidence for bi-allelic disease. Three different animal models support gene-disease association.; to: More than 7 unrelated families reported with microphthalmia/anophthalmia/coloboma and rhizomelia. Several individuals with the c.151C > T (p.Arg51Cys) variant also had ID. One family reported with eye phenotype and bi-allelic missense variants, LIMITED evidence for bi-allelic disease. Three different animal models support gene-disease association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5804 | PDSS1 | Paul De Fazio reviewed gene: PDSS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17332895, 22494076, 33285023; Phenotypes: Coenzyme Q10 deficiency, primary, 2 MIM#614651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5775 | NSD1 | Chern Lim reviewed gene: NSD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16010675, 15942875; Phenotypes: Sotos syndrome 1 (MIM#117550), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5718 | PGM3 |
Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported. |
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| Mendeliome v0.5677 | SLC2A1 | Elena Savva reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:18451999, 20129935, 10980529, 20221955, 31196579; Phenotypes: GLUT1 deficiency syndrome 1, infantile onset, severe, MIM#606777, Dystonia 9, MIM#601042, Stomatin-deficient cryohydrocytosis with neurologic defects, MIM#608885, GLUT1 deficiency syndrome 2, childhood onset, MIM#612126, {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM#614847; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5665 | POR | Elena Savva reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27068427; Phenotypes: Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, MIM#201750, Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM#613571; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5644 | MSH5 |
Bryony Thompson gene: MSH5 was added gene: MSH5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MSH5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MSH5 were set to 28175301; 9916805; 24970489 Phenotypes for gene: MSH5 were set to Premature ovarian failure 13 MIM#617442 Review for gene: MSH5 was set to AMBER Added comment: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.5590 | RNASEH2C | Chern Lim reviewed gene: RNASEH2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 24183309, 23322642; Phenotypes: Aicardi-Goutieres syndrome 3 (MIM# 610329), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5577 | FBXO28 |
Zornitza Stark gene: FBXO28 was added gene: FBXO28 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBXO28 were set to 33280099 Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy Review for gene: FBXO28 was set to GREEN Added comment: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features. Sources: Literature |
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| Mendeliome v0.5572 | CLCN6 | Zornitza Stark edited their review of gene: CLCN6: Added comment: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans.; Changed rating: GREEN; Changed publications: 25794116, 21107136, 33217309; Changed phenotypes: Neurodegeneration, Benign partial epilepsy, febrile seizures, NCL; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5567 | VPS4A |
Kristin Rigbye changed review comment from: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." Sources: Literature; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." |
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| Mendeliome v0.5567 | VPS4A |
Elena Savva changed review comment from: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." |
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| Mendeliome v0.5567 | VPS4A | Elena Savva Added comment: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5558 | VPS4A |
Kristin Rigbye gene: VPS4A was added gene: VPS4A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS4A were set to PMID: 33186543; 33186545 Phenotypes for gene: VPS4A were set to Neurodevelopmental disorder Review for gene: VPS4A was set to GREEN Added comment: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." Sources: Literature |
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| Mendeliome v0.5557 | AGO2 |
Zornitza Stark gene: AGO2 was added gene: AGO2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AGO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AGO2 were set to 33199684 Phenotypes for gene: AGO2 were set to Intellectual disability Review for gene: AGO2 was set to GREEN Added comment: 21 individuals reported, five variants (p.L192P, p.G201V, p.T357M, p.M364T, p.C751Y) were recurrent. Variable ID. Sources: Literature |
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| Mendeliome v0.5554 | BICRA |
Paul De Fazio gene: BICRA was added gene: BICRA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BICRA were set to 33232675 Phenotypes for gene: BICRA were set to Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features Review for gene: BICRA was set to GREEN gene: BICRA was marked as current diagnostic Added comment: 12 individuals reported, 11 de novo (1 not resolved), "with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features". Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association. Sources: Literature |
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| Mendeliome v0.5554 | HS2ST1 |
Ain Roesley gene: HS2ST1 was added gene: HS2ST1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HS2ST1 were set to 33159882 Penetrance for gene: HS2ST1 were set to unknown Review for gene: HS2ST1 was set to GREEN Added comment: - 4 affected from 3 unrelated families - 3 unique missense and 2 PTCs - Developmental Delay, Corpus Callosum Hypoplasia or Aplasia, and Skeletal and Renal Abnormalities Sources: Literature |
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| Mendeliome v0.5553 | MINPP1 |
Zornitza Stark gene: MINPP1 was added gene: MINPP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MINPP1 were set to 33257696 Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia Review for gene: MINPP1 was set to GREEN Added comment: 8 individuals from 6 unrelated families reported with bi-allelic LOF variants. All presented with almost complete absence of motor and cognitive development, progressive or congenital microcephaly, spastic tetraplegia or dystonia, and vision impairments. For most, the first symptoms included neonatal severe axial hypotonia and epilepsy that started during the first months or years of life. Prenatal symptoms of microcephaly associated with increased thalami echogenicity were detected in one, while the seven other individuals presented with progressive microcephaly. Some exhibited rapidly progressive phenotype and the affected children died in their infancy or middle-childhood. Strikingly, all the affected children had a unique brain MRI showing a mild to severe PCH, fluid-filled posterior fossa, with dilated lateral ventricles. In addition, severe atrophy at the level of the basal ganglia or thalami often associated with typical T2 hypersignal were identified in all the patients MRI. Supportive functional data showing accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. Sources: Literature |
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| Mendeliome v0.5552 | UNC45B |
Paul De Fazio gene: UNC45B was added gene: UNC45B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UNC45B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNC45B were set to 33217308 Phenotypes for gene: UNC45B were set to Progressive Myopathy with Eccentric Cores Review for gene: UNC45B was set to GREEN gene: UNC45B was marked as current diagnostic Added comment: 10 individuals from 8 families reported with biallelic variants clinically manifesting with childhood-onset, progressive proximal and axial muscle weakness and various degrees of respiratory insufficiency. 4 missense variants and a +5 splice variant reported, p.Arg754Gln is recurrent. Functional studies support pathogenicity. Sources: Literature |
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| Mendeliome v0.5549 | DNAJB11 | Zornitza Stark changed review comment from: Seven unrelated. families described with phenotypes overlapping ADTKD and ADPKD, five different variants, one of these, p.Arg206* recurrent in three families.; to: Seven unrelated. families described with phenotypes overlapping ADTKD and ADPKD, five different mono-allelic variants, one of these, p.Arg206* recurrent in three families. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5549 | DNAJB11 | Zornitza Stark edited their review of gene: DNAJB11: Added comment: Single family reported with bi-allelic variant and severe, fetal onset renal cystic disease, dilation and proliferation of pancreatic duct cells, and liver ductal plate malformation, an association known as Ivemark II syndrome.; Changed publications: 29706351, 29777155, 33129895; Changed phenotypes: Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061, Ivermark II syndrome.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5507 | FKBP8 |
Eleanor Williams gene: FKBP8 was added gene: FKBP8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FKBP8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FKBP8 were set to 32969478 Phenotypes for gene: FKBP8 were set to spina bifida HP:0002414 Review for gene: FKBP8 was set to AMBER Added comment: Not associated with a phenotype in OMIM. PMID: 32969478 - Tian et al 2020 - performed Sanger sequencing of FKBP8 on DNA samples from 472 spina bifida (SB) affected fetuses and 565 unaffected controls. 5 different rare heterozygous variants (MAF ≤ 0.001) were identified among the SB patients, while no deleterious rare variants were identified in the controls. 4 of the variants are missense, the other is a stop-gain. 2 cases were in white-Hispanic patients while the other 3 were non-white Hispanic. Functional studies showed that p.Glu140* affected FKBP8 localization to the mitochondria and impaired its interaction with BCL2 ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. Gene expression was studied in mouse Fkbp8-/- embryos and found to be abnormal. Previous mouse models have shown neural tube defects. Sufficient cases to rate green, but only the FKBP8 gene looked at so perhaps some caution required while further evidence is gathered. Sources: Literature |
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| Mendeliome v0.5507 | CAPN15 |
Eleanor Williams changed review comment from: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Sources: Literature; to: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. Sources: Literature |
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| Mendeliome v0.5507 | CAPN15 |
Eleanor Williams gene: CAPN15 was added gene: CAPN15 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CAPN15 were set to 32885237 Phenotypes for gene: CAPN15 were set to microphthalmia HP:0000568; coloboma HP:0000589 Review for gene: CAPN15 was set to GREEN Added comment: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Sources: Literature |
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| Mendeliome v0.5449 | ALG8 | Zornitza Stark changed review comment from: Review of 15 reported individuals in PMID: 26066342: multiple prenatal abnormalities were present in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birth weight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydrops fetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomental retardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears, macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy, in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDG typical skin involvement was reported in 8/13.; to: Bi-allelic variants and CDG: Review of 15 reported individuals in PMID: 26066342. Multiple prenatal abnormalities were present in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birth weight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydrops fetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomental retardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears, macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy, in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDG typical skin involvement was reported in 8/13. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5407 | CRTAP | Paul De Fazio reviewed gene: CRTAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 21955071, 19846465, 17192541; Phenotypes: Osteogenesis imperfecta, type VII MIM#610682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5407 | USP9X | Paul De Fazio reviewed gene: USP9X: Rating: GREEN; Mode of pathogenicity: None; Publications: 31443933, 26833328; Phenotypes: Mental retardation, X-linked 99, XLR (MIM#300919) and XLD (MIM#300968); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5381 | NPHS2 | Chern Lim reviewed gene: NPHS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32467597, 30260545, 24509478; Phenotypes: Nephrotic syndrome, type 2 (MIM#600995), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5357 | KCNQ2 | Elena Savva reviewed gene: KCNQ2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 25959266, 32917465, 24318194; Phenotypes: Epileptic encephalopathy, early infantile, 7, 613720, Seizures, benign neonatal, 1, 121200, Myokymia, 121200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5357 | FGFR1 | Elena Savva reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 18034870, 23812909, 26942290; Phenotypes: Encephalocraniocutaneous lipomatosis, somatic mosaic 613001, Hartsfield syndrome 615465, Hypogonadotropic hypogonadism 2 with or without anosmia 147950, Jackson-Weiss syndrome 123150, Osteoglophonic dysplasia 166250, Pfeiffer syndrome 101600, Trigonocephaly 1 190440; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5331 | ALDOB | Elena Savva reviewed gene: ALDOB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 3083321; Phenotypes: Fructose intolerance, hereditary, 229600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5327 | LMX1B |
Zornitza Stark commented on gene: LMX1B: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. Some variants in the homeodomain of LMX1B cause isolated nephropathy without nail, patellar or skeletal abnormality (LMX1B-associated nephropathy). >300 families reported. |
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| Mendeliome v0.5315 | ZFHX4 |
Bryony Thompson changed review comment from: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). Sources: Literature; to: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). PMID: 24038936 - a single case with developmental delay, macrocephaly, ventriculomegaly, hypermetropia, recurrent infections, dysmorphism and a de novo deletion of the last 7 exons of the gene. Sources: Literature |
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| Mendeliome v0.5290 | MSL2 |
Bryony Thompson gene: MSL2 was added gene: MSL2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MSL2 were set to 31332282; 33057194 Phenotypes for gene: MSL2 were set to Developmental disorders; autism Review for gene: MSL2 was set to AMBER Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 13 de novo variants (9 frameshift, 4 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). PMID: 31332282 - candidate gene in a single autism study, with recurrent de novo variants in a potential oligogenic model Sources: Literature |
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| Mendeliome v0.5272 | PRKG2 |
Arina Puzriakova gene: PRKG2 was added gene: PRKG2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRKG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRKG2 were set to 33106379 Phenotypes for gene: PRKG2 were set to Acromesomelic dysplasia Review for gene: PRKG2 was set to GREEN Added comment: - PMID: 33106379 (2020) - Distinct homozygous variants in PRKG2 identified in two unrelated individuals, both with a skeletal dysplasia associated with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional studies showed both variants result in NMD and disrupt the downstream MAPK signalling pathway in response to FGF2. The role of cGKII, encoded by PRKG2, in skeletal growth has been established in several animal models (references provided in paper). Sources: Literature |
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| Mendeliome v0.5254 | FBXO31 |
Kristin Rigbye changed review comment from: 2 unrelated probands with CP harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.; to: 2 unrelated probands with CP harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression. Extended patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2). |
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| Mendeliome v0.5251 | RHOB |
Crystle Lee gene: RHOB was added gene: RHOB was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: RHOB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RHOB were set to 32989326 Phenotypes for gene: RHOB were set to Cerebral Palsy (PMID:32989326) Mode of pathogenicity for gene: RHOB was set to Other Review for gene: RHOB was set to AMBER Added comment: Candidate disease-causing gene for CP. Recurrent de novo missense variant reported in 2 unrelated families with supporting functional studies. Sources: Expert list |
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| Mendeliome v0.5248 | NHLRC2 |
Paul De Fazio changed review comment from: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty) PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region. PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.; to: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty) PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region. PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel. |
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| Mendeliome v0.5248 | NHLRC2 |
Paul De Fazio changed review comment from: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty) PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Zebrafish knockdown affected the integrity of cells in the midbrain region. PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.; to: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty) PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region. PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel. |
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| Mendeliome v0.5246 | NHLRC2 | Paul De Fazio reviewed gene: NHLRC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29423877, 32435055; Phenotypes: Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome MIM#618278; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5240 | AMOTL1 |
Zornitza Stark gene: AMOTL1 was added gene: AMOTL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AMOTL1 were set to 33026150 Phenotypes for gene: AMOTL1 were set to Cleft lip and palate; imperforate anus; dysmorphism Review for gene: AMOTL1 was set to RED Added comment: Two unrelated families reported. In one, the variant was identified in parent and child who had orofacial cleft and cardiac abnormalities. Second report in PMID 33026150, de novo missense variant and cleft lip/palate, imperforate anus and dysmorphism. Mouse model does not recapitulate phenotype. Sources: Literature |
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| Mendeliome v0.5236 | GFRA1 |
Zornitza Stark gene: GFRA1 was added gene: GFRA1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GFRA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GFRA1 were set to 33020172 Phenotypes for gene: GFRA1 were set to Renal agenesis Review for gene: GFRA1 was set to AMBER Added comment: Two unrelated families reported with bi-allelic LOF variants identified in individuals with bilateral renal agenesis. GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system. Sources: Literature |
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| Mendeliome v0.5229 | PRKAR1B |
Konstantinos Varvagiannis gene: PRKAR1B was added gene: PRKAR1B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040 Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure Penetrance for gene: PRKAR1B were set to unknown Review for gene: PRKAR1B was set to AMBER Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence. Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants. All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4). 3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24. In all cases were parental samples were available (5/6), the variant had occurred as a de novo event. Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus. The functional consequences of the variants at cellular level were not studied. Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided]. The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious]. Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040]. Sources: Literature |
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| Mendeliome v0.5216 | SCYL1 | Zornitza Stark commented on gene: SCYL1: Autosomal recessive spinocerebellar ataxia-21 is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur. More than 5 unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5174 | NUS1 | Elena Savva reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25066056, 29100083, 31656175, 32485575; Phenotypes: ?Congenital disorder of glycosylation, type 1aa 617082, Mental retardation, autosomal dominant 55, with seizures 617831; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5174 | HBB | Elena Savva reviewed gene: HBB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31788855, 20301599, 29700171; Phenotypes: {Malaria, resistance to} 611162, Delta-beta thalassemia 141749, Erythrocytosis 6 617980, Heinz body anemia 140700, Hereditary persistence of fetal hemoglobin 141749, Methemoglobinemia, beta type 617971, Sickle cell anemia 603903, Thalassemia-beta, dominant inclusion-body 603902, Thalassemia, beta 613985; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5168 | SLC35A3 | Zornitza Stark edited their review of gene: SLC35A3: Added comment: Third unrelated family reported in PMID 28777481 with prenatally diagnosed anomalous vertebrae, including butterfly, and hemivertebrae throughout the spine, as well as cleft palate, micrognathia, patent foramen ovale, patent ductus arteriosus, posterior embryotoxon, short limbs, camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism including proptosis, nevus flammeus, and a cupped left ear. Unclear if this is a distinct phenotype (note Holstein cows with variants in this gene have a skeletal phenotype) or part of a spectrum for a CDG. However, abnormal protein glycosylation, consistent with a defective Golgi UDP-GlcNAc transporter demonstrated, so overall, promoted to Green for CDG.; Changed rating: GREEN; Changed publications: 28777481, 28328131, 24031089; Changed phenotypes: Arthrogryposis, mental retardation, and seizures OMIM #615553, Skeletal dysplasia, Congenital disorder of glycosylation; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5139 | CTNNA3 |
Bryony Thompson gene: CTNNA3 was added gene: CTNNA3 was added to Mendeliome. Sources: ClinGen Mode of inheritance for gene: CTNNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CTNNA3 were set to 23136403; 21254927; 22421363; 30415094; 31539150 Phenotypes for gene: CTNNA3 were set to Arrhythmogenic right ventricular cardiomyopathy; Arrhythmogenic right ventricular dysplasia, familial, 13 MIM#615616 Review for gene: CTNNA3 was set to AMBER Added comment: Gene is classified as Limited by the ClinGen ARVC GCEP (Classification - 08/06/2019). PMID: 23136403 - an assumed de novo missense (V94D) was identified in an Italian proband with arrhythmogenic right ventricular dysplasia. An inframe deletion (Leu765del) was identified in a proband with arrhythmogenic right ventricular dysplasia, and was also present in the proband's asymptomatic father and paternal aunt, who had mild right ventricular dilation on echocardiography and increased trabeculations in the right ventricular apex on MRI, respectively, as well as in the aunt's asymptomatic son. There was supporting in vitro functional assay evidence for both variants. PMID: 21254927 - a missense variant was found in one of 55 Danish ARVD patients, but was found 37 times in 276,338 (1 homozygous) reference alleles in gnomAD making it less likely as a causal variant. PMID: 22421363 - null mice exhibit progressive dilated cardiomyopathy, gap junction remodelling, and increased sensitivity to ventricular arrhythmia following acute ischaemia, but not spontaneous ARVC. Additional publications identified - PMID: 30415094 - a VUS identified in a sudden unexpected death case with slight LV hypertrophy. PMID: 31539150 - 2 VUS and a nonsense variant identified in 3 probands with atrial fibrillation, with the nonsense variant segregating in an affected first-degree relative. Sources: ClinGen |
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| Mendeliome v0.5102 | PRKACB |
Konstantinos Varvagiannis gene: PRKACB was added gene: PRKACB was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKACB were set to 33058759 Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability Penetrance for gene: PRKACB were set to unknown Mode of pathogenicity for gene: PRKACB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: PRKACB was set to GREEN Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants. The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD. Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors. Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID. As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes. WES was carried out in all. PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD). PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo. Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt). By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals. As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284). Sources: Literature |
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| Mendeliome v0.5102 | PRKACA |
Konstantinos Varvagiannis gene: PRKACA was added gene: PRKACA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKACA were set to 33058759; 31130284 Phenotypes for gene: PRKACA were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability Penetrance for gene: PRKACA were set to unknown Mode of pathogenicity for gene: PRKACA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: PRKACA was set to GREEN Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants. The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD. Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors. Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID. As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes. WES was carried out in all. PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD). PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo. Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt). By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals. As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284). Sources: Literature |
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| Mendeliome v0.5085 | SYT2 |
Zornitza Stark changed review comment from: Mono-allelic disease, PMID 25192047: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in two families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.; to: Mono-allelic disease, PMID 25192047 and 30533528: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function. |
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| Mendeliome v0.5060 | NUDT2 | Zornitza Stark edited their review of gene: NUDT2: Added comment: Three individuals from two additional families reported with a different homozygous variant and ID/polyneuropathy phenotype. Upgrade to Green.; Changed rating: GREEN; Changed publications: 27431290, 30059600, 33058507 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5049 | NR5A1 | Zornitza Stark Phenotypes for gene: NR5A1 were changed from to Adrenocortical insufficiency, (MIM#612964); 46, XX sex reversal 4, (MIM# 617480); Premature ovarian failure 7, (MIM#612964); Spermatogenic failure 8, (MIM#613957); 46XY sex reversal 3, (MIM#612965) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5046 | NR5A1 | Zornitza Stark reviewed gene: NR5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31513305; Phenotypes: Adrenocortical insufficiency, (MIM#612964), 46, XX sex reversal 4, (MIM# 617480), Premature ovarian failure 7, (MIM#612964), Spermatogenic failure 8, (MIM#613957), 46XY sex reversal 3, (MIM#612965); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4998 | CSNK1G1 |
Zornitza Stark gene: CSNK1G1 was added gene: CSNK1G1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CSNK1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CSNK1G1 were set to 33009664 Phenotypes for gene: CSNK1G1 were set to Global developmental delay; Intellectual disability; Autism; Seizures Review for gene: CSNK1G1 was set to GREEN Added comment: Borderline Green/Amber rating. Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883). Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress). CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited). One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn]. Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD. There were no variant studies performed. The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies). Sources: Literature |
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| Mendeliome v0.4993 | LMNB1 | Zornitza Stark edited their review of gene: LMNB1: Added comment: Additional study PMID 33033404 reporting 7 individuals with recurrent missense variants in this gene and ID/microcephaly phenotype.; Changed publications: 32910914, 16951681, 19151023, 33033404 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4886 | SPATA7 | Chern Lim reviewed gene: SPATA7: Rating: GREEN; Mode of pathogenicity: None; Publications: 31908400, 32799588; Phenotypes: Leber congenital amaurosis 3, MIM#604232, Autosomal recessive juvenile retinitis pigmentosa, MIM#604232; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4874 | ITFG2 |
Zornitza Stark gene: ITFG2 was added gene: ITFG2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia Review for gene: ITFG2 was set to AMBER Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51). Cheema et al (2020 - https://doi.org/10.1038/s41525-020-00150-z) report briefly on a male, born to consanguineous parents presenting with NDD, seizures, regression and ataxia. There was a similarly affected female sibling. Evaluation of ROH revealed a homozygous ITFG2 nonsense variant [NM_018463.3:c.361C>T / p.(Gln121*)]. Families in this study were investigated by trio WES or WGS. Evaluation of data of the same lab revealed 3 additional unrelated subjects with overlapping phenotypes, notably NDD and ataxia. These individuals were - each - homozygous for pLoF variants [NM_018463.3:c.848-1G>A; NM_018463.3:c.704dupC, p.(Ala236fs), NM_018463.3:c.1000_1001delAT, p.(Ile334fs)]. As discussed in OMIM, ITFG2 encodes a subunit of the KICSTOR protein complex, having a role in regulating nutrient sensing by MTOR complex-1 (Wolfson et al 2017 - PMID : 28199306). Rated Amber as Cheema et al report on diagnostic outcomes and multiple candidate genes as part of a heterogenous cohort and details are therefore limited. Sources: Literature |
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| Mendeliome v0.4860 | VPS16 |
Zornitza Stark gene: VPS16 was added gene: VPS16 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS16 were set to 32808683 Phenotypes for gene: VPS16 were set to Dystonia Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood. Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals. Sources: Literature |
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| Mendeliome v0.4843 | ARX | Elena Savva reviewed gene: ARX: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 14722918, 19738637, 32519823, 28150386, 21496008; Phenotypes: Epileptic encephalopathy, early infantile, 1 MIM#308350, Hydranencephaly with abnormal genitalia MIM#300215, Lissencephaly, X-linked 2 MIM#300215, Mental retardation, X-linked 29 and others MIM#300419, Partington syndrome MIM#309510, Proud syndrome MIM#300004; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4829 | NEK9 | Zornitza Stark edited their review of gene: NEK9: Added comment: Another Saudi family described with which 2 sisters and a female cousin who had a similar disorder characterised by arthrogryposis apparent since early childhood, avascular necrosis of the hip (Perthes disease), and upward gaze palsy. Homozygous missense variant segregated with the phenotype. Given the small number of reports, it is unclear whether this represents a distinct association is part of a spectrum with includes the more severe phenotype described in the Irish traveller families.; Changed publications: 26908619, 21271645; Changed phenotypes: Lethal congenital contracture syndrome 10, MIM# 617022, Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262, Skeletal dysplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4788 | AKNA |
Elena Savva gene: AKNA was added gene: AKNA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AKNA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AKNA were set to PMID: 21606955 Phenotypes for gene: AKNA were set to Primary ciliary dyskinesia Review for gene: AKNA was set to RED Added comment: https://link.springer.com/article/10.1007/s00439-020-02170-2 Two siblings with homozygous PTCs with PCD. Carrier parents and mutation negative siblings (5) was normal. PMID: 21606955: Null mice have neonatal death with systemic inflammation and alveolar loss Sources: Literature |
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| Mendeliome v0.4786 | AP1S1 | Ee Ming Wong reviewed gene: AP1S1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32306098; Phenotypes: non-syndromic congenital intestinal failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4783 | NUAK2 |
Seb Lunke gene: NUAK2 was added gene: NUAK2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NUAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NUAK2 were set to 32845958 Phenotypes for gene: NUAK2 were set to ANENCEPHALY (OMIM#206500) Review for gene: NUAK2 was set to AMBER Added comment: Novel gene described in single consanguineous family with three FDIU and extensive anencephaly. Hom inframe del affecting functional kinase domain, parents confirmed carriers. Good functional data showing loss of enzyme function and mouse model with 40% anencephaly after knock-out. Sources: Literature |
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| Mendeliome v0.4780 | GBF1 |
Paul De Fazio gene: GBF1 was added gene: GBF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: GBF1 were set to 32937143 Phenotypes for gene: GBF1 were set to Axonal Neuropathy Review for gene: GBF1 was set to GREEN gene: GBF1 was marked as current diagnostic Added comment: Four unrelated families with individuals affected by sporadic or dominant Distal hereditary motor neuropathies (HMNs) or axonal Charcot-Marie-Tooth neuropathy (CMT2). 3 missense variants (1 de novo) and 1 nonsense variant (de novo). Authors observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals. Sources: Literature |
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| Mendeliome v0.4777 | GREB1L | Zornitza Stark Phenotypes for gene: GREB1L were changed from to Renal hypodysplasia/aplasia 3, OMIM# 617805 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4774 | GREB1L | Zornitza Stark reviewed gene: GREB1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100091; Phenotypes: Renal hypodysplasia/aplasia 3, OMIM# 617805; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4749 | SETD1A |
Zornitza Stark gene: SETD1A was added gene: SETD1A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SETD1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SETD1A were set to 31197650; 32346159 Phenotypes for gene: SETD1A were set to Epilepsy, early-onset, with or without developmental delay, MIM# 618832 Review for gene: SETD1A was set to GREEN Added comment: 19 unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype, primarily manifesting and ID and seizures. LOF mechanism supported by functional data. Three mouse models. SNPs in this gene have also been associated with risk of developing schizophrenia. Sources: Literature |
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| Mendeliome v0.4743 | PRKD1 |
Zornitza Stark changed review comment from: PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation. c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; to: PMID: 27479907 (2016): three individuals reported, two with the c.1774G>A variant and one with the c.896T>G variant. All had congenital heart disease, two had some developmental delay, and two had variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth; the third individuals had a 'disorganized eyebrow.' PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation. c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals. |
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| Mendeliome v0.4724 | IGSF10 |
Bryony Thompson gene: IGSF10 was added gene: IGSF10 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: IGSF10 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: IGSF10 were set to 27137492; 31042289 Phenotypes for gene: IGSF10 were set to delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency Review for gene: IGSF10 was set to AMBER Added comment: PMID: 27137492 - 4 Finnish families segregating p.Glu161Lys, but Finnish MAF in ExAC is 2%. Another six additional families with a possible missense, but variants are seen in ExAC suggesting incomplete penetrance. Supporting in vitro functional assays and zebrafish model. PMID: 31042289 - 2 unrelated consanguineous families with homozygous variants and family with a heterozygous frameshift and apparent incomplete penetrance. Sources: Literature |
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| Mendeliome v0.4685 | RPL9 | Arina Puzriakova changed review comment from: PMID: 31799629 (2020) - One individual diagnosed with Diamond Blackfan anaemia carrying a de novo variant (c.-2+1G>C) in the 5′UTR of RPL9, predicted to affect the donor splice site of exon 1. Functional studies showed the variant impairs processing of pre-rRNA during ribosome biogenesis, stabilises TP53 and impairs the proliferation and differentiation of erythroid cells. Zebrafish models of RPL9 LoF recapitulate the anaemia phenotype.; to: PMID: 31799629 (2020) - Female infant diagnosed with Diamond-Blackfan anaemia carrying a de novo variant (c.-2+1G>C) in the 5′UTR of RPL9, predicted to affect the donor splice site of exon 1. Phenotypic overlap can be seen with the previously reported case with the same variant, including colitis, thumb anomaly, and microcephaly. Functional studies showed the variant impairs processing of pre-rRNA during ribosome biogenesis, stabilises TP53 and impairs the proliferation and differentiation of erythroid cells. Zebrafish models of RPL9 LoF recapitulate the anaemia phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4668 | BLOC1S5 |
Zornitza Stark gene: BLOC1S5 was added gene: BLOC1S5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BLOC1S5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BLOC1S5 were set to 32565547 Phenotypes for gene: BLOC1S5 were set to Hermansky–Pudlak syndrome Review for gene: BLOC1S5 was set to GREEN Added comment: 2 unrelated patients with mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Identified distinct homozygous variants in the BLOC1S5 gene (patient 1: deletion of exons 3 and 4, patient 2: 1-bp deletion in exon 4). Parental segregation confirmatory in patient 1, quantitative PCR analysis confirmatory in patient 2). Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele. Pathogenic variants in the genes encoding three other BLOC-1 subunits (DTNBP1, BLOC1S3, and BLOC1S6) underlie HPS types 7, 8, and 9 respectively. Sources: Literature |
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| Mendeliome v0.4643 | GATA3 | Zornitza Stark Phenotypes for gene: GATA3 were changed from to Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4640 | GATA3 | Zornitza Stark reviewed gene: GATA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10935639, 11389161, 21120445, 26316437, 25771973, 27387476, 30396722; Phenotypes: Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4586 | ATP6V1B1 | Zornitza Stark Phenotypes for gene: ATP6V1B1 were changed from to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4583 | ATP6V1B1 | Zornitza Stark reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916796, 12414817, 16611712, 18798332; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4560 | TRRAP | Chern Lim reviewed gene: TRRAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 30827496, 31231791; Phenotypes: Developmental delay with or without dysmorphic facies and autism (MIM#618454), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4560 | SPAST | Chern Lim reviewed gene: SPAST: Rating: GREEN; Mode of pathogenicity: None; Publications: 30476002, 30006150; Phenotypes: Spastic paraplegia 4, autosomal dominant (MIM#182601), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4560 | TRRAP | Chern Lim reviewed gene: TRRAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 30827496; Phenotypes: Developmental delay with or without dysmorphic facies and autism (MIM#618454), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4528 | CYP11B2 | Paul De Fazio reviewed gene: CYP11B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8439335, 9360501, 15240589, 9814506, 12788848, 8772616; Phenotypes: Hypoaldosteronism, congenital, due to CMO I deficiency (MIM#203400) or due to CMO II deficiency (MIM#610600).; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4520 | SLC12A2 |
Zornitza Stark edited their review of gene: SLC12A2: Added comment: Monoallelic : DD/ID was a feature in >= 6 individuals with monoallelic de novo SLC12A2. An individual with an exon 22 truncating variant was reported to have normal milestones and cognitive function. Exon 21 variants have been described in individuals with rather isolated hearing impairment (possibly some associated motor delay, but normal cognition). Hearing impairment was also reported in 2/6 patients with variants in other exons (1 missense / 1 frameshift). Biallelic : DD/ID was reported in at least 3 individuals in literature. Hearing impairment has been reported on 2 occasions (although this was not probably evaluated in all subjects). --- Monoallelic SLC12A2 mutations : ► Individuals with de novo mutations and developmental disorder were first identified by the DDD study (2017 - PMID: 28135719). 5 of them have been reported in detail by McNeill et al (below). ► McNeill et al (2020 - PMID: 32658972) report on 6 individuals with neurodevelopmental disorder due to de novo SLC12A2 mutation. All presented DD or ID ranging from mild to severe. ASD was reported in 3/6. Sensorineural hearing loss was a feature in 2/6 with the remaining having normal formal evaluations. Brain, cardiac and/or additional malformations were reported in a single individual. Following non-diagnostic prior work-up (CMA, FMR1 or other investigations) trio exome sequencing revealed missense (4/6) or truncating variants (2/6). Three additional individuals (incl. a father and his son) with missense variants in exon 21 (NM_001046.3 / p.Glu979Lys and p.Glu980Lys) presented with bilateral sensorineural hearing loss. Speech and/or motor delay reported in these cases were attributed to the hearing impairment/vestibular arreflexia (cognitive abilities not tested). SLC12A2 encodes sodium-potassium-chloride transporter 1 (also NKCC1). The GTEx project has identified 8 isoforms. In brain both exon 21-containing/deleted isoforms are expressed (cited Morita et al 2014 - PMID: 24695712). As the authors discuss, RNA-seq of the developing mouse cochlea suggests that the exon 21 containing isoform is the single transcript expressed. Evidence from RNA-seq data (BrainSpan project) and literature suggests that the significant amounts of exon 21 lacking isoforms in fetal brain compensate for the deleterious effects of exon 21 variants and explain the lack of NDD in relevant patients. Slc12a2 (NKCC1) null mouse model has demonstrated that the transporter plays a role in accumulation of the potassium rich endolymph in the inner ear, with NKCC1 absence causing sensorineural deafness and imbalance. Slc12a2 display cochlear malformations, loss of hair cells and hearing impairment (cited Delpire et al 1999 - PMID: 10369265). The brain phenotype has not been studied extensively, although loss of Slc12a2 has been shown to inhibit neurogenesis (cited: Magalhães and Rivera et al. - PMID: 27582690). Slc12a2 null zebrafish display a collapse of the otic vesicle and reduced endolymph (Abbas and Whitfield, 2009 - PMID: 19633174) relevant to the human hearing disorder. In vitro assessment of NKCC1 ion transporter function in Xenopus laevis, supported the deleterious effect of the identified variants (significant reduction in K+ influx). Using available single cell RNA-seq data the authors further demonstrated that SLC12A2 expressing cells display transcriptomic profiles reflective of active neurogenesis. ► Delpire et al (2016 - PMID: 27900370 - not reviewed in detail) described a 13 y.o. girl harboring a de novo 11-bp deletion in SLC12A2 exon 22. This individual reached developmental milestones on time and had a NORMAL cognitive function. Hearing was seemingly normal. Features included orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency and multiorgan failure incl. gut and bladder. Exome in the proband, parents and 3 unaffected sibs suggested SLC12A2 as the only candidate for her phenotype. Functional analyses in Xenopus laevis oocytes suggested that a non functional transporter was expressed and trafficked to the membrane as the wt. Detection of the truncated protein at higher molecular sizes suggested either enhanced dimerization or misfolded aggregate. There was no dominant-negative effect of mutant NKCC1. In patient fibroblasts a reduced total and NKCC1-mediated K+ influx. ► Mutai et al (2020 - PMID: 32294086) report on several individuals from 4 families, harboring variants within exon 21 or - in one case - at it's 3' splice-site (leading to skipping oe this exon at the mRNA level). All subjects were investigated for severe/profound hearing loss (in line with the role of exon 21-included isoforms in cochlea. The variant segregated with hearing impairment in 3 generations of a family while in all other subjects the variant had occured as de novo event. Despite motor delays (e.g. the subject from fam2 could not hold head or sit at the age of 10m / the proband in Fam3 was able to hold his head and walk at 6 and 20 m respectively) behavior and cognition were commented to be within normal range. ----- Biallelic SLC12A2 mutations: ► Anazi et al (2017 - PMID: 29288388) briefly reported on a 3 y.o. boy (17DG0776) with central hypotonia, neonatal respiratory distress, failure to thrive, global DD and microcephaly and a skeletal survey suggestive of osteopenia. After non-diagnostic prior investigations (CMA revealing a 1p duplication classified as VUS, extensive metabolic workup), WES revealed a homozygous SLC12A2 splicing variant [NM_001046.2:c.2617-2A>G]. ► Macnamara et al (2019 - PMID: 30740830) described a 5.5 y.o. male with sensorineural hearing loss, profound delays in all developmental areas among several other features (choanal atresia, failure to thrive, respiratory problems, absent sweat and tear production or salivation, GI abnormalities). Genetic testing for several disorders considered (cystic fibrosis, spinal muscular atrophy, sequencing and del/dup analysis of mtDNA) was normal. CMA revealed paternal uniparental isodisomy for chr. 5 and WGS a homozygous 22kb deletion in SLC12A2. This was followed by confirmation of homozygosity in the proband, heterozygosity of the unaffected father, delineation of breakpoints (chr5:127441491-127471419). mRNA studies in patient fibroblasts confirmed deletion of ex2-7, splicing of ex1 directly to ex8 and introduction of a premature stop codon in ex9. qRT-PCR confirmed that mRNA is likely subjected to NMD (expression ~80% of control). Western blot confirmed absence of the protein in the patient's fibroblasts. Again mouse models are thought to recapitulate the hearing defect but also the deficient saliva production (cited Evans et al 2000 - PMID: 10831596). Again the authors speculate a role of SLC12A2 in brain development based on evidence from murine models (migration, dendritic growth, increse in neuron density through regulation of GABAergic signalling (Young et al 2012 - PMID: 23015452). Hypotheses are also made on a regulatory relationship between NKCC1 and CFTR based on mRNA data from the ko mouse model. ► Stödberg et al (2020 - PMID: 32754646) reported 2 sibs with a complex neurodevelopmental disorder due to compound heterozygosity for a frameshift SLC12A2 variant and a splicing one (NM_001046:c.1431delT and c.2006-1G>A). Both presented hypotonia, neonatal S. aureus parotitis and respiratory problems (incl. apneas). While the older sib died at the age of 22 days, the younger one had persistent respiratory issues incl. a dry respiratory mucosa motivating metabolic, immunology investigations and testing for CF. She displayed microcephaly (OFC -2.5 SD, H was also -3.5SD), severe intellectual disability. MRI was suggestive of white matter and basal ganglia abnormalities. Other features incl. hearing impairment, and lack of tears,saliva and sweat, constipation and intestinal malrotation. There was facial dysmorphism. The variants were the only retained following WGS of the 2 affected sisters, parents and an unaffected brother. The splicing variant was shown to result in skipping of exon 13, while the indel in NMD. Again the authors discuss that the deficient saliva production, impaired hearing and GI problems are recapitulated in the mouse model (several refs provided).; Changed rating: GREEN; Changed publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Changed phenotypes: Kilquist syndrome, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.4503 | ZMYM2 |
Zornitza Stark gene: ZMYM2 was added gene: ZMYM2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZMYM2 were set to 32891193 Phenotypes for gene: ZMYM2 were set to Congenital anomalies of kidney and urinary tract; Neurodevelopmental disorder Review for gene: ZMYM2 was set to GREEN Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. -- Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly. 14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family. The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT. ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body). It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors. The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT). Sources: Literature |
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| Mendeliome v0.4501 | MTX2 |
Zornitza Stark gene: MTX2 was added gene: MTX2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTX2 were set to 32917887 Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia; lipodystrophy; arterial calcification Review for gene: MTX2 was set to GREEN Added comment: Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Sources: Literature |
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| Mendeliome v0.4496 | FNIP1 |
Arina Puzriakova gene: FNIP1 was added gene: FNIP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FNIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FNIP1 were set to 32181500; 32905580 Phenotypes for gene: FNIP1 were set to Hypertrophic Cardiomyopathy; Primary Immunodeficiency; Agammaglobulinemia; Neutropenia Review for gene: FNIP1 was set to GREEN Added comment: - PMID: 32181500 (2020) - Three patients from two independent consanguineous families with homozygous variants (c.3353G>A, p.Ser1118Asn and c.1289delA, p.His430Profs7*) in the FNIP1 gene. Both variants segregated with the disease phenotype in each family. Clinically, patients presented with combined immunodeficiency, cardiac findings (hypertrophic cardiomyopathy, Wolff‐Parkinson‐White syndrome), and myopathy of skeletal muscles with motor DD. Authors note phenotypic overlap with the murine model of FNIP1 deficiency, but no functional analyses of the variants or patient cells were performed. - PMID: 32905580 (2020) - Three cases from unrelated families, all harbouring novel biallelic variants in FNIP1. Clinical manifestations in all patients include hypertrophic cardiomyopathy, severe and/or recurrent infections, absent circulating B-cells, and agammaglobulinemia; as well as either severe or intermittent neutropenia in two cases. Functional studies showed impairment of B-cell metabolism, including disruptions to mitochondrial numbers/activity and the PI3K/AKT pathway. Sources: Literature |
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| Mendeliome v0.4466 | GGT1 |
Elena Savva edited their review of gene: GGT1: Added comment: PMID: 29483667 - 1 family (2 sibs) w/ a homozygous 16.9kb deletion spanning part of the gene and no others. Carrier parents were normal. PMID: 23615310 - homozygous mutant mouse model have dwarfism, cataracts and coat colour abnormalities. Protein activity reduced to 4% of wildtype. Noted it was for use as a GGT deficiency model. PMID: 31520399 - 2 families with AD inheritance showing GGT1 deficiency but NO clinical symptoms. Authors call GGTemia a benign condition.; Changed publications: PMID: 29483667, 23615310, 31520399 |
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| Mendeliome v0.4380 | KCNA2 | Zornitza Stark commented on gene: KCNA2: Review of 23 affected individuals in PMID 29050392: some variants are LoF and others GoF, and some genotype-phenotype correlations made. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalised and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4317 | ATAD1 | Zornitza Stark changed review comment from: Severe progressive neurological disorder, severe/profound intellectual disability is a feature; to: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures. Severe progressive neurological disorder, severe/profound intellectual disability is a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4315 | ADAT1 |
Zornitza Stark gene: ADAT1 was added gene: ADAT1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ADAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAT1 were set to 28180185; 29390050; 29659736 Phenotypes for gene: ADAT1 were set to Hyperekplexia 4, MIM#618011 Review for gene: ADAT1 was set to GREEN Added comment: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures. Sources: Expert list |
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| Mendeliome v0.4309 | OCA2 | Elena Savva reviewed gene: OCA2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32741191, 24518832; Phenotypes: [Skin/hair/eye pigmentation 1, blond/brown hair] 227220, [Skin/hair/eye pigmentation 1, blue/nonblue eyes] 227220, Albinism, brown oculocutaneous 203200, Albinism, oculocutaneous, type II 203200, autosomal dominant Albinism, oculocutaneous; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4309 | ZSWIM6 |
Zornitza Stark changed review comment from: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype. MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X) identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype. MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp |
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| Mendeliome v0.4309 | ZSWIM6 |
Zornitza Stark changed review comment from: MIM #617865 A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype. MIM#603671: recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype. MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp |
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| Mendeliome v0.4256 | HSPA9 | Zornitza Stark Phenotypes for gene: HSPA9 were changed from to Anemia, sideroblastic, 4, MIM# 182170; Even-plus syndrome, MIM#616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4250 | HSPA9 | Sue White reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26598328, 32869452; Phenotypes: https://www.omim.org/entry/616854, skeletal anomalies, congenital cardiac and renal anomalies: marked small nose; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4229 | TET2 | Zornitza Stark changed review comment from: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.; to: Mono-allelic variants: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4229 | TET2 | Zornitza Stark changed review comment from: PMID 32518946: 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin, and bi-allelic variants in TET2.; to: Bi-allelic variants PMID 32518946: 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin, and bi-allelic variants in TET2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4229 | TET2 | Zornitza Stark changed review comment from: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.; to: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4229 | TET2 | Zornitza Stark edited their review of gene: TET2: Added comment: PMID 32518946: 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin, and bi-allelic variants in TET2.; Changed rating: GREEN; Changed publications: 30890702, 31827242, 32330418, 32518946; Changed phenotypes: Dementia, Lymphoma/myeloid malignancy, Immunodeficiency; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4204 | DDX54 |
Zornitza Stark gene: DDX54 was added gene: DDX54 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DDX54 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: DDX54 were set to 31256877 Phenotypes for gene: DDX54 were set to Intellectual disability; congenital anomalies Review for gene: DDX54 was set to RED Added comment: Three individuals reported with different MOIs and different phenotypes. One with de novo variant and ID, another with bi-allelic variants and ID, and a third with bi-allelic variants and CAKUT. All variants are missense, no functional data. Overall, Red rating given inconsistent phenotypes and modes of inheritance, each one is essentially treated separately for now until further cases identified. Sources: Literature |
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| Mendeliome v0.4125 | CRIPT |
Ain Roesley gene: CRIPT was added gene: CRIPT was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRIPT were set to 24389050; 27250922 Phenotypes for gene: CRIPT were set to Short stature with microcephaly and distinctive facies (MIM#615789) Penetrance for gene: CRIPT were set to unknown Review for gene: CRIPT was set to AMBER Added comment: PMID: 24389050 - 2 unrelated probands homozygous for PTVs. However 1 was deceased and DNA was unavailable therefore parents were sequenced PMID: 27250922 - 1x proband - het for a missense which was maternally inherited. Because the father was negative for SNVs, they did CMA and found a small heterozygous deletion 1.6kb in size encompassing exon 1 of CRIPT. This deletion was paternally inherited *did not find new reports since Sources: Literature |
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| Mendeliome v0.4121 | UFC1 |
Paul De Fazio gene: UFC1 was added gene: UFC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UFC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UFC1 were set to 29868776; 30552426 Phenotypes for gene: UFC1 were set to Neurodevelopmental disorder with spasticity and poor growth (MIM#618076) Review for gene: UFC1 was set to GREEN gene: UFC1 was marked as current diagnostic Added comment: PMID 29868776: 8 affected individuals from 4 families reported. 7 were described to be postnatally microcephalic (at or below 3rd percentile). One was -5.1SD and one was -3.6SD. SD values for the others weren't provided. The following head circumference measurements were provided for 6 of the affecteds: 51cm at 16yo; 50cm at 19yo; 42.5cm at 12mo, 45cm at 28mo, 45.2cm at 7yo; 45cm at 4yo. 3 of the families were consanguineous Saudi families with the same homozygous missense variant. In vitro functional expression studies showed that both mutations caused impaired thioester binding with UFM1. Patient cells also showed decreased UFC1 intermediate formation with UFM1. The decrease in function was consistent with a hypomorphic allele, and the authors suggested that complete loss of function would be embryonic lethal. PMID 30552426: 1 more individual with epileptic encephalopathy reported with a different homozygous missense variant in UFC1. The patient had microcephaly <3rd percentile. Sources: Literature |
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| Mendeliome v0.4091 | CTNND1 | Eleanor Williams changed review comment from: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).; to: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4091 | TRPM7 | Eleanor Williams commented on gene: TRPM7: PMID: 31423533 - Cartwright et al 2020 - functional studies on four heterozygous nonsynonymous variants that were observed in TRPM7 in four individual cases of unexplained still birth which were screened for variants in 35 candidate genes in PMID: 29874177 (Munroe et al 2018). TRPM7 is a ubiquitously expressed ion channel known to regulate cardiac development and repolarization in mice. They found two variants in TRPM7, p.G179V and p.T860M, reduce ion channel current expression, which in the case of p.T860M is likely due to rapid degradation mediated by the proteasome. In addition, the p.R494Q TRPM7 variant significantly increases TRPM7 ion channel current, in a cell-type specific manner. They believe that TRPM7 may play a key role in ensuring correct cardiac development of the fetus. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4091 | ZFYVE19 |
Arina Puzriakova gene: ZFYVE19 was added gene: ZFYVE19 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZFYVE19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZFYVE19 were set to 32737136 Phenotypes for gene: ZFYVE19 were set to Cholestasis Review for gene: ZFYVE19 was set to GREEN Added comment: PMID: 32737136 (2020) - Nine Han Chinese children from seven families with biallelic, predicted complete LoF variants in ZFYVE19. All patients had high-GGT intrahepatic cholestasis, portal hypertension, and histopathological features of the ductal plate malformation/congenital hepatic fibrosis. ZFYVE19 depletion in cultured cells from one patient yielded centriolar and axonemal abnormalities, and immunostaining for two ciliary proteins DCDC2 and ACALT showed abnormal localisation in patient cholangiocytes, indicating this as a novel ciliopathy disorder. Sources: Literature |
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| Mendeliome v0.4022 | ABCB11 | Zornitza Stark Phenotypes for gene: ABCB11 were changed from to Cholestasis, progressive familial intrahepatic 2, MIM# 601847; Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4019 | ABCB11 | Zornitza Stark reviewed gene: ABCB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 16871584, 23141890, 9806540, 15300568, 11172067; Phenotypes: Cholestasis, progressive familial intrahepatic 2, MIM# 601847, Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3872 | LMBRD2 |
Zornitza Stark gene: LMBRD2 was added gene: LMBRD2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787 Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye Mode of pathogenicity for gene: LMBRD2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: LMBRD2 was set to GREEN Added comment: 13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies. ► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants. Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific). All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity. 5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect. There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H). The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely. As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation. It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling. ► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies. Sources: Literature |
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| Mendeliome v0.3839 | SOS2 | Chern Lim reviewed gene: SOS2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 26173643; Phenotypes: Noonan syndrome 9, MIM#616559, AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3834 | TAF1C |
Zornitza Stark gene: TAF1C was added gene: TAF1C was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TAF1C were set to 32779182 Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology Review for gene: TAF1C was set to AMBER Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants. Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual). Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1). The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele. TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit. RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs). A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data). The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual). Sources: Expert list |
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| Mendeliome v0.3785 | PLA2G4A |
Zornitza Stark gene: PLA2G4A was added gene: PLA2G4A was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PLA2G4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLA2G4A were set to 18451993; 25102815; 23268370 Phenotypes for gene: PLA2G4A were set to Gastrointestinal ulceration, recurrent, with dysfunctional platelets, MIM# 618372 Review for gene: PLA2G4A was set to GREEN Added comment: At least three unrelated individuals reported. Sources: Expert list |
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| Mendeliome v0.3745 | DSG3 |
Zornitza Stark gene: DSG3 was added gene: DSG3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: DSG3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DSG3 were set to 30528827 Phenotypes for gene: DSG3 were set to Mucosal blistering Review for gene: DSG3 was set to RED Added comment: One individual with recurrent blisters and erosions in the oral mucosa since birth homozygous for p(.R287*). Sources: Expert list |
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| Mendeliome v0.3732 | FAM50A |
Zornitza Stark gene: FAM50A was added gene: FAM50A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAM50A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: FAM50A were set to 32703943 Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261) Review for gene: FAM50A was set to GREEN Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.). Sources: Literature |
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| Mendeliome v0.3718 | MPDZ | Zornitza Stark changed review comment from: Five Saudi families reported with same homozygous variant, p.Gln210Ter, founder effect. Additional 4 families report from different ethnic backgrounds and at least 4 different variants. Mouse model.; to: Five Saudi families reported with same homozygous variant, p.Gln210Ter, founder effect. Additional 4 families reported from different ethnic backgrounds and at least 4 different variants. Mouse model. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3675 | FRMD7 | Elena Savva reviewed gene: FRMD7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19072571, 23406872; Phenotypes: Nystagmus 1, congenital, X-linked 310700, Nystagmus, infantile periodic alternating, X-linked 310700; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3675 | PIGQ |
Zornitza Stark edited their review of gene: PIGQ: Added comment: Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548). Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362). Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality. PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis. More than 10 variants have been reported to date (missense / pLoF).; Changed phenotypes: Epileptic encephalopathy, early infantile, 77, MIM# 618548 |
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| Mendeliome v0.3673 | SEC61B |
Zornitza Stark gene: SEC61B was added gene: SEC61B was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SEC61B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SEC61B were set to 28862642; 30652979; 28375157 Phenotypes for gene: SEC61B were set to Polycystic liver disease with or without renal cysts Review for gene: SEC61B was set to AMBER Added comment: Two unrelated individuals reported. Sources: Expert list |
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| Mendeliome v0.3672 | CHI3L1 | Zornitza Stark Phenotypes for gene: CHI3L1 were changed from to {Asthma-related traits, susceptibility to, 7} 611960; {Schizophrenia, susceptibility to} 181500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3670 | CHI3L1 | Zornitza Stark reviewed gene: CHI3L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Asthma-related traits, susceptibility to, 7} 611960, {Schizophrenia, susceptibility to} 181500; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3668 | NDUFA8 |
Zornitza Stark gene: NDUFA8 was added gene: NDUFA8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NDUFA8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NDUFA8 were set to 32385911 Phenotypes for gene: NDUFA8 were set to NDUFA8-related mitochondrial disease; Developmental delay; microcehaly; seizures Review for gene: NDUFA8 was set to RED Added comment: Single individual reported with homozygous variant, fibroblasts showed apparent biochemical defects in mitochondrial complex I. Sources: Literature |
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| Mendeliome v0.3657 | CALCRL |
Hazel Phillimore gene: CALCRL was added gene: CALCRL was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CALCRL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CALCRL were set to PMID: 30115739 Phenotypes for gene: CALCRL were set to ?Lymphatic malformation 8 (MIM# 618773); hydrops fetalis Review for gene: CALCRL was set to RED Added comment: Homozygous in-frame deletion (Val205del) in the CALCRL gene (Val205del) in a 22 week-old fetus with hydrops details due to lymphatic malformation. Consanguineous parents. Heterozygosity of the variant was also suggested to be associated with spontaneous miscarriage and subfertility. Consanguineous family with 8 total miscarriages from 3 carrier women, and 2 of these were confirmed to be due to hydrops fetalis. Note: possible association of a variant in ASAH1 gene that is associated with Farber lipogranulomatosis which can sometimes present with antenatal hydrops fetalis. (Homozygosity in one of the fetuses, fetus and heterozygosity in some of the family members). In vitro biochemical assays indicated that the variant causes misfolding of the protein and reduced association with its chaperone, RAMP2, and reduced translocation to the plasma membrane. (PMID: 30115739; Mackie, DI. et al., 2018). Sources: Literature |
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| Mendeliome v0.3657 | M1AP |
Ee Ming Wong gene: M1AP was added gene: M1AP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: M1AP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: M1AP were set to PMID: 32673564 Phenotypes for gene: M1AP were set to non-obstructive azoospermia (NOA); severe spermatogenic failure; male infertility Review for gene: M1AP was set to GREEN gene: M1AP was marked as current diagnostic Added comment: - One frameshift variant identified in 9 infertile men either in homozygous or compound heterozygous form - One missense variant segregated with infertility in five men from a consanguineous Turkish family Sources: Literature |
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| Mendeliome v0.3653 | CRY1 |
Ee Ming Wong gene: CRY1 was added gene: CRY1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CRY1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRY1 were set to PMID: 28388406; PMID: 32538895 Phenotypes for gene: CRY1 were set to Attention deficit/hyperactivity disorder (ADHD); Delayed sleep phase disorder (DSPD), Penetrance for gene: CRY1 were set to Incomplete Review for gene: CRY1 was set to GREEN gene: CRY1 was marked as current diagnostic Added comment: - Splice variants identified in 7 families with ADHD and DSPD - Gain of function suggested for CRY1Δ11 (PMID: 28388406) - Loss of function suggested for CRY1Δ6 (HEK293T cells transfected with a Per1::Luc reporter plasmid showed reduced repressor activity compared to WT and CRY1Δ11) Sources: Literature |
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| Mendeliome v0.3648 | FBXL7 |
Hazel Phillimore changed review comment from: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous. Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae. Sources: Literature; to: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous. Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae. Sources: Literature |
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| Mendeliome v0.3647 | FBXL7 |
Hazel Phillimore gene: FBXL7 was added gene: FBXL7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FBXL7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FBXL7 were set to PMID: 31633297 Phenotypes for gene: FBXL7 were set to Hennekam lymphangiectasia-lymphedema syndrome; lymphedema; protein‐losing enteropathy; dental anomalies; camptodactyly; microtia; small auditory canals; ductive hearing loss; middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae. Review for gene: FBXL7 was set to AMBER Added comment: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous. Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae. Sources: Literature |
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| Mendeliome v0.3646 | PJA1 |
Zornitza Stark gene: PJA1 was added gene: PJA1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PJA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: PJA1 were set to 32530565 Phenotypes for gene: PJA1 were set to Intellectual disability; trigonocephaly Review for gene: PJA1 was set to AMBER Added comment: Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals, supportive mouse model. Individuals shared a common haplotype, suggestive of founder effect Sources: Literature |
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| Mendeliome v0.3645 | MYLPF |
Crystle Lee gene: MYLPF was added gene: MYLPF was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: MYLPF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: MYLPF were set to 32707087 Phenotypes for gene: MYLPF were set to Distal arthrogryoposis Review for gene: MYLPF was set to GREEN Added comment: 2 different homozygous variants reported in 6 consanguineous families with DA and an additional 2 different dominantly inherited variants in 2 families, with supporting animal model. Sources: Expert Review |
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| Mendeliome v0.3645 | NCKAP1L |
Michelle Torres gene: NCKAP1L was added gene: NCKAP1L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NCKAP1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NCKAP1L were set to 32647003 Phenotypes for gene: NCKAP1L were set to Immunodeficiency Review for gene: NCKAP1L was set to GREEN Added comment: 5 patients from 4 families with recurrent bacterial and viral skin infections, severe respiratory tract infections leading to pneumonia and bronchiectasis. Functional of the 4 missense reported were performed. Sources: Literature |
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| Mendeliome v0.3643 | NARS |
Zornitza Stark gene: NARS was added gene: NARS was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NARS were set to 32738225 Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy Review for gene: NARS was set to GREEN Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model). Sources: Literature |
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| Mendeliome v0.3624 | ERLEC1 |
Bryony Thompson gene: ERLEC1 was added gene: ERLEC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ERLEC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ERLEC1 were set to 32442352 Phenotypes for gene: ERLEC1 were set to Class III malocclusion Review for gene: ERLEC1 was set to GREEN Added comment: A heterozygous missense variant was found to co-segregate with dentofacial deformity in a multi-generational Chinese pedigree (2 unaffected carriers & 11 affected carriers), and 3 additional missense variants were identified in 3 unrelated cases from a sporadic malocclusion cohort. Additional functional assays were conducted to demonstrate that the proper level of ERLEC1 expression is crucial for proper osteogenic differentiation. All identified missense variants were assessed using luciferase reporter assays, and altered activity. Sources: Literature |
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| Mendeliome v0.3611 | PMP22 | Zornitza Stark Phenotypes for gene: PMP22 were changed from to Charcot-Marie-Tooth disease, type 1A, MIM# 118220; Charcot-Marie-Tooth disease, type 1E, MIM# 118300; Dejerine-Sottas disease, MIM# 145900; Neuropathy, recurrent, with pressure palsies 162500; Roussy-Levy syndrome 180800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3608 | PMP22 | Zornitza Stark reviewed gene: PMP22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, type 1A, MIM# 118220, Charcot-Marie-Tooth disease, type 1E, MIM# 118300, Dejerine-Sottas disease, MIM# 145900, Neuropathy, recurrent, with pressure palsies 162500, Roussy-Levy syndrome 180800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3590 | ANO1 |
Arina Puzriakova changed review comment from: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model. Sources: Literature; to: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model. Sources: Literature |
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| Mendeliome v0.3590 | ANO1 |
Arina Puzriakova gene: ANO1 was added gene: ANO1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ANO1 were set to 32487539 Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model. Sources: Literature |
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| Mendeliome v0.3590 | GNPNAT1 |
Arina Puzriakova changed review comment from: Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype. Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Sources: Literature; to: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype. Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1. Sources: Literature |
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| Mendeliome v0.3590 | GNPNAT1 |
Arina Puzriakova gene: GNPNAT1 was added gene: GNPNAT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNPNAT1 were set to 32591345 Phenotypes for gene: GNPNAT1 were set to Rhizomelic skeletal dysplasia Review for gene: GNPNAT1 was set to RED Added comment: Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype. Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Sources: Literature |
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| Mendeliome v0.3561 | OBSCN |
Paul De Fazio gene: OBSCN was added gene: OBSCN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OBSCN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: OBSCN were set to 30681346; 26573135; 17716621; 25173926; 28630914 Phenotypes for gene: OBSCN were set to Hypertrophic cardiomyopathy Review for gene: OBSCN was set to RED gene: OBSCN was marked as current diagnostic Added comment: Limited evidence by ClinGen working group. Via ClinGen: 8 probands in 3 publications but only 3 probands from 1 publication were though to have pathogenic variants (others were excluded based on population frequency and expert review). No additional case reports were found. A mouse model lends some support to the association of this gene with heart disease although not HCM specifically. Sources: Literature |
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| Mendeliome v0.3561 | MYOZ2 | Paul De Fazio reviewed gene: MYOZ2: Rating: RED; Mode of pathogenicity: None; Publications: 17347475, 18591919, 28296734, 30681346, 22987565; Phenotypes: Cardiomyopathy, hypertrophic, 16 MIM#613838; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3561 | KLF10 |
Paul De Fazio gene: KLF10 was added gene: KLF10 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KLF10 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KLF10 were set to 22234868 Phenotypes for gene: KLF10 were set to HCM gene: KLF10 was marked as current diagnostic Added comment: Curated by ClinGen and rated as limited evidence. Misssense mutations reported in six unrelated individuals patients (two males/four females), with family history of HCM only reported for one individual (PMID: 22234868). No further reports in the literature. Sources: Literature |
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| Mendeliome v0.3496 | MPL | Chern Lim reviewed gene: MPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28955303, 26423830; Phenotypes: Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503, Thrombocythemia 2, MIM#601977, AD, SMu, Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3472 | REN | Zornitza Stark Marked gene: REN as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3472 | REN | Zornitza Stark Gene: ren has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3472 | REN | Zornitza Stark Phenotypes for gene: REN were changed from to Renal tubular dysgenesis, MIM# 267430; Autosomal dominant tubulointerstitial disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3471 | REN | Zornitza Stark Publications for gene: REN were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3470 | REN | Zornitza Stark Mode of inheritance for gene: REN was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3469 | REN | Zornitza Stark reviewed gene: REN: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 31586593, 31406136, 28701203, 21473025; Phenotypes: Renal tubular dysgenesis, MIM# 267430, Autosomal dominant tubulointerstitial disease; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3468 | IL6R | Zornitza Stark Phenotypes for gene: IL6R were changed from Recurrent pyogenic infections, cold abscesses; High circulating IL-6 levels; High IgE to Recurrent pyogenic infections, cold abscesses; High circulating IL-6 levels; High IgE; IgE recurrent infection syndrome, MIM#618944 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3467 | IL6R | Zornitza Stark edited their review of gene: IL6R: Changed phenotypes: Recurrent pyogenic infections, cold abscesses, High circulating IL-6 levels, High IgE, IgE recurrent infection syndrome, MIM#618944 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3450 | DACT1 |
Natalie Tan gene: DACT1 was added gene: DACT1 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: DACT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DACT1 were set to PMID: 28054444; 22610794; 19701191 Phenotypes for gene: DACT1 were set to ?Townes-Brocks syndrome 2 (OMIM #617466) Review for gene: DACT1 was set to RED Added comment: Webb et al. (2017) reported 6 affected members of a 3-generation family with ?Townes-Brocks syndrome-2, identified heterozygosity for a nonsense mutation in the DACT1 gene that segregated with disease. Clinical features include imperforate anus, rectovaginal fistula, crossed fused renal ectopia, vesicoureteral reflux, unilateral microtia, overfolded helices and cupped ears. One family member (proband's mother) with scoliosis and spina bifida occulta. Neural tube defects reported in a study of human fetuses (PMID: 22610794) and a mouse model (PMID: 19701191). Listed in Decipher v10.0 for an individual with abnormalities of (i) head or neck (ii) nervous system (iii) skeletal system. Unlike the gene SALL1 that causes Townes-Brocks syndrome 1, there is no information specifically relating to DACT1 with radial dysplasia, as these were not observed in the family with ?Townes-Brocks syndrome 2 (PMID: 28054444). Sources: NHS GMS |
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| Mendeliome v0.3444 | G6PC3 | Belinda Chong reviewed gene: G6PC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21385794; Phenotypes: Dursun syndrome 612541, Neutropenia, severe congenital 4, autosomal recessive 612541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3444 | SEC23A | Paul De Fazio reviewed gene: SEC23A: Rating: AMBER; Mode of pathogenicity: None; Publications: 16980979, 21039434, 16980978, 27148587; Phenotypes: Craniolenticulosutural dysplasia (MIM# 607812); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3444 | ARSG | Zornitza Stark Added comment: Comment when marking as ready: Additional family reported with a different variant, upgrade to Amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3433 | NR0B1 | Zornitza Stark Phenotypes for gene: NR0B1 were changed from Adrenal hypoplasia, congenital (MIM# 300200) to Adrenal hypoplasia, congenital (MIM# 300200); 46XY sex reversal 2, dosage-sensitive, MIM# 300018 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3430 | NR0B1 | Zornitza Stark Phenotypes for gene: NR0B1 were changed from to Adrenal hypoplasia, congenital (MIM# 300200) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3413 | NR0B1 | Ain Roesley reviewed gene: NR0B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19508677, 26030781; Phenotypes: Adrenal hypoplasia, congenital (MIM# 300200); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3383 | CUX2 | Zornitza Stark Added comment: Comment when marking as ready: At least 10 individuals reported with same recurrent de novo missense variant. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3376 | GIPC1 |
Zornitza Stark gene: GIPC1 was added gene: GIPC1 was added to Mendeliome. Sources: Literature 5'UTR, STR tags were added to gene: GIPC1. Mode of inheritance for gene: GIPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GIPC1 were set to 32413282 Phenotypes for gene: GIPC1 were set to Oculopharyngodistal myopathy-2 (OPDM2), MIM#618940 Review for gene: GIPC1 was set to AMBER Added comment: 19 families reported with heterozygous trinucleotide repeat expansion in the 5-prime untranslated region and onset of distal muscle weakness, mainly of the lower limbs, and/or ophthalmoplegia in the second or third decades of life. Note this is unlikely to be tractable currently by most NGS assays. Sources: Literature |
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| Mendeliome v0.3342 | PIGM | Paul De Fazio reviewed gene: PIGM: Rating: AMBER; Mode of pathogenicity: None; Publications: 31445883, 16767100; Phenotypes: portal vein thrombosis, persistent absence seizures, macrocephaly, infantile-onset cerebrovascular thrombotic events; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3321 | CCDC174 |
Zornitza Stark gene: CCDC174 was added gene: CCDC174 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CCDC174 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC174 were set to 26358778 Phenotypes for gene: CCDC174 were set to Hypotonia, infantile, with psychomotor retardation - IHPMR, 616816 Review for gene: CCDC174 was set to AMBER Added comment: Biallelic pathogenic CCDC174 variants cause Hypotonia, infantile, with psychomotor retardation - IHPMR (MIM 616816). Volodarsky et al [2015 - PMID: 26358778] describe 6 children from 2 unrelated families with - among others - severe hypotonia, psychomotor delay and abducens nerve palsy. All affected subjects were homozygous for a stoploss variant. Evidence from functional studies/animal model is provided supporting the role of the gene in this phenotype. Overall this gene can be considered for inclusion in the ID panel with amber rating (2 families, single founder variant, consistent phenotype, supportive studies) pending further reports. Sources: Expert Review |
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| Mendeliome v0.3318 | ABCA2 |
Zornitza Stark gene: ABCA2 was added gene: ABCA2 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799 Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808 Review for gene: ABCA2 was set to GREEN Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808). There are 3 relevant publications (01-07-2020) : - Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations. - Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures. - Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype. All subjects harbored biallelic pLoF variants. N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency. Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals). Sources: Expert Review |
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| Mendeliome v0.3266 | GGPS1 |
Zornitza Stark gene: GGPS1 was added gene: GGPS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GGPS1 were set to 32403198 Phenotypes for gene: GGPS1 were set to Muscular dystrophy; Deafness; Ovarian insufficiency Review for gene: GGPS1 was set to GREEN Added comment: 11 individuals from 6 unrelated families reported. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. Knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality. Sources: Literature |
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| Mendeliome v0.3264 | DNMBP |
Seb Lunke gene: DNMBP was added gene: DNMBP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DNMBP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNMBP were set to 30290152 Phenotypes for gene: DNMBP were set to congenital cataract Review for gene: DNMBP was set to GREEN gene: DNMBP was marked as current diagnostic Added comment: Multiple individuals from three independent large consanguineous families with bilateral infantile cataracts. Seperate hom nonsense variants. Sources: Literature |
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| Mendeliome v0.3248 | ASPRV1 |
Ee Ming Wong gene: ASPRV1 was added gene: ASPRV1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ASPRV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ASPRV1 were set to PMID: 32516568 Phenotypes for gene: ASPRV1 were set to palmoplantar keratoderma; lamellar ichthyosis Review for gene: ASPRV1 was set to GREEN gene: ASPRV1 was marked as current diagnostic Added comment: -3 heterozygous missense variants identified across 4 unrelated kindreds -mutant ASPRV1 expressed in human keratinocytes suggests impaired filaggrin processing Sources: Literature |
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| Mendeliome v0.3242 | SREBF1 |
Paul De Fazio gene: SREBF1 was added gene: SREBF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SREBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SREBF1 were set to 32497488 Phenotypes for gene: SREBF1 were set to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome Review for gene: SREBF1 was set to GREEN gene: SREBF1 was marked as current diagnostic Added comment: 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. 3 different msisense variants identified affecting the same region (residues 527, 528, and 530). Functional studies support impaired function (impaired nuclear translocation of the transcriptionally active form of SREBP1 resulting in lower expression of the SREBP1 variants). Increased keratinocyte apoptosis was observed in patient scalp samples. Sources: Literature |
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| Mendeliome v0.3242 | CNOT1 | Chern Lim reviewed gene: CNOT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32553196; Phenotypes: Neurodevelopmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3209 | PPP3R1 | Zornitza Stark Added comment: Comment when marking as ready: Currently just a locus; note multiple mouse models implicating a role for this gene in cardiovascular, renal and brain development. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3207 | CNRIP1 | Zornitza Stark Added comment: Comment when marking as ready: Currently just a locus, insufficient evidence for gene-disease association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3202 | CCDC32 |
Eleanor Williams gene: CCDC32 was added gene: CCDC32 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC32 were set to 32307552 Phenotypes for gene: CCDC32 were set to craniofacial, cardiac and neurodevelopmental anomalies Review for gene: CCDC32 was set to AMBER Added comment: PMID: 32307552 - Harel et al 2020 - reports 2 unrelated consanguineous families with probands with homozygous frameshift variants in CCDC32. Parents are heterozygous. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies. Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and shows a role for ccdc32 in craniofacial, brain and left/right axis development. Sources: Literature |
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| Mendeliome v0.3194 | PDCD6IP |
Zornitza Stark gene: PDCD6IP was added gene: PDCD6IP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDCD6IP were set to 32286682 Phenotypes for gene: PDCD6IP were set to Microcephaly; intellectual disability Review for gene: PDCD6IP was set to AMBER Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies. Sources: Literature |
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| Mendeliome v0.3192 | NME5 |
Zornitza Stark gene: NME5 was added gene: NME5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NME5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NME5 were set to 32185794 Phenotypes for gene: NME5 were set to Primary ciliary dyskinesia Review for gene: NME5 was set to AMBER Added comment: One patient with PCD with situs solitus, with radial spokes (RS) and central pair (CP) defects. Patient had a homozygous nonsense variant in NME5, with parents as carriers. Morpholino knockdown of nme5 in zebrafish embryos resulted in motile cilia defects with phenotypes compatible with ciliopathy. Sources: Literature |
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| Mendeliome v0.3189 | EMILIN1 |
Naomi Baker changed review comment from: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein. Sources: Literature; to: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein. Sources: Literature |
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| Mendeliome v0.3189 | EMILIN1 |
Naomi Baker gene: EMILIN1 was added gene: EMILIN1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EMILIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EMILIN1 were set to PMID: 31978608; 26462740. Phenotypes for gene: EMILIN1 were set to peripheral neuropathy Penetrance for gene: EMILIN1 were set to unknown Review for gene: EMILIN1 was set to AMBER Added comment: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein. Sources: Literature |
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| Mendeliome v0.3185 | MYH8 | Zornitza Stark Added comment: Comment when marking as ready: Recurrent variant p.R674Q has occurred de novo in at least some families. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3177 | GATA6 | Elena Savva reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:20581743, 19666519; Phenotypes: Pancreatic agenesis and congenital heart defects, 600001, Atrial septal defect 9, 614475, Atrioventricular septal defect 5, 614474, Tetralogy of Fallot, 187500, Persistent truncus arteriosus, 217095; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3111 | KDM6A | Elena Savva reviewed gene: KDM6A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:27302555, 24664873; Phenotypes: Kabuki syndrome 2, 300867; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3086 | ARL6IP1 |
Bryony Thompson gene: ARL6IP1 was added gene: ARL6IP1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ARL6IP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARL6IP1 were set to 24482476; 31272422; 30980493; 28471035 Phenotypes for gene: ARL6IP1 were set to Spastic paraplegia 61, autosomal recessive MIM#615685 Review for gene: ARL6IP1 was set to GREEN gene: ARL6IP1 was marked as current diagnostic Added comment: At least 4 families reported with paediatric onset complicated spastic paraplegia and neuropathy. Supporting zebrafish model. Sources: Expert list |
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| Mendeliome v0.3054 | GATM | Zornitza Stark Phenotypes for gene: GATM were changed from to Cerebral creatine deficiency syndrome 3, MIM# 612718; Fanconi renotubular syndrome 1, MIM# 134600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3051 | GATM | Zornitza Stark reviewed gene: GATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 12468279, 20682460, 22386973, 29654216; Phenotypes: Cerebral creatine deficiency syndrome 3, MIM# 612718, Fanconi renotubular syndrome 1, MIM# 134600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3050 | SLC6A1 | Chern Lim reviewed gene: SLC6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29315614; Phenotypes: Myoclonic-atonic epilepsy, MIM#616421; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3050 | NEFH | Chern Lim reviewed gene: NEFH: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30992180, 27040688, 28709447; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2CC, MIM#616924; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3050 | LIMS2 |
Zornitza Stark gene: LIMS2 was added gene: LIMS2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: LIMS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIMS2 were set to 25589244; 16317048 Phenotypes for gene: LIMS2 were set to Muscular dystrophy, autosomal recessive, with cardiomyopathy and triangular tongue MIM#616827 Review for gene: LIMS2 was set to RED Added comment: Only one family reported and Pinch2 -/- mice were viable and fertile with no apparent phenotype. Sources: Expert list |
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| Mendeliome v0.3049 | FAN1 | Elena Savva reviewed gene: FAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22772369; Phenotypes: Interstitial nephritis, karyomegalic 614817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3022 | GRM7 |
Zornitza Stark gene: GRM7 was added gene: GRM7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GRM7 were set to 32286009; 32248644 Phenotypes for gene: GRM7 were set to Epilepsy, microcephaly, developmental delay Review for gene: GRM7 was set to GREEN Added comment: Eleven individuals from six families reported, three different homozygous variants (two missense, one LoF). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Supportive mouse model. Sources: Literature |
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| Mendeliome v0.3015 | ADCY6 |
Zornitza Stark gene: ADCY6 was added gene: ADCY6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ADCY6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADCY6 were set to 24319099; 26257172; 31846058 Phenotypes for gene: ADCY6 were set to Lethal congenital contracture syndrome 8, OMIM # 616287 Review for gene: ADCY6 was set to GREEN Added comment: Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies. Sources: Literature |
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| Mendeliome v0.3010 | OTUD7A |
Zornitza Stark gene: OTUD7A was added gene: OTUD7A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OTUD7A were set to 31997314 Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, no OMIM# yet Review for gene: OTUD7A was set to RED Added comment: One patient with severe global developmental delay, language impairment and epileptic encephalopathy. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Sources: Literature |
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| Mendeliome v0.2965 | USP8 |
Bryony Thompson gene: USP8 was added gene: USP8 was added to Mendeliome. Sources: Expert list somatic tags were added to gene: USP8. Mode of inheritance for gene: USP8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: USP8 were set to 25675982; 24482476; 25485838; 25942478 Phenotypes for gene: USP8 were set to Pituitary adenoma 4, ACTH-secreting, somatic MIM#219090; hereditary spastic paraplegia Review for gene: USP8 was set to GREEN Added comment: Recurrent somatic gain of function missense variants in pituitary adenomas cause Cushing's disease. A single family reported with spastic paraplegia with a homozygous variant, and a zebrafish model with a movement disorder. Sources: Expert list |
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| Mendeliome v0.2955 | VWA3B |
Bryony Thompson gene: VWA3B was added gene: VWA3B was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: VWA3B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VWA3B were set to 26157035 Phenotypes for gene: VWA3B were set to Spinocerebellar ataxia, autosomal recessive 22 MIM#616948 Review for gene: VWA3B was set to AMBER Added comment: A homozygous missense variant was identified in 3 brothers from a single consanguineous Japanese family with autosomal recessive cerebellar ataxia. Transfection of the mutant VWA3B protein into several different cultured cell lines resulted in decreased cell viability. Sources: Expert list |
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| Mendeliome v0.2944 | POC5 |
Bryony Thompson gene: POC5 was added gene: POC5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: POC5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: POC5 were set to 25642776; 29272404 Phenotypes for gene: POC5 were set to Idiopathic scoliosis; retinitis pigmentosa; short stature; microcephaly; recurrent glomerulonephritis Review for gene: POC5 was set to GREEN Added comment: Three heterozygous missense variants identified in three families segregating with idiopathic scoliosis, and supporting zebrafish models for each of the missense variants. Also, one case reported with retinitis pigmentosa, short stature, microcephaly, and recurrent glomerulonephritis with a homozygous truncating variant and a supporting zebrafish model. Sources: Literature |
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| Mendeliome v0.2943 | CNP |
Kristin Rigbye gene: CNP was added gene: CNP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CNP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CNP were set to 32128616; 12590258 Phenotypes for gene: CNP were set to Hypomyelinating leukodystrophy Review for gene: CNP was set to AMBER Added comment: Single consanguineous family described with homozygous missense in affected child (additional two affected deceased offspring unavailable for testing; healthy carrier parents and sibling). Loss of protein by Western blot and defect in F-actin structure and organization observed in patient fibroblasts. Deficiency of CNP in mouse has previously been shown to cause a lethal white matter neurodegenerative phenotype (PMID: 12590258), similar to the phenotype observed in this family. Sources: Literature |
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| Mendeliome v0.2943 | TRIM71 |
Elena Savva gene: TRIM71 was added gene: TRIM71 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRIM71 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TRIM71 were set to PMID: 29983323; 32168371; 30975633 Phenotypes for gene: TRIM71 were set to Hydrocephalus, congenital communicating, 1 618667 Mode of pathogenicity for gene: TRIM71 was set to Other Added comment: PMID: 29983323 - 3 unrelated patients with de novo missense and hydrocephalus with ventriculomegaly (p.Arg608His recurrent). One patient then transmitted the variant to an affected child. PMID: 32168371 - refers to the gene as an established sources of neurodevelopmental disorder PMID: 30975633 - identifies and proves by functional studies that TRIM71 is essential for neurodevelopment. Proposes a LOF mechanism. Sources: Literature |
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| Mendeliome v0.2940 | SORD |
Seb Lunke gene: SORD was added gene: SORD was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SORD were set to 32367058 Phenotypes for gene: SORD were set to isolated hereditary neuropathy Review for gene: SORD was set to GREEN gene: SORD was marked as current diagnostic Added comment: 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state Sources: Literature |
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| Mendeliome v0.2906 | SNRNP200 |
Ain Roesley changed review comment from: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD) PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA) PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.4Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo; to: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD) PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA) PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.1Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo |
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| Mendeliome v0.2906 | SNRNP200 |
Ain Roesley changed review comment from: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD) PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA) PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.1Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo; to: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD) PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA) PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.4Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo |
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| Mendeliome v0.2902 | ALOXE3 | Chern Lim reviewed gene: ALOXE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116617, 31046801, 26370990; Phenotypes: Ichthyosis, congenital, autosomal recessive 3, MIM#606545; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2867 | DHX30 | Zornitza Stark Added comment: Comment when marking as ready: Twelve unrelated individuals reported with de novo missense variants, some recurrent. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2861 | KRAS | Elena Savva reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 23059812, 17056636; Phenotypes: Arteriovenous malformation of the brain, somatic 108010, Bladder cancer, somatic 109800, Breast cancer, somatic 114480, Cardiofaciocutaneous syndrome 2 615278, Gastric cancer, somatic 137215, Leukemia, acute myeloid 601626, . Lung cancer, somatic 211980, Noonan syndrome 3 609942, Pancreatic carcinoma, somatic 260350, RAS-associated autoimmune leukoproliferative disorder 614470, Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 163200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2861 | DHX30 | Elena Savva reviewed gene: DHX30: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29100085; Phenotypes: Neurodevelopmental disorder with severe motor impairment and absent language, 617804; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2825 | PDXK |
Russell Gear gene: PDXK was added gene: PDXK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PDXK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDXK were set to (PMID: 31187503) Phenotypes for gene: PDXK were set to Axonal polyneuropathy; optic atrophy Review for gene: PDXK was set to RED Added comment: Currently two unrelated families with axonal polyneuropathy and optic atrophy described in the same paper, with bi-allelic PDXK pathogenic variants. Functional work in the same paper includes work on patient derived fibroblasts, measurement of an axonal damage biomarker (NFL protein), and response to PLP supplementation treatment. Need one further unrelated family to upgrade to green? Sources: Literature |
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| Mendeliome v0.2786 | TOMM70 |
Zornitza Stark gene: TOMM70 was added gene: TOMM70 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TOMM70 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TOMM70 were set to 31907385; 32356556 Phenotypes for gene: TOMM70 were set to Severe anaemia, lactic acidosis, developmental delay; White matter abnormalities, developmental delay, regression, movement disorder Review for gene: TOMM70 was set to AMBER Added comment: TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria. Bi-allelic disease: one individual reported with compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)]. Clinical features included severe anaemia, lactic acidosis, and developmental delay. Some functional data: in vitro cell model compensatory experiments. Monoallelic disease: de novo mono allelic variants in the C-terminal region of TOMM70 reported in two individuals. While both individuals exhibited shared symptoms including hypotonia, hyperreflexia, ataxia, dystonia, and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset, with one experiencing episodes of regression. Some functional data. Sources: Expert list |
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| Mendeliome v0.2767 | UGDH |
Zornitza Stark gene: UGDH was added gene: UGDH was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UGDH were set to 32001716 Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792 Review for gene: UGDH was set to GREEN Added comment: 36 individuals with biallelic UGDH pathogenic variants reported. The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode. UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate. Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate). Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ. Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors Sources: Literature |
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| Mendeliome v0.2759 | TNRC6B | Zornitza Stark edited their review of gene: TNRC6B: Added comment: 17 unrelated individuals with heterozygous TNRC6B variants reported. Features included hypotonia (10/17), DD/ID (17/17 - ID was not universal: average IQ of 12 individuals was 73 (range : 50-113) with 4 having below 70), ADHD (11/17), ASD or autistic traits (8/17 and 5/17). Some/few presented with abnormal OFC (micro- / macrocephaly in 3/17 and 2/17), abnormal vision or hearing, variable other congenital anomalies, echocardiographic, GI or renal abnormalities, etc. Epilepsy was reported in 1/17. There was no recognisable gestalt.Detected variants included 14 pLoF, 1 missense SNV and 2 intragenic deletions. Variants had occurred as de novo events in 10/13 subjects for whom testing of both parents was possible. 3/13 subjects had inherited the variant from a parent with milder phenotype. Based on the type of variants identified, the pLI score of 1 in gnomAD and the HI index of 5.61%, the authors suggest haploinsufficiency as the most likely mechanism. Individuals with de novo TNRC6B variants have also been reported in larger cohorts (e.g. DDD study - PMID: 28135719, Iossifov et al - PMID: 25363768, Lelieveld et al - PMID: 27479843, Jónsson et al - PMID: 28959963). A previous study provided details on 2 sibs harboring a translocation which disrupted both TNRC6B and TCF20 (also associated with ID)(Babbs et al - PMID: 25228304).; Changed rating: GREEN; Changed publications: 32152250, 28135719, 25363768, 27479843, 28959963, 25228304; Changed phenotypes: Global developmental delay, Intellectual disability, Autistic behavior; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2729 | CCDC28B | Zornitza Stark edited their review of gene: CCDC28B: Added comment: PMID: 32139166 - Single family with Joubert syndrome. Patient was homozygous for a missense, with polydactyly, severe ID, and the molar tooth sign observed in MRI. Sibling fetus MRI showed vermis hypoplasia, and was also homozygous for the variant. Parents confirmed unaffected carriers. Knockdown of CCDC28B in human TERT retinal pigment epithelial cells reduced both the number and length of cilia 430C-T variant is postulated to be a modifier of BBS.; Changed rating: AMBER; Changed publications: 32139166; Changed phenotypes: {Bardet-Biedl syndrome 1, modifier of}, MIM#209900, Joubert syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2729 | C21orf59 | Zornitza Stark Added comment: Comment when marking as ready: p.Tyr245* recurrent in the Ashkenazi Jewish population | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2625 | ALPK1 | Zornitza Stark edited their review of gene: ALPK1: Added comment: Six unrelated families reported with same recurrent missense variant c.710C>T, (p.Thr237Met) and ROSAH syndrome phenotype. Pancytopaenia and recurrent infections present in some.; Changed rating: GREEN; Changed publications: 31053777, 30967659, 31939038; Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, ROSAH syndrome, retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2621 | POLR3GL | Zornitza Stark Added comment: Comment when marking as ready: Three cases altogether but the phenotypes are very different -- may still represent a spectrum with the more severe phenotypes resulting from truncating variants but further cases needed. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2620 | GALM |
Hazel Phillimore gene: GALM was added gene: GALM was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GALM were set to PMID: 30451973; 30910422 Phenotypes for gene: GALM were set to galactosaemia; type IV galactosaemia Review for gene: GALM was set to GREEN Added comment: Homozygous and compound heterozygous variants (missense, nonsense and frameshift) found in 8 Japanese patients from unrelated families with unexplained galactosaemia. (No variants in GALT, GALK1, and GALE). This is therefore type IV galactosaemia. In vitro expression analysis and enzyme activity assay of the patients’ peripheral blood mononuclear cells showed total lack of or compromised expression of GALM protein. Loss-of-function mechanism. One homozygote for one of these variants p.(Gly142Arg) in gnomAD (African population). (Wada, Y. et al 2019; PMID: 30451973) In vitro expression assay and an enzyme activity assay of 67 GALM variants, taken from ExAc database (missense, nonsense, frameshift and splice). 30 variants concluded to be pathogenic due to no protein expression or faint expression. 5 variants with mildly lower levels were determined as likely pathogenic. All concluded to be loss-of-function mechanism. Incidence of galactosaemia by GALM deficiency is comparable to that of other galactosaemias. Carrier frequency and incidence was estimated for different populations. (Iwasawa, S. et al. (2019); PMID: 30910422) Sources: Literature |
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| Mendeliome v0.2620 | POLR3GL |
Paul De Fazio gene: POLR3GL was added gene: POLR3GL was added to Mendeliome. Sources: Literature Mode of inheritance for gene: POLR3GL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR3GL were set to 31089205; 31695177 Phenotypes for gene: POLR3GL were set to endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy Review for gene: POLR3GL was set to AMBER gene: POLR3GL was marked as current diagnostic Added comment: Biallelic canonical splice variants were identified in monozygotic twins and another individual with similar phenotypes from 2 unrelated families. Variants were inherited from carrier parents. RNA studies confirmed exon skipping occurs in all affected individuals. A separate study identified a homozygous nonsense variant in an individual with features of Neonatal progeroid syndrome/Wiedemann–Rautenstrauch syndrome. Quantitative PCR showed reduction in mRNA suggestive of NMD. Sources: Literature |
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| Mendeliome v0.2611 | TSPEAR | Chern Lim reviewed gene: TSPEAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 27736875, 30046887; Phenotypes: Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2611 | TBL1Y |
Paul De Fazio gene: TBL1Y was added gene: TBL1Y was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TBL1Y was set to Other Publications for gene: TBL1Y were set to 30341416 Phenotypes for gene: TBL1Y were set to Hearing loss Review for gene: TBL1Y was set to RED gene: TBL1Y was marked as current diagnostic Added comment: 9 affected males in a single pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate. Sources: Literature |
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| Mendeliome v0.2610 | DGCR8 |
Chern Lim gene: DGCR8 was added gene: DGCR8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DGCR8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DGCR8 were set to 31805011 Phenotypes for gene: DGCR8 were set to Early-onset multinodular goiter and schwannomatosis Review for gene: DGCR8 was set to RED Added comment: A germline missense variant segregates in one family with autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter (MNG) with schwannomatosis. The missense is also a recurrent somatic missense variant in Wilms tumour. (PMID:31805011) Sources: Literature |
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| Mendeliome v0.2607 | FOXF2 |
Hazel Phillimore changed review comment from: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639). This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403). Sources: Literature; to: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639). This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403). Previous names for FOXF2 include FKHL6 and FREAC2. Sources: Literature |
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| Mendeliome v0.2607 | FOXF2 |
Hazel Phillimore gene: FOXF2 was added gene: FOXF2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FOXF2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FOXF2 were set to PMID: 30561639; 22022403 Phenotypes for gene: FOXF2 were set to profound sensorineural hearing loss (SNHL); cochlea malformations; incomplete partition type I anomaly of the cochlea Review for gene: FOXF2 was set to AMBER Added comment: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639). This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403). Sources: Literature |
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| Mendeliome v0.2587 | KIF12 | Zornitza Stark Phenotypes for gene: KIF12 were changed from Prenatal cholestasis; High Gamma-Glutamyltransferase (GGT) to Cholestasis; High Gamma-Glutamyltransferase (GGT) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2580 | KIF12 |
Ee Ming Wong gene: KIF12 was added gene: KIF12 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KIF12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIF12 were set to PMID: 30250217; 30976738 Phenotypes for gene: KIF12 were set to Prenatal cholestasis; High Gamma-Glutamyltransferase (GGT) Review for gene: KIF12 was set to AMBER gene: KIF12 was marked as current diagnostic Added comment: > 3 unrelated families,but they are all consanguineous families Sources: Literature |
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| Mendeliome v0.2574 | IQCE |
Zornitza Stark gene: IQCE was added gene: IQCE was added to Mendeliome. Sources: Literature Mode of inheritance for gene: IQCE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IQCE were set to 31549751; 28488682 Phenotypes for gene: IQCE were set to Postaxial polydactyly Review for gene: IQCE was set to GREEN Added comment: Four families reported with bi-allelic variants in this gene. The c.895_904del (p.Val301Serfs*8) was found in three of the families without sharing a common haplotype, suggesting a recurrent mechanism. RNA expression analysis on patients’ fibroblasts showed that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog‐signaling pathway, and zebrafish experiments demonstrated a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. Sources: Literature |
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| Mendeliome v0.2493 | C1orf194 | Zornitza Stark Added comment: Comment when marking as ready: Two unrelated families with missense variants, one with intermediate CMT, the other with demyelinating CMT. Different phenotypic manifestations may relate to different mechanism, but this remains to be fully elucidated. Supportive mouse model. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2470 | ABCC1 |
Zornitza Stark gene: ABCC1 was added gene: ABCC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ABCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ABCC1 were set to 31273342 Phenotypes for gene: ABCC1 were set to Nonsyndromic hearing loss Review for gene: ABCC1 was set to AMBER Added comment: Total of 3 variants reported in 3 families, including 1 which segregates in a large family (10 affected) PMID: 31273342; Li 2019: Reported 3 different het missense in 3 families with postlingual ADNSHL. 1 missense segregated in a large Chinese family. This variant is present in gnomAD (10 hets), but onset noted to be in 2nd or 3rd decade of life. Functional studies performed. Other 2 variants reported absent in gnomAD. Amber rating in light of gnomad frequency of one of the reported variants. Sources: Literature |
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| Mendeliome v0.2440 | SLC6A6 |
Chern Lim gene: SLC6A6 was added gene: SLC6A6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC6A6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034 Phenotypes for gene: SLC6A6 were set to Early retinal degeneration; cardiomyopathy Review for gene: SLC6A6 was set to AMBER Added comment: Different homozygous missense variants in 2 unrelated consanguineous families with early retinal degeneration, some functional studies. Patients in one of the families also had cardiomyopathy. (PMIDs: 31345061, 31903486) One dilated cardiomyopathy patient with a homozygous deletion at a splice site (PMID: 29886034). Sources: Literature |
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| Mendeliome v0.2440 | PKDCC |
Paul De Fazio changed review comment from: 2 ("apparently") unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice. Sources: Literature; to: 2 apparently unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice. Sources: Literature |
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| Mendeliome v0.2440 | ORAI1 |
Natalie Tan changed review comment from: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence): - Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias) - Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy); to: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence): - Dominant ORAI1 missense variants via a GOF mechanism cause a slowly progressive myopathy (tubular aggregate myopathy/TAM) - Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy) |
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| Mendeliome v0.2440 | CDKL5 | Teresa Zhao reviewed gene: CDKL5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 2, MIM 300672; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2440 | STIM1 | Natalie Tan reviewed gene: STIM1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 31448844; Phenotypes: Myopathy, immunodeficiency; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2440 | ORAI1 |
Natalie Tan changed review comment from: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence): - Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias) - Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy); to: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence): - Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias) - Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy) |
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| Mendeliome v0.2440 | ORAI1 | Natalie Tan reviewed gene: ORAI1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 31448844; Phenotypes: Progressive myopathy, contractures; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2439 | SLC35D1 | Teresa Zhao reviewed gene: SLC35D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31423530, 19508970; Phenotypes: Schneckenbecken dysplasia, MIM 269250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2439 | POLR1B |
Paul De Fazio gene: POLR1B was added gene: POLR1B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: POLR1B were set to 31649276 Phenotypes for gene: POLR1B were set to bilateral malar and mandibular hypoplasia; microtia; coloboma; downslanting palpebral fissures; conductive deafness; cleft palate; heart malformations Review for gene: POLR1B was set to AMBER gene: POLR1B was marked as current diagnostic Added comment: 6 individuals with Treacher-Collins syndrome described: 3 with de novo variants, one inherited from a mosaic father, and two inherited from affected mothers. Knockdown in zebrafish mimics the phenotype. Sources: Literature |
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| Mendeliome v0.2427 | SLC9A7 | Dean Phelan reviewed gene: SLC9A7: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30335141; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2421 | TLK2 | Teresa Zhao reviewed gene: TLK2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:29861108, 29942082, 27479843, 23911319, 30559488, 29942082, 31558842; Phenotypes: Intellectual disability, MIM 618050, Neurodevelopmental disease; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2416 | CFAP69 | Ee Ming Wong reviewed gene: CFAP69: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29606301, 30415212; Phenotypes: Asthenoteratospermia (Impaired sperm motility, severe flagellar abnormalities (short, coiled, absent or irregular calibre)); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2416 | RASA1 | Chern Lim reviewed gene: RASA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14639529, 29891884, 24038909, 31300548; Phenotypes: Capillary malformation-arteriovenous malformation 1, MIM#608354; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2416 | ADAMTS19 |
Alison Yeung Added comment: Comment on list classification: Two different homozygous variants in two consanguineous families. Animal model demonstrates cardiac phenotype Await further reported families |
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| Mendeliome v0.2411 | CAP2 |
Alison Yeung Added comment: Comment on list classification: Currently only one consanguineous family reported. Knockout mouse model shows cardiomyopathy but not other clinical features reported in this family |
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| Mendeliome v0.2406 | CHD4 | Teresa Zhao reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:31388190; Phenotypes: Sifrim-Hitz-Weiss syndrome, MIM 617159; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2401 | CPSF1 |
Kristin Rigbye changed review comment from: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (30689892). Sources: Literature; to: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (PMID: 30689892). Sources: Literature |
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| Mendeliome v0.2401 | CPSF1 |
Kristin Rigbye gene: CPSF1 was added gene: CPSF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CPSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CPSF1 were set to 30689892 Phenotypes for gene: CPSF1 were set to Myopia 27, 618827; high myopia; early-onset high myopiaHigh myopia Review for gene: CPSF1 was set to GREEN Added comment: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (30689892). Sources: Literature |
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| Mendeliome v0.2395 | CDC45 | Teresa Zhao reviewed gene: CDC45: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31474763; Phenotypes: Meier-Gorlin syndrome 7, MIM 617063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2392 | ATOH7 | Paul De Fazio reviewed gene: ATOH7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22068589, 22645276, 31696227, 11493566, 11493566; Phenotypes: microphthalmia, cataract, glaucoma, congenital retinal nonattachment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2383 | SMCHD1 |
Teresa Zhao changed review comment from: Seven probands with FSHD reported to have LP/P variants, which all predicted to disrupt the structure and conformation of SMCHD1.; to: Seven probands with FSHD reported to have LP/P variants, which all predicted to disrupt the structure and conformation of SMCHD1. No particular geno-pheno correlation, but location of missense variants within the ATPase domain of MSCHD1 may contribute to the differences in phenotypic outcome (PMID: 31243061) |
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| Mendeliome v0.2377 | TBX6 | Dean Phelan reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30307510, 31015262; Phenotypes: congenital vertebral malformations, congenital scoliosis, spondylocostal dysostosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2377 | SMCHD1 | Teresa Zhao reviewed gene: SMCHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31600781; Phenotypes: Bosma arhinia microphthalmia syndrome, MIM 603457, Fascioscapulohumeral muscular dystrophy 2, digenic; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2376 | PKDCC |
Alison Yeung Added comment: Comment on list classification: Two unrelated consanguineous families reported with different homozygous variants Pre-existing mouse model has similar phenotype Needs more functional evidence or further reported families |
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| Mendeliome v0.2375 | SPEF2 |
Chern Lim gene: SPEF2 was added gene: SPEF2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SPEF2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPEF2 were set to 31151990; 31278745; 31048344 Phenotypes for gene: SPEF2 were set to Spermatogenic failure 43, MIM#618751 Review for gene: SPEF2 was set to GREEN gene: SPEF2 was marked as current diagnostic Added comment: More than 3 unrelated families reported, all PTVs or splice variant. Functional studies showed SPEF2 protein levels were reduced in patients’ spermatozoa. (PMIDs: 31151990, 31278745, 31048344). Sources: Literature |
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| Mendeliome v0.2372 | ACKR3 |
Elena Savva gene: ACKR3 was added gene: ACKR3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ACKR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACKR3 were set to PMID: 3121183 Phenotypes for gene: ACKR3 were set to Oculomotor synkinesis Review for gene: ACKR3 was set to AMBER Added comment: No phenotype currently listed in OMIM PMID: 3121183 - 1 family (3 siblings and a cousin) with congenital ptosis and oculomotor synkinesis. Mouse model reciprocated the phenotype. Functional assay using transfected HEK293 cells show protein mislocalization and lower binding affinity Emerging gene-disease association Sources: Literature |
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| Mendeliome v0.2371 | PCDH19 | Ee Ming Wong reviewed gene: PCDH19: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 18469813, 30287595; Phenotypes: PCDH19-related epilepsy (early seizure onset, generalised or focused seizures), cognitive impairment; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2368 | GFAP | Paul De Fazio reviewed gene: GFAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 11138011, 12034785, 31004048, 15732097; Phenotypes: Leukodystrophy, macrocephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2365 | COPA | Teresa Zhao reviewed gene: COPA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31455335, 30804679; Phenotypes: Autoimmune interstitial lung, joint, and kidney disease, MIM 616414; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2365 | PLOD3 | Sarah Pantaleo reviewed gene: PLOD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18834968, 31129566, 30237576, 30463024; Phenotypes: Lysyl hydroxylase 3 deficiency, MIM#612394; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2365 | TBX6 | Sarah Pantaleo reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 8954725, 20503311, 23335591, 25564734, 31015262; Phenotypes: Skeletal dysplasia, spondylocostal dysostosis, congenital scoliosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2365 | ELOVL1 | Hazel Phillimore changed review comment from: De novo in 2 unrelated patients. Decrease in ELOVL1 enzyme activity. The same 2 patients are in PMIDs: 30487246 and 29496980 but with different clinical findings. Deafness and optic atrophy are the additional features.; to: De novo missense (S165F) in 2 unrelated patients. Decrease in ELOVL1 enzyme activity. The same 2 patients are in PMIDs: 30487246 and 29496980 but with different clinical findings. Deafness and optic atrophy are the additional features. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2364 | YARS | Dean Phelan reviewed gene: YARS: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 30304524, 29232904, 27633801, 19561293; Phenotypes: peripheral neuropathy, multisystem disease, CMT; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2364 | CFAP65 |
Daniel Flanagan gene: CFAP65 was added gene: CFAP65 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CFAP65 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CFAP65 were set to 31501240; 31413122 Phenotypes for gene: CFAP65 were set to Spermatogenic failure 40 618664 Penetrance for gene: CFAP65 were set to unknown Review for gene: CFAP65 was set to GREEN gene: CFAP65 was marked as current diagnostic Added comment: 9 patients with multiple morphological abnormalities of the sperm flagella (MMAF) or completely immotile spermatozoa, in which, homozygous or compound heterozygous truncating CFAP65 variants were identified. Cfap65-mutated male mice displayed typical MMAF phenotypes with severe morphological abnormalities of the sperm flagella (PMID: 31501240, 31413122). Sources: Literature |
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| Mendeliome v0.2362 | SCN1A | Ee Ming Wong reviewed gene: SCN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30368457, 12754708, 25754450; Phenotypes: Dravet Syndrome, Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome, Febrile seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2361 | NAA10 | Naomi Baker reviewed gene: NAA10: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30842225.; Phenotypes: syndromic X-linked microphthalmia; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2361 | ASCC1 | Sarah Pantaleo reviewed gene: ASCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30327447, 12077347, 26924529, 31880396, 26503956; Phenotypes: Arthrogryposis, congenital bone fractures, spinal muscular atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2361 | RXFP2 | Teresa Zhao reviewed gene: RXFP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31167797, 20963592; Phenotypes: Cryptorchidism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2361 | PKDCC |
Paul De Fazio gene: PKDCC was added gene: PKDCC was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PKDCC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PKDCC were set to PMID:30478137; 19097194 Phenotypes for gene: PKDCC were set to Dysmorphism; shortening of extremities Review for gene: PKDCC was set to AMBER gene: PKDCC was marked as current diagnostic Added comment: 2 ("apparently") unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice. Sources: Literature |
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| Mendeliome v0.2361 | TNFRSF21 |
Shannon Cowie gene: TNFRSF21 was added gene: TNFRSF21 was added to Mendeliome. Sources: Other Mode of inheritance for gene: TNFRSF21 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TNFRSF21 were set to PMID: 31189563 Phenotypes for gene: TNFRSF21 were set to high myopia Review for gene: TNFRSF21 was set to RED gene: TNFRSF21 was marked as current diagnostic Added comment: Source: JMG review Oct 2019 Large Chinese family, including 12 patients with non-syndromic HM Immunofluorescence assay indicated that it is strongly expressed in the mouse eye. Sources: Other |
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| Mendeliome v0.2305 | MED13L | Elena Savva reviewed gene: MED13L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID 29511999; Phenotypes: Mental retardation and distinctive facial features with or without cardiac defects 616789, Transposition of the great arteries, dextro-looped 1 608808; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2304 | XRCC1 |
Bryony Thompson gene: XRCC1 was added gene: XRCC1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: XRCC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: XRCC1 were set to 28002403; 29472272 Phenotypes for gene: XRCC1 were set to Spinocerebellar ataxia, autosomal recessive 26 MIM#617633 Review for gene: XRCC1 was set to GREEN Added comment: Three South Asian cases (one with early adult onset and the other two with onset in childhood) reported with slowly progressive cerebellar ataxia accompanied by sensorimotor neuropathy. All with the recurrent splice variant (c.1293G>C, 2 homozygotes and a compound heterozygote). Mice with conditional deletion of the Xrcc1 gene in the brain showed cerebellar ataxia. Sources: Expert list |
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| Mendeliome v0.2303 | TECTA | Elena Savva reviewed gene: TECTA: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:22718023, 17136632, 31554319, 21520338; Phenotypes: Deafness, autosomal recessive 21 603629, Deafness, autosomal dominant 8/12 601543; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2303 | NF1 | Elena Savva reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukemia, juvenile myelomonocytic 607785, Neurofibromatosis, familial spinal 162210, Neurofibromatosis, type 1 162200, Neurofibromatosis-Noonan syndrome 601321, Watson syndrome 193520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2301 | SEC63 | Elena Savva reviewed gene: SEC63: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23209713, 20095989; Phenotypes: Polycystic liver disease 2 617004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2287 | LARS |
Zornitza Stark gene: LARS was added gene: LARS was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LARS were set to 28774368; 30349989; 22607940 Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438 Review for gene: LARS was set to GREEN gene: LARS was marked as current diagnostic Added comment: Six unrelated families reported in the literature, reviewed in PMID: 30349989. Sources: NHS GMS |
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| Mendeliome v0.2280 | KCNJ11 |
Elena Savva edited their review of gene: KCNJ11: Added comment: Congenital hyperinsulinism (HI) variants are generally reported in heterozygous patients where they also carry a somatic 2nd hit, or have isodisomy of the paternal allele (focal HI), or in bilallelic patients (diffuse HI). This condition can be dominant (but rarely), where patients with these missense are diazoxide-responsive. Patients with recessively inherited variants are diazoxide-unresponsive (OMIM, PMID:11395395, PMID: 23275527, PMID: 23345197). Genotype-phenotype correlation: Permanent neonatal diabetes – GOF (OMIM) Permanent neonatal diabetes + other features – GOF (OMIM) Congenital hyperinsulinism – LOF (PMID:18250167). PTCs - LOF Missense - Loss and gain of function LOF – cause reduce channel expression, channel activity and increase current decay (PMID:18250167) GOF - impair ATP-based sensitivity, more open state channel (OMIM) Mutations generally occur on the paternal allele (PMID: 23345197).; Changed publications: PMID:18250167, 11395395, 23275527, 23345197 |
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| Mendeliome v0.2259 | MARS2 | Zornitza Stark changed review comment from: 1 family with 2 sibs with combined oxidative phosphorylation deficiency-25 (with ID) with compound heterozygous mutations in the MARS2 gene. Patient fibroblasts showed decreased activities of mitochondrial complexes I and IV, consistent with a mitochondrial translation defect. Immunoblot analysis showed reduced MARS2 protein levels as well as reduced levels of selected subunits of complexes I and IV.; to: 1 family with 2 sibs with combined oxidative phosphorylation deficiency-25 (with ID) with compound heterozygous mutations in the MARS2 gene. Patient fibroblasts showed decreased activities of mitochondrial complexes I and IV, consistent with a mitochondrial translation defect. Immunoblot analysis showed reduced MARS2 protein levels as well as reduced levels of selected subunits of complexes I and IV. Spastic ataxia association: note complex chromosomal rearrangements rather than SNVs reported in group of 54 French Canadians. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2250 | NPHP3 | Zornitza Stark Phenotypes for gene: NPHP3 were changed from to Meckel syndrome 7, MIM# 267010; Nephronophthisis 3, MIM# 604387; Renal-hepatic-pancreatic dysplasia 1, MIM# 208540 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2248 | NPHP3 | Zornitza Stark reviewed gene: NPHP3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Meckel syndrome 7, MIM# 267010, Nephronophthisis 3, MIM# 604387, Renal-hepatic-pancreatic dysplasia 1, MIM# 208540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2225 | SHANK2 | Zornitza Stark Added comment: Comment when marking as ready: Reports of CNVs, LoF variants, and missense variants in this gene, generally ascertained in autism cohorts. Some de novo and others inherited from parents with a range of neuropsychiatric phenotypes. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2161 | TNFSF12 | Zornitza Stark Phenotypes for gene: TNFSF12 were changed from to Recurrent infections, poor antibody responses, decreased immunoglobulins | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2157 | TNFSF12 | Zornitza Stark reviewed gene: TNFSF12: Rating: RED; Mode of pathogenicity: None; Publications: 23493554; Phenotypes: Recurrent infections, poor antibody responses, decreased immunoglobulins; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2110 | NFAT5 | Zornitza Stark Phenotypes for gene: NFAT5 were changed from to Recurrent infections; Autoimmune enterocolopathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2106 | NFAT5 | Zornitza Stark reviewed gene: NFAT5: Rating: RED; Mode of pathogenicity: None; Publications: 25667416; Phenotypes: Recurrent infections, Autoimmune enterocolopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2050 | CD247 | Zornitza Stark changed review comment from: Also known as CD3Z. Single individual reported with homozygous germline nonsense variant, which was present in some T cells, but others had the nonsense variant in combination with one of three different missense somatic variants.; to: Also known as CD3Z. Note one individual reported with homozygous germline nonsense variant, which was present in some T cells, but others had the nonsense variant in combination with one of three different missense somatic variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2029 | TBX19 | Zornitza Stark Phenotypes for gene: TBX19 were changed from to Adrenocorticotropic hormone deficiency, 201400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2020 | ICOSLG | Zornitza Stark Phenotypes for gene: ICOSLG were changed from to Combined immunodeficiency; recurrent bacterial and viral infections; neutropaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2016 | ICOSLG | Zornitza Stark reviewed gene: ICOSLG: Rating: AMBER; Mode of pathogenicity: None; Publications: 31532372, 30498080; Phenotypes: Combined immunodeficiency, recurrent bacterial and viral infections, neutropaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2016 | IL6ST | Zornitza Stark Phenotypes for gene: IL6ST were changed from Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response. to Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response; Hyper-IgE syndrome, autosomal dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2013 | IL6ST |
Zornitza Stark changed review comment from: Also known as gp130. Two families with bi-allelic missense variants and immunological phenotype described initially. More recently, five individuals from three families reported with a more complex Stuve-Wiedemann-like phenotype reported, including skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. These three families had bi-allelic LoF variants (nonsense and canonical splice site). Several mouse models support gene-disease association. Sources: Expert list; to: Also known as gp130. Two families with bi-allelic missense variants and immunological phenotype described initially. More recently, five individuals from three families reported with a more complex Stuve-Wiedemann-like phenotype reported, including skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. These three families had bi-allelic LoF variants (nonsense and canonical splice site). Several mouse models support gene-disease association. 2020: 12 individuals from 8 unrelated families with seven different mono-allelic truncating variants, dominant negative effect proposed. Sources: Expert list |
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| Mendeliome v0.2013 | IL6ST | Zornitza Stark edited their review of gene: IL6ST: Changed publications: 28747427, 30309848, 12370259, 16041381, 31914175, 32207811; Changed phenotypes: Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523, Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response, Hyper-IgE syndrome, autosomal dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2013 | TBX19 | Kristin Rigbye reviewed gene: TBX19: Rating: GREEN; Mode of pathogenicity: None; Publications: 15613420, 15613420; Phenotypes: Adrenocorticotropic hormone deficiency, 201400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1999 | HAVCR2 |
Zornitza Stark gene: HAVCR2 was added gene: HAVCR2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: HAVCR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HAVCR2 were set to 30374066; 30792187 Phenotypes for gene: HAVCR2 were set to T-cell lymphoma, subcutaneous panniculitis-like, MIM# 618398 Review for gene: HAVCR2 was set to GREEN Added comment: Over 20 unrelated individuals reported, note germline confirmation in only a few. Some variants are recurrent: c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met). Sources: Expert list |
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| Mendeliome v0.1993 | NLRP1 | Zornitza Stark Phenotypes for gene: NLRP1 were changed from to Autoinflammation with arthritis and dyskeratosis, MIM# 617388; Palmoplantar carcinoma, multiple self-healing, MIM# 615225; Recurrent respiratory papillomatosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1990 | NLRP1 | Zornitza Stark reviewed gene: NLRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27965258, 31484767, 27662089; Phenotypes: Autoinflammation with arthritis and dyskeratosis, MIM# 617388, Palmoplantar carcinoma, multiple self-healing 615225, Recurrent respiratory papillomatosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1987 | TIRAP | Zornitza Stark changed review comment from: No evidence currently for Mendelian disease association. Some evidence for polymorphisms in this gene influencing susceptibility/protection from infectious disease.; to: No evidence currently for Mendelian disease association. Some evidence for polymorphisms in this gene influencing susceptibility/protection from infectious disease. One family with 8 individuals and bi-allelic variants and susceptibility to staphylococcal disease reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1965 | JAK1 |
Zornitza Stark changed review comment from: Single family reported (mother and two children) with GoF variant. Sources: Expert list; to: Single family reported (mother and two children) with GoF variant and immune dysregulation phenotype. Another individual reported with bi-allelic LoF and susceptibility to mycobacterial infections. Mouse model with NK defect. Sources: Expert list |
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| Mendeliome v0.1964 | SPPL2A |
Zornitza Stark gene: SPPL2A was added gene: SPPL2A was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SPPL2A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPPL2A were set to 30127434 Phenotypes for gene: SPPL2A were set to Susceptibility to mycobacteria and Salmonella Review for gene: SPPL2A was set to AMBER Added comment: Three individuals from two unrelated consanguineous family with two different homozygous splice site variants, functional data. Sources: Expert list |
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| Mendeliome v0.1957 | C17orf62 |
Zornitza Stark gene: C17orf62 was added gene: C17orf62 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: C17orf62 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C17orf62 were set to 30361506; 30312704; 28351984 Phenotypes for gene: C17orf62 were set to Chronic granulomatous disease Review for gene: C17orf62 was set to GREEN Added comment: Seven Icelandic families reported with same homozygous variant, p.Tyr2Ter and an additional family from different ethnic background with different homozygous splice site variant. Functional data, including mouse model. Gene also known as EROS and CYBC1 (HGNC approved name) Sources: Expert list |
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| Mendeliome v0.1949 | CTPS1 | Zornitza Stark Phenotypes for gene: CTPS1 were changed from to Immunodeficiency 24, MIM# 615897; Recurrent/chronic bacterial and viral infections (EBV, VZV); EBV lymphoproliferation; B-cell non-Hodgkin lymphoma | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1946 | CTPS1 | Zornitza Stark reviewed gene: CTPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24870241; Phenotypes: Immunodeficiency 24, MIM# 615897, Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1946 | JAK1 |
Zornitza Stark gene: JAK1 was added gene: JAK1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: JAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: JAK1 were set to 28111307 Phenotypes for gene: JAK1 were set to Eosinophilia; Eosinophilic enteritis; Thyroid disease; Poor growth; Viral infections Review for gene: JAK1 was set to RED Added comment: Single family reported (mother and two children) with GoF variant. Sources: Expert list |
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| Mendeliome v0.1944 | IL2RB |
Zornitza Stark gene: IL2RB was added gene: IL2RB was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: IL2RB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL2RB were set to 31040184; 31040185 Phenotypes for gene: IL2RB were set to Immunodeficiency 63 with lymphoproliferation and autoimmunity, MIM# 618495; Lymphoproliferation, lymphadenopathy, hepatosplenomegaly, autoimmune haemolytic anaemia, dermatitis, enteropathy, hypergammaglobulinaemia, recurrent viral (EBV, CMV) infections Review for gene: IL2RB was set to GREEN Added comment: Five families reported. Sources: Expert list |
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| Mendeliome v0.1943 | AP3D1 |
Zornitza Stark gene: AP3D1 was added gene: AP3D1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: AP3D1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP3D1 were set to 26744459; 9697856 Phenotypes for gene: AP3D1 were set to Hermansky-Pudlak syndrome 10, MIM# 617050; Oculocutaneous albinism; Severe neutropaenia; Recurrent infections; Seizures; Hearing loss; Neurodevelopmental delay Review for gene: AP3D1 was set to RED Added comment: Single family and a mouse model. Sources: Expert list |
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| Mendeliome v0.1935 | TOP2B | Zornitza Stark Phenotypes for gene: TOP2B were changed from Autosomal dominant deafness to Autosomal dominant deafness; Antibody deficiency, recurrent infections, facial dysmorphism, limb anomalies; Intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1933 | TOP2B | Zornitza Stark edited their review of gene: TOP2B: Changed publications: 28343847, 31198993, 31409799, 12773624; Changed phenotypes: Autosomal dominant deafness, Antibody deficiency, recurrent infections, facial dysmorphism, limb anomalies, Intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1932 | TOP2B | Zornitza Stark edited their review of gene: TOP2B: Changed rating: GREEN; Changed publications: 31198993, 31409799, 31953910; Changed phenotypes: Autosomal dominant deafness, Antibody deficiency, recurrent infections, facial dysmorphism, limb anomalies | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1929 | NFE2L2 |
Zornitza Stark gene: NFE2L2 was added gene: NFE2L2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NFE2L2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NFE2L2 were set to 29018201 Phenotypes for gene: NFE2L2 were set to Immunodeficiency, developmental delay, and hypohomocysteinemia, MIM# 617744; Recurrent respiratory and skin infection; Growth retardation; Developmental delay, borderline ID; White matter cerebral lesions Review for gene: NFE2L2 was set to GREEN Added comment: Four unrelated individuals reported. Sources: Expert list |
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| Mendeliome v0.1927 | ERBIN |
Zornitza Stark gene: ERBIN was added gene: ERBIN was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ERBIN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ERBIN were set to 28126831 Phenotypes for gene: ERBIN were set to Recurrent respiratory infections; Susceptibility to S.aureus; Eczema; Hyperextensible joints; Scoliosis; Arterial dilatation in some Review for gene: ERBIN was set to AMBER Added comment: Single family and functional data. Sources: Expert list |
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| Mendeliome v0.1925 | ZNF341 |
Zornitza Stark gene: ZNF341 was added gene: ZNF341 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ZNF341 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF341 were set to 29907691; 29907690 Phenotypes for gene: ZNF341 were set to Hyper-IgE recurrent infection syndrome 3, autosomal recessive, MIM# 618282; Mild facial dysmorphism; Early onset eczema; Recurrent bacterial skin infections, abscesses; Recurrent respiratory infections, lung abscesses and pneumothoraces; Hyperextensible joints, bone fractures, retention of primary teeth Review for gene: ZNF341 was set to GREEN Added comment: 19 individuals from 10 families reported, some sharing the same homozygous variants (at least 4 different LoF variants reported). Sources: Expert list |
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| Mendeliome v0.1923 | IL6ST |
Zornitza Stark gene: IL6ST was added gene: IL6ST was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: IL6ST was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL6ST were set to 28747427; 30309848; 12370259; 16041381; 31914175 Phenotypes for gene: IL6ST were set to Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response. Review for gene: IL6ST was set to GREEN Added comment: Also known as gp130. Two families with bi-allelic missense variants and immunological phenotype described initially. More recently, five individuals from three families reported with a more complex Stuve-Wiedemann-like phenotype reported, including skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. These three families had bi-allelic LoF variants (nonsense and canonical splice site). Several mouse models support gene-disease association. Sources: Expert list |
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| Mendeliome v0.1922 | IL6R | Zornitza Stark Phenotypes for gene: IL6R were changed from to Recurrent pyogenic infections, cold abscesses; High circulating IL-6 levels; High IgE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1918 | IL6R | Zornitza Stark reviewed gene: IL6R: Rating: AMBER; Mode of pathogenicity: None; Publications: 31235509; Phenotypes: Recurrent pyogenic infections, cold abscesses, High circulating IL-6 levels, High IgE; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1917 | LIG1 |
Zornitza Stark gene: LIG1 was added gene: LIG1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: LIG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIG1 were set to 30395541 Phenotypes for gene: LIG1 were set to Combined immunodeficiency; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis Review for gene: LIG1 was set to GREEN Added comment: Five individuals from three families. Sources: Expert list |
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| Mendeliome v0.1916 | POLE2 |
Zornitza Stark gene: POLE2 was added gene: POLE2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: POLE2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLE2 were set to 26365386 Phenotypes for gene: POLE2 were set to Combined immunodeficiency; Lymphopaenia; Lack of TRECS, absent proliferation in response to antigens; Hypoglobulinaemia; Recurrent infections, disseminated BCG infections; Autoimmunity; Facial dysmorphism Review for gene: POLE2 was set to RED Added comment: Single family reported with homozygous splice site variant. Sources: Expert list |
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| Mendeliome v0.1914 | FCHO1 |
Zornitza Stark gene: FCHO1 was added gene: FCHO1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FCHO1 were set to 32098969; 30822429 Phenotypes for gene: FCHO1 were set to Combined immunodeficiency; T cells: low, poor proliferation; B cells: normal number; Recurrent infections (viral, mycobacteria, bacterial, fungal); lymphoproliferation; Failure to thrive; Increased activation-induced T-cell death; Defective clathrin-mediated endocytosis Review for gene: FCHO1 was set to GREEN Added comment: More than 10 affected individuals with bi-allelic variants in this gene reported. Functional data. Sources: Expert list |
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| Mendeliome v0.1913 | REL |
Zornitza Stark gene: REL was added gene: REL was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: REL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: REL were set to 31103457 Phenotypes for gene: REL were set to Combined immunodeficiency; T cells: normal, decreased memory CD4, poor proliferation; B cells: low, mostly naive, few switched memory B cells, impaired proliferation; Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms; Defective innate immunity Review for gene: REL was set to RED Added comment: Single individual from consanguineous family reported with homozygous canonical splice site variant, no functional data. Sources: Expert list |
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| Mendeliome v0.1912 | TFRC | Zornitza Stark Phenotypes for gene: TFRC were changed from to Immunodeficiency 46, MIM# 616740; T cells: normal number, poor proliferation; B cells: normal number, low memory B cells; recurrent infections, neutorpaenia; thrombocytopaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1908 | TFRC | Zornitza Stark reviewed gene: TFRC: Rating: AMBER; Mode of pathogenicity: None; Publications: 26642240; Phenotypes: Immunodeficiency 46, MIM# 616740, T cells: normal number, poor proliferation, B cells: normal number, low memory B cells, recurrent infections, neutorpaenia, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1908 | TET2 | Zornitza Stark changed review comment from: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma.; to: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1907 | RELA |
Zornitza Stark gene: RELA was added gene: RELA was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: RELA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RELA were set to 28600438; 29305315 Phenotypes for gene: RELA were set to Mucocutaneous ulceration, chronic, MIM# 618287; Impaired NFkB activation; reduced production of inflammatory cytokines; autoimmune cytopaenias Review for gene: RELA was set to AMBER Added comment: Two families reported, somewhat different phenotypes. Sources: Expert list |
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| Mendeliome v0.1905 | RELB |
Zornitza Stark gene: RELB was added gene: RELB was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: RELB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RELB were set to 7834753; 26385063 Phenotypes for gene: RELB were set to Immunodeficiency 53, MIM# 617585; T cells: normal number, poor diversity, poor function; recurrent infections Review for gene: RELB was set to AMBER Added comment: Single family reported, functional data. Sources: Expert list |
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| Mendeliome v0.1892 | FRMD4A |
Zornitza Stark gene: FRMD4A was added gene: FRMD4A was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: FRMD4A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FRMD4A were set to 25388005; 30214071 Phenotypes for gene: FRMD4A were set to Intellectual disability; microcephaly; Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia, MIM# 616819 Review for gene: FRMD4A was set to AMBER Added comment: Single Bedouin Israeli family reported with homozygous variant initially. Good segregation data. No functional data. Another family reported as part of a large consanguineous microcephaly cohort, different variant. Sources: Expert Review |
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| Mendeliome v0.1871 | BTBD7 | Zornitza Stark Added comment: Comment when marking as ready: Agreed, no evidence currently for Mendelian gene-disease association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1861 | PQBP1 | Zornitza Stark Phenotypes for gene: PQBP1 were changed from to Renpenning syndrome, MIM#309500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1842 | ADGRG6 | Zornitza Stark edited their review of gene: ADGRG6: Added comment: Three families reported originally with severe prenatal-onset arthrogryposis (PMID: 26004201), one family with more complex neurological phenotype (PMID:30549416).; Changed rating: GREEN; Changed publications: 30549416, 26004201; Changed phenotypes: Lethal congenital contracture syndrome 9, OMIM #616503; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1842 | ARID2 | Elena Savva reviewed gene: ARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:30838730; Phenotypes: Coffin-Siris syndrome 6; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1842 | PQBP1 | Elena Savva reviewed gene: PQBP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:31840929, 14634649, 20410308; Phenotypes: Renpenning syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1842 | FBN2 | Elena Savva reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID 19473076, 11068201; Phenotypes: Contractural arachnodactyly, congenital 121050, Macular degeneration, early-onset 616118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1834 | NRROS |
Sue White gene: NRROS was added gene: NRROS was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NRROS were set to 32100099; 32197075 Phenotypes for gene: NRROS were set to neurodegeneration; intracranial calcification; epilepsy Penetrance for gene: NRROS were set to Complete Review for gene: NRROS was set to GREEN Added comment: normal development or mild developmental delay until onset of regression around age of 1 concurrent with epilepsy biallelic LOF mutations with functional evidence of pathogenicity Sources: Literature |
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| Mendeliome v0.1827 | HTR3C | Zornitza Stark Added comment: Comment when marking as ready: Agree no evidence for Mendelian gene-disease association currently. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1799 | MRPL3 | Zornitza Stark changed review comment from: 1 French family with 4 sibs with severe mitochondrial disorder - compound heterozygous mutations in the MRPL3 gene, no functional studies. 1 male infant with a severe mitochondrial disorder - compound heterozygous mutations in the MRPL3 gene, no functional studies.; to: 1 French family with 4 sibs with severe mitochondrial disorder - compound heterozygous mutations in the MRPL3 gene, some functional studies. 1 male infant with a severe mitochondrial disorder - compound heterozygous mutations in the MRPL3 gene, no functional studies. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1777 | TIMMDC1 |
Zornitza Stark gene: TIMMDC1 was added gene: TIMMDC1 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: TIMMDC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TIMMDC1 were set to 28604674; 30981218 Phenotypes for gene: TIMMDC1 were set to Mitochondrial complex I deficiency, nuclear type 31 MIM#618251 Review for gene: TIMMDC1 was set to AMBER Added comment: A deep intronic variant (c.597-1340A>G, only detectable by WGS) that causes a splicing aberration was identified in a homozygous state in 3 unrelated cases from different ethnic backgrounds. A patient with Leigh-like syndrome had a homozygous stopgain variant in PDHX and a homozygous stopgain variant in TIMMDC1 (p.Arg225*). The TIMMDC1 mutant protein could still rescue complex I assembly in TIMMDC1 knockout cells and the patient’s clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect. Sources: NHS GMS |
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| Mendeliome v0.1774 | FECH | Michelle Torres reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 20105171, 23016163; Phenotypes: Protoporphyria, erythropoietic, 1 177000 AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1766 | ANXA11 |
Bryony Thompson gene: ANXA11 was added gene: ANXA11 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ANXA11 were set to 28469040; 29845112; 30109997 Phenotypes for gene: ANXA11 were set to Amytrophic lateral sclerosis 23 MIM#617839 Review for gene: ANXA11 was set to GREEN Added comment: 4 different missense variants in 10 patients from 7 unrelated families with amyotrophic lateral sclerosis and functional assays supporting association. Sources: Expert list |
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| Mendeliome v0.1727 | NADK2 |
Zornitza Stark gene: NADK2 was added gene: NADK2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NADK2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NADK2 were set to 24847004; 29388319; 27940755 Phenotypes for gene: NADK2 were set to 2,4-dienoyl-CoA reductase deficiency, MIM# 616034 Review for gene: NADK2 was set to GREEN gene: NADK2 was marked as current diagnostic Added comment: Mitochondrial dysfunction resulting in severe neurologic and metabolic dysfunction beginning in early infancy reported in two individuals with confirmed variants in this gene. Another individual with homozygous hypomorphic start loss variant g.36241900 A>G p. Met1Val and milder phenotype reported (PMID:29388319). Sources: Expert list |
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| Mendeliome v0.1725 | ISCA1 |
Zornitza Stark gene: ISCA1 was added gene: ISCA1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ISCA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ISCA1 were set to 28356563; 32092383; 31016283; 30113620; 30105122 Phenotypes for gene: ISCA1 were set to Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613 Review for gene: ISCA1 was set to GREEN gene: ISCA1 was marked as current diagnostic Added comment: Multiple unrelated families reported. Severe disorder characterised by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Rat model results in early lethality. Founder variant c.259G > A, p.(Glu87Lys) reported in Indian families. Sources: Expert list |
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| Mendeliome v0.1699 | TNNI3K |
Zornitza Stark gene: TNNI3K was added gene: TNNI3K was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TNNI3K was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TNNI3K were set to 30010057; 29355681 Phenotypes for gene: TNNI3K were set to Cardiac conduction disease with or without dilated cardiomyopathy, MIM# 616117 Review for gene: TNNI3K was set to GREEN gene: TNNI3K was marked as current diagnostic Added comment: At least 6 multigenerational families reported where variants segregated with disease. Sources: Expert list |
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| Mendeliome v0.1657 | MCM3AP |
Zornitza Stark gene: MCM3AP was added gene: MCM3AP was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MCM3AP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295 Phenotypes for gene: MCM3AP were set to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development, MIM#618124 Review for gene: MCM3AP was set to GREEN gene: MCM3AP was marked as current diagnostic Added comment: At least 10 families reported. Sources: Expert list |
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| Mendeliome v0.1656 | MAPRE2 | Zornitza Stark Phenotypes for gene: MAPRE2 were changed from to Symmetric circumferential skin creases, congenital, 2, MIM# 616734 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1653 | MAPRE2 | Zornitza Stark reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26637975; Phenotypes: Symmetric circumferential skin creases, congenital, 2, MIM# 616734; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1635 | MAN1B1 | Elena Savva reviewed gene: MAN1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24348268; Phenotypes: Mental retardation, autosomal recessive 15; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1634 | NKAP |
Zornitza Stark gene: NKAP was added gene: NKAP was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NKAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NKAP were set to 26358559; 26350204; 31587868 Phenotypes for gene: NKAP were set to Intellectual disability Review for gene: NKAP was set to GREEN gene: NKAP was marked as current diagnostic Added comment: 10 males from 8 unrelated families with missense mutations in NKAP (on Xq24) Hypotonia and tall stature with Marfanoid habitus was predominant phenotype. One variant (NM_024528:c.988G>A / p.Arg333Gln) Sources: Expert list |
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| Mendeliome v0.1552 | TMEM260 | Zornitza Stark Phenotypes for gene: TMEM260 were changed from to Structural heart defects and renal anomalies syndrome, MIM# 617478 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1548 | TMEM260 | Zornitza Stark reviewed gene: TMEM260: Rating: AMBER; Mode of pathogenicity: None; Publications: 28318500; Phenotypes: Structural heart defects and renal anomalies syndrome, MIM# 617478; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1487 | CYP21A2 | Zornitza Stark Phenotypes for gene: CYP21A2 were changed from to Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, 201910; Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency, 201910 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1476 | PNPLA6 | Zornitza Stark Phenotypes for gene: PNPLA6 were changed from to Boucher-Neuhauser syndrome, 215470; ?Laurence-Moon syndrome, 245800; Oliver-McFarlane syndrome, 275400; Spastic paraplegia 39, autosomal recessive, 612020 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1473 | MC4R | Michelle Torres reviewed gene: MC4R: Rating: GREEN; Mode of pathogenicity: None; Publications: 29970488; Phenotypes: {Obesity, resistence to (BMIQ20)} 618306, Obesity (BMIQ20) 618406 AD, AR; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1473 | KMT2A | Michelle Torres reviewed gene: KMT2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16990798; Phenotypes: Leukemia, myeloid/lymphoid or mixed-lineage 159555 AD, Wiedemann-Steiner syndrome 605130 AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1473 | COL2A1 | Elena Savva reviewed gene: COL2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 15895462, 17721977, 27234559, 20179744; Phenotypes: Achondrogenesis, type II or hypochondrogenesis 200610, Avascular necrosis of the femoral head 608805, Czech dysplasia 609162, Epiphyseal dysplasia, multiple, with myopia and deafness 132450, Kniest dysplasia 156550, Legg-Calve-Perthes disease 150600, Osteoarthritis with mild chondrodysplasia 604864, Platyspondylic skeletal dysplasia, Torrance type 151210, SED congenita 183900, SMED Strudwick type 184250, Spondyloepiphyseal dysplasia, Stanescu type 616583, Spondyloperipheral dysplasia 271700, Stickler sydrome, type I, nonsyndromic ocular 609508, Stickler syndrome, type I 108300, Vitreoretinopathy with phalangeal epiphyseal dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1473 | CYP21A2 | Elena Savva reviewed gene: CYP21A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, 201910, Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency, 201910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1473 | PNPLA6 | Elena Savva reviewed gene: PNPLA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25480986, 24355708; Phenotypes: Boucher-Neuhauser syndrome, 215470, ?Laurence-Moon syndrome, 245800, Oliver-McFarlane syndrome, 275400, Spastic paraplegia 39, autosomal recessive, 612020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1415 | PLPBP | Elena Savva reviewed gene: PLPBP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29689137, 27912044; Phenotypes: Epilepsy, early-onset, vitamin B6-dependent, 617290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1386 | TREX1 | Kristin Rigbye reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 21937424; Phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive, Chilblain lupus, {Systemic lupus erythematosus, susceptibility to}, Vasculopathy, retinal, with cerebral leukodystrophy; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1386 | PNKP | Kristin Rigbye reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31436889, 31707899; Phenotypes: Ataxia-oculomotor apraxia 4, Microcephaly, seizures, and developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1382 | F2 | Zornitza Stark Phenotypes for gene: F2 were changed from to {Pregnancy loss, recurrent, susceptibility to, 2} 614390 AD; {Stroke, ischemic, susceptibility to} 601367 Mu; Dysprothrombinemia 613679 AR; Hypoprothrombinemia 613679 AR; Thrombophilia due to thrombin defect 188050 AD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1379 | F2 | Zornitza Stark reviewed gene: F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30297698; Phenotypes: {Pregnancy loss, recurrent, susceptibility to, 2} 614390 AD, {Stroke, ischemic, susceptibility to} 601367 Mu, Dysprothrombinemia 613679 AR, Hypoprothrombinemia 613679 AR, Thrombophilia due to thrombin defect 188050 AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1374 | UGT1A4 | Zornitza Stark Added comment: Comment when marking as ready: Agree, no evidence currently for Mendelian gene-disease association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1373 | CHD2 | Teresa Zhao reviewed gene: CHD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, childhood-onset (MIM # 615369); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1357 | KMT2E | Elena Savva reviewed gene: KMT2E: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31079897; Phenotypes: O'Donnell-Luria-Rodan syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1346 | PITRM1 |
Zornitza Stark gene: PITRM1 was added gene: PITRM1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PITRM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PITRM1 were set to 26697887; 29764912; 29383861 Phenotypes for gene: PITRM1 were set to Ataxia; Intellectual disability Review for gene: PITRM1 was set to GREEN gene: PITRM1 was marked as current diagnostic Added comment: Three unrelated families reported with bi-allelic variants in this gene. Sources: Expert list |
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| Mendeliome v0.1337 | BCKDHB | Melanie Marty reviewed gene: BCKDHB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Maple syrup urine disease, type Ib 248600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1325 | MAP3K20 |
Bryony Thompson gene: MAP3K20 was added gene: MAP3K20 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MAP3K20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAP3K20 were set to 27816943; 26755636 Phenotypes for gene: MAP3K20 were set to Centronuclear myopathy 6 with fiber-type disproportion MIM#617760; Split-foot malformation with mesoaxial polydactyly MIM#616890 Review for gene: MAP3K20 was set to GREEN Added comment: 3 unrelated consanguineous families homozygous for 3 different variants with centronuclear myopathy, and at least 2 families reported with split-foot malformation. Null mouse model is embryonic lethal due to severe cardiac edema and growth retardation. Gene alias of ZAK used in the published studies. Sources: Expert list |
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| Mendeliome v0.1289 | PLEC | Elena Savva reviewed gene: PLEC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22144912; Phenotypes: ?Epidermolysis bullosa simplex with nail dystrophy, Epidermolysis bullosa simplex with muscular dystrophy, Epidermolysis bullosa simplex with pyloric atresia, Epidermolysis bullosa simplex, Ogna type, Muscular dystrophy, limb-girdle; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1285 | WNT10A | Elena Savva reviewed gene: WNT10A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19559398, 30426266; Phenotypes: Odontoonychodermal dysplasia, Schopf-Schulz-Passarge syndrome, Tooth agenesis, selective, 4; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1274 | IQSEC2 | Elena Savva reviewed gene: IQSEC2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 31415821, 20473311, 30842726; Phenotypes: Mental retardation, X-linked 1/78; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1273 | GRIA1 |
Zornitza Stark gene: GRIA1 was added gene: GRIA1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: GRIA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178 Phenotypes for gene: GRIA1 were set to Intellectual disability; autism Review for gene: GRIA1 was set to GREEN Added comment: Multiple affected individuals reported but in large ID cohorts reporting multiple candidate genes. Recurrent (p.A636T) variant. Sources: Expert list |
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| Mendeliome v0.1262 | HDAC4 | Elena Savva reviewed gene: HDAC4: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 24715439, 20691407, 31209962; Phenotypes: Brachydactyly mental retardation syndrome, Brachydactyly without intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1258 | TRAPPC4 |
Zornitza Stark gene: TRAPPC4 was added gene: TRAPPC4 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAPPC4 were set to 31794024 Phenotypes for gene: TRAPPC4 were set to intellectual disability; epilepsy; spasticity; microcephaly Review for gene: TRAPPC4 was set to GREEN Added comment: Seven individuals from three unrelated families reported; recurrent splice site variant (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G), not a founder variant. Sources: Expert Review |
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| Mendeliome v0.1252 | KAT8 |
Zornitza Stark gene: KAT8 was added gene: KAT8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KAT8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KAT8 were set to 31794431 Phenotypes for gene: KAT8 were set to Intellectual disability; seizures; autism; dysmorphic features Review for gene: KAT8 was set to GREEN Added comment: Eight unrelated individuals reported with de novo variants in this gene and a mouse model. All variants missense, in the chromobarrel domain or the acetyltransferase domain; three individuals had the same variant p.Tyr90Cys . One more individual reported with bi-allelic variants: one missense and one frameshift; carrier parents were normal suggesting that may be haploinsuffiency is not the mechanism. Sources: Literature |
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| Mendeliome v0.1239 | TTC7A | Melanie Marty reviewed gene: TTC7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30553809, 28936210; Phenotypes: Gastrointestinal defects and immunodeficiency syndrome, 243150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1220 | OPA1 | Ee Ming Wong reviewed gene: OPA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30165240; Phenotypes: 1. ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) 6168963, 2. {Glaucoma, normal tension, susceptibility to} 6066573, 3. Behr syndrome 210000 AR, 4. Optic atrophy 1 165500 AD, 5. Optic atrophy plus syndrome 125250 AD; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1220 | ACTB | Melanie Marty reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29220674; Phenotypes: ?Dystonia, juvenile-onset 607371, Baraitser-Winter syndrome 1 243310, ACTB-related neurodevelopment disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1150 | DLG4 | Zornitza Stark edited their review of gene: DLG4: Added comment: Four unrelated individuals reported.; Changed rating: GREEN; Changed publications: 27479843, 25123844, 19617690, 29460436, 23020937, 28135719; Changed phenotypes: Intellectual disability, Marfanoid habitus; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1144 | DCPS |
Zornitza Stark gene: DCPS was added gene: DCPS was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: DCPS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DCPS were set to 25701870; 30289615; 25712129 Phenotypes for gene: DCPS were set to Al-Raqad syndrome, MIM#616459 Review for gene: DCPS was set to GREEN gene: DCPS was marked as current diagnostic Added comment: 7 individuals from 3 families reported. Sources: Expert list |
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| Mendeliome v0.1142 | CUX1 |
Zornitza Stark gene: CUX1 was added gene: CUX1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CUX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CUX1 were set to 25059644; 20510857; 30014507 Phenotypes for gene: CUX1 were set to Global developmental delay with or without impaired intellectual development, 618330 Review for gene: CUX1 was set to GREEN gene: CUX1 was marked as current diagnostic Added comment: Nine individuals from 7 families reported. Three individuals had normal intelligence at school age despite significant early developmental delay. Sources: Expert list |
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| Mendeliome v0.1089 | ALDH3A2 | Zornitza Stark Phenotypes for gene: ALDH3A2 were changed from to Sjogren-Larsson syndrome MIM#270200; spasticity; ichthyosis; intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1086 | ALDH3A2 | Zornitza Stark reviewed gene: ALDH3A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31273323; Phenotypes: Sjogren-Larsson syndrome MIM#270200, spasticity, ichthyosis, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1069 | LIPE |
Kristin Rigbye gene: LIPE was added gene: LIPE was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: LIPE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIPE were set to 27862896; 25475467; 24848981 Phenotypes for gene: LIPE were set to Lipodystrophy, familial partial, type 6, 615980 Review for gene: LIPE was set to GREEN gene: LIPE was marked as current diagnostic Added comment: LIPE is confirmed to be associated with partial familial lipodystrophy in OMIM. There are 3 unrelated cases of patients with partial lipodystrophy with different loss of function variants in the LIPE gene. Sources: Expert list |
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| Mendeliome v0.1050 | KMT5B | Elena Savva reviewed gene: KMT5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal dominant 51; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1029 | EGF | Zornitza Stark Phenotypes for gene: EGF were changed from to Hypomagnesemia 4, renal, MIM#611718 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1026 | EGF | Zornitza Stark reviewed gene: EGF: Rating: RED; Mode of pathogenicity: None; Publications: 17671655; Phenotypes: Hypomagnesemia 4, renal, MIM#611718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1025 | MYRF |
Zornitza Stark gene: MYRF was added gene: MYRF was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MYRF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYRF were set to 31048900; 31172260; 31266062; 31700225 Phenotypes for gene: MYRF were set to Nanophthalmos; High hyperopia Review for gene: MYRF was set to GREEN gene: MYRF was marked as current diagnostic Added comment: Multiple affected individuals reported. Sources: Expert list |
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| Mendeliome v0.1020 | ANAPC1 |
Alison Yeung gene: ANAPC1 was added gene: ANAPC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ANAPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ANAPC1 were set to PMID: 31303264 Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM 618625 Review for gene: ANAPC1 was set to GREEN gene: ANAPC1 was marked as current diagnostic Added comment: 7 unrelated families reported Sources: Literature |
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| Mendeliome v0.1018 | RINT1 |
Alison Yeung gene: RINT1 was added gene: RINT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RINT1 were set to PMID: 31204009 Phenotypes for gene: RINT1 were set to Recurrent acute liver failure Review for gene: RINT1 was set to GREEN gene: RINT1 was marked as current diagnostic Added comment: three unrelated individuals reported Sources: Literature |
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| Mendeliome v0.1001 | ATP6V1C2 |
Zornitza Stark gene: ATP6V1C2 was added gene: ATP6V1C2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP6V1C2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATP6V1C2 were set to 31959358 Phenotypes for gene: ATP6V1C2 were set to Distal renal tubular acidosis Review for gene: ATP6V1C2 was set to RED Added comment: Single family reported, limited functional data. Sources: Literature |
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| Mendeliome v0.991 | CTBP1 |
Zornitza Stark gene: CTBP1 was added gene: CTBP1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CTBP1 were set to 27094857; 28955726; 31041561 Phenotypes for gene: CTBP1 were set to Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome, MIM#617915 Review for gene: CTBP1 was set to GREEN gene: CTBP1 was marked as current diagnostic Added comment: At least 12 unrelated individuals reported with this neurodevelopmental disorder. Sources: Expert list |
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| Mendeliome v0.987 | CNOT2 |
Sebastian Lunke gene: CNOT2 was added gene: CNOT2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CNOT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CNOT2 were set to 31512373; 31145527; 28135719 Phenotypes for gene: CNOT2 were set to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies 618608 Review for gene: CNOT2 was set to GREEN gene: CNOT2 was marked as current diagnostic Added comment: From GEL: Three independent patients with non-sense or intra-genic deletions Sources: Expert list |
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| Mendeliome v0.982 | CCDC88C | Sebastian Lunke reviewed gene: CCDC88C: Rating: GREEN; Mode of pathogenicity: None; Publications: 23042809, 21031079, 25062847, 30398676; Phenotypes: Spinocerebellar ataxia 40, MIM#616053, Hydrocephalus, nonsyndromic, autosomal recessive 236600 AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.981 | CCDC47 |
Sebastian Lunke gene: CCDC47 was added gene: CCDC47 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CCDC47 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC47 were set to 30401460 Phenotypes for gene: CCDC47 were set to Trichohepatoneurodevelopmental syndrome, 618268 Review for gene: CCDC47 was set to GREEN gene: CCDC47 was marked as current diagnostic Added comment: From GEL: Morimoto el al. (PMID: 30401460) report on 4 individuals from 4 unrelated families with biallelic LoF variants in CCDC47. The phenotype consisted of abnormal (woolly) hair, liver dysfunction, common facial features as well as DD/ID Sources: Expert list |
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| Mendeliome v0.955 | ZNF142 |
Zornitza Stark gene: ZNF142 was added gene: ZNF142 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF142 were set to 31036918 Phenotypes for gene: ZNF142 were set to Neurodevelopmental disorder with impaired speech and hyperkinetic movements, MIM#618425 Review for gene: ZNF142 was set to GREEN gene: ZNF142 was marked as current diagnostic Added comment: 7 individuals from 4 unrelated families reported. Sources: Expert list |
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| Mendeliome v0.953 | RALA |
Zornitza Stark gene: RALA was added gene: RALA was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: RALA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RALA were set to 30500825 Phenotypes for gene: RALA were set to Intellectual disability; Seizures Review for gene: RALA was set to GREEN gene: RALA was marked as current diagnostic Added comment: 11 individuals from 10 unrelated families reported with this neurodevelopmental syndrome, half had seizures. Sources: Expert list |
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| Mendeliome v0.951 | NBEA |
Zornitza Stark gene: NBEA was added gene: NBEA was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NBEA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NBEA were set to 30269351; 28554332; 12746398; 12826745; 11450821; 3377648; 23277425; 22109531; 23153818 Phenotypes for gene: NBEA were set to Intellectual disability; Seizures Review for gene: NBEA was set to GREEN gene: NBEA was marked as current diagnostic Added comment: 24 de novo variants reported in individuals with a neurodevelopmental disorder Sources: Expert list |
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| Mendeliome v0.939 | HNRNPR |
Zornitza Stark gene: HNRNPR was added gene: HNRNPR was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HNRNPR were set to 26795593; 31079900 Phenotypes for gene: HNRNPR were set to Intellectual disability; seizures Review for gene: HNRNPR was set to GREEN gene: HNRNPR was marked as current diagnostic Added comment: Five unrelated individuals reported with de novo variants and a neurodevelopmental disorder. Sources: Expert list |
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| Mendeliome v0.912 | DHPS |
Zornitza Stark gene: DHPS was added gene: DHPS was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: DHPS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHPS were set to 30661771 Phenotypes for gene: DHPS were set to Neurodevelopmental disorder with seizures and speech and walking impairment, MIM#618480 Review for gene: DHPS was set to GREEN gene: DHPS was marked as current diagnostic Added comment: 5 individuals from 4 unrelated families with biallelic pathogenic variants in DHPS, note one variant is recurrent (c.518A>G or p.Asn173Ser). The phenotype consisted of DD/ID (5/5), tone abnormalities (hypotonia/hypertonia/spasticity - 5/5), seizures (5/5 - in one case though unclear staring spells) with EEG abnormalities (5/5). Additionally most individuals displayed behavioral issues, or some common facial features Sources: Expert list |
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| Mendeliome v0.901 | PIK3C2A |
Zornitza Stark gene: PIK3C2A was added gene: PIK3C2A was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PIK3C2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PIK3C2A were set to 31034465 Phenotypes for gene: PIK3C2A were set to Oculoskeletodental syndrome, MIM# 618440 Review for gene: PIK3C2A was set to GREEN gene: PIK3C2A was marked as current diagnostic Added comment: Three unrelated consanguineous families reported. Sources: Expert list |
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| Mendeliome v0.899 | FGF16 |
Zornitza Stark gene: FGF16 was added gene: FGF16 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: FGF16 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: FGF16 were set to Metacarpal 4-5 fusion, MIM# 309630 Review for gene: FGF16 was set to GREEN gene: FGF16 was marked as current diagnostic Added comment: Sources: Expert list |
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| Mendeliome v0.844 | KCNN3 |
Alison Yeung gene: KCNN3 was added gene: KCNN3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KCNN3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KCNN3 were set to PMID: 31155282 Phenotypes for gene: KCNN3 were set to Zimmermann-Laband syndrome 3; OMIM# 618658 Review for gene: KCNN3 was set to GREEN gene: KCNN3 was marked as current diagnostic Added comment: Three unrelated individuals reported Sources: Literature |
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| Mendeliome v0.837 | CNOT1 |
Alison Yeung gene: CNOT1 was added gene: CNOT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CNOT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CNOT1 were set to PMID: 31006513 Phenotypes for gene: CNOT1 were set to Holoprosencephaly 12, with or without pancreatic agenesis; OMIM# 618500 Review for gene: CNOT1 was set to GREEN gene: CNOT1 was marked as current diagnostic Added comment: Reported in 3 unrelated individuals Sources: Literature |
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| Mendeliome v0.830 | GPC4 | Alison Yeung reviewed gene: GPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30982611; Phenotypes: Keipert syndrome OMIM# 301026; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.822 | FAM149B1 |
Alison Yeung gene: FAM149B1 was added gene: FAM149B1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM149B1 were set to PMID: 30905400 Phenotypes for gene: FAM149B1 were set to Joubert; Ciliopathy Review for gene: FAM149B1 was set to GREEN gene: FAM149B1 was marked as current diagnostic Added comment: Four unrelated families reported Sources: Literature |
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| Mendeliome v0.811 | BICC1 | Zornitza Stark Phenotypes for gene: BICC1 were changed from to {Renal dysplasia, cystic, susceptibility to}; OMIM #601331 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.807 | BNC2 |
Zornitza Stark gene: BNC2 was added gene: BNC2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: BNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BNC2 were set to 31656805; 31051115 Phenotypes for gene: BNC2 were set to Lower urinary tract obstruction, congenital; OMIM #618612 Review for gene: BNC2 was set to GREEN gene: BNC2 was marked as current diagnostic Added comment: At least four unrelated families reported. Sources: Expert list |
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| Mendeliome v0.763 | NOTCH2NL |
Sue White gene: NOTCH2NL was added gene: NOTCH2NL was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: NOTCH2NL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NOTCH2NL were set to 31332381 Phenotypes for gene: NOTCH2NL were set to OMIM 603472 NEURONAL INTRANUCLEAR INCLUSION DISEASE; NIID Penetrance for gene: NOTCH2NL were set to unknown Mode of pathogenicity for gene: NOTCH2NL was set to Other Review for gene: NOTCH2NL was set to GREEN gene: NOTCH2NL was marked as current diagnostic Added comment: adult onset neurodegenerative condition caused by STR expansion 5' of NOTCH2NL Sources: Literature |
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| Mendeliome v0.749 | AVPR2 | Belinda Chong reviewed gene: AVPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 9127330, PubMed: 15872203; Phenotypes: Diabetes insipidus, nephrogenic 304800, Nephrogenic syndrome of inappropriate antidiuresis 300539; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.741 | EHHADH | Zornitza Stark Phenotypes for gene: EHHADH were changed from to Fanconi renotubular syndrome 3; OMIM#615605 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.738 | EHHADH | Zornitza Stark reviewed gene: EHHADH: Rating: RED; Mode of pathogenicity: None; Publications: 24401050; Phenotypes: Fanconi renotubular syndrome 3, OMIM#615605; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.709 | NUP214 |
Sue White gene: NUP214 was added gene: NUP214 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUP214 were set to 31178128 Phenotypes for gene: NUP214 were set to epileptic encephalopathy; developmental regression; microcephaly Penetrance for gene: NUP214 were set to Complete Review for gene: NUP214 was set to GREEN gene: NUP214 was marked as current diagnostic Added comment: Sources: Literature |
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| Mendeliome v0.707 | ATP2B2 |
Sue White gene: ATP2B2 was added gene: ATP2B2 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ATP2B2 were set to progressive sensorineural deafness Penetrance for gene: ATP2B2 were set to unknown Review for gene: ATP2B2 was set to GREEN gene: ATP2B2 was marked as current diagnostic Added comment: Sources: Literature |
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| Mendeliome v0.703 | AP2M1 |
Zornitza Stark gene: AP2M1 was added gene: AP2M1 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AP2M1 were set to 31104773 Phenotypes for gene: AP2M1 were set to Intellectual developmental disorder 60 with seizures, MIM# 618587 Review for gene: AP2M1 was set to GREEN Added comment: Four unrelated individuals reported, recurrent variant, NM_004068.3:c.508C>T or p.Arg170Trp. Sources: Expert list |
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| Mendeliome v0.697 | RHOA |
Sue White gene: RHOA was added gene: RHOA was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: RHOA was set to Other Publications for gene: RHOA were set to 31570889 Phenotypes for gene: RHOA were set to normal cognition; leukoencephalopathy; micro-ophthalmia; strabismus; linear hypopigmentation; malar hypoplasia; downslanting palpebral fissures; microstomia Penetrance for gene: RHOA were set to Complete Review for gene: RHOA was set to GREEN gene: RHOA was marked as current diagnostic Added comment: mosaic heterozygous missense variants cause linear hypopigmentation, brain MRI changes with normal cognition, ocular and acral changes Sources: Literature |
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| Mendeliome v0.669 | MIPEP |
Zornitza Stark gene: MIPEP was added gene: MIPEP was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: MIPEP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MIPEP were set to 27799064 Phenotypes for gene: MIPEP were set to Combined oxidative phosphorylation deficiency 31, MIM# 617228 Review for gene: MIPEP was set to GREEN Added comment: Four unrelated children reported. Sources: Expert list |
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| Mendeliome v0.660 | AIMP2 |
Zornitza Stark gene: AIMP2 was added gene: AIMP2 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: AIMP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AIMP2 were set to 29215095 Phenotypes for gene: AIMP2 were set to Leukodystrophy, hypomyelinating, 17 618006 Review for gene: AIMP2 was set to RED Added comment: Two apparently unrelated consanguineous families, however same homozygous variant identified in both. Affected individuals had early-onset multifocal seizures, spasticity, poor overall growth, and microcephaly (up to -10 SD). Brain imaging showed multiple abnormalities, including cerebral and cerebellar atrophy, thin corpus callosum, abnormal signals in the basal ganglia, and features suggesting hypo- or demyelination Sources: Expert list |
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| Mendeliome v0.658 | TMEM63A |
Zornitza Stark gene: TMEM63A was added gene: TMEM63A was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: TMEM63A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TMEM63A were set to 31587869 Phenotypes for gene: TMEM63A were set to Leukodystrophy, hypomyelinating, 19, transient infantile, MIM# 618688 Review for gene: TMEM63A was set to GREEN Added comment: Four unrelated families reported; in three individuals, the variant was de novo, and inherited from a deceased parent in the fourth. Sources: Expert list |
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| Mendeliome v0.624 | TRPM3 |
Zornitza Stark gene: TRPM3 was added gene: TRPM3 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRPM3 were set to 31278393 Phenotypes for gene: TRPM3 were set to Intellectual disability; epilepsy Review for gene: TRPM3 was set to GREEN Added comment: 8 unrelated individuals with de novo variants in this gene. Recurrent variant p.(Val837Met) identified in 7/8. Sources: Literature |
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| Mendeliome v0.529 | GRAP |
Zornitza Stark gene: GRAP was added gene: GRAP was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: GRAP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GRAP were set to 30610177 Phenotypes for gene: GRAP were set to Deafness, autosomal recessive 114, MIM# 618456 Review for gene: GRAP was set to RED Added comment: Two apparently unrelated Turkish families reported, however same homozygous missense variant, and SNP analysis indicated identity by descent. Sources: Expert list |
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| Mendeliome v0.519 | PPIP5K2 |
Zornitza Stark gene: PPIP5K2 was added gene: PPIP5K2 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: PPIP5K2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPIP5K2 were set to 29590114 Phenotypes for gene: PPIP5K2 were set to Deafness, autosomal recessive 100, MIM# 618422 Review for gene: PPIP5K2 was set to AMBER Added comment: Two apparently unrelated families with multiple affecteds segregating a homozygous missense variant; mouse model. Sources: Expert list |
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| Mendeliome v0.448 | CACNB4 | Zornitza Stark Added comment: Comment on phenotypes: One family with episodic ataxia; susceptibility locus for different types of epilepsy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.425 | FAT2 |
Zornitza Stark gene: FAT2 was added gene: FAT2 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: FAT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FAT2 were set to 29053796 Phenotypes for gene: FAT2 were set to Spinocerebellar ataxia 45, MIM#617769 Review for gene: FAT2 was set to AMBER Added comment: Segregates in one family, and identified in one apparently sporadic case. In vitro functional evidence. Sources: Expert list |
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| Mendeliome v0.417 | NDUFAF8 |
Zornitza Stark gene: NDUFAF8 was added gene: NDUFAF8 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: NDUFAF8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NDUFAF8 were set to 31866046 Phenotypes for gene: NDUFAF8 were set to Leigh syndrome Review for gene: NDUFAF8 was set to GREEN Added comment: Three unrelated individuals with bi-allelic variants in this gene; functional data. Beware recurrent deep intronic splicing variant. Sources: Literature |
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| Mendeliome v0.391 | EXOC3L2 | Zornitza Stark Phenotypes for gene: EXOC3L2 were changed from to Dandy-Walker malformation; renal dysplasia; bone marrow failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.370 | KCNT2 |
Zornitza Stark gene: KCNT2 was added gene: KCNT2 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: KCNT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNT2 were set to 29069600; 29740868 Phenotypes for gene: KCNT2 were set to Epileptic encephalopathy, early infantile, 57, MIM#617771; Developmental and epileptic encephalopathy Review for gene: KCNT2 was set to GREEN Added comment: Reviewed by E Palmer: Ambrosino et al described 2 unrelated females with de novo variants in KCNT2. The first patient had the variant p.(Arg190His) had with West syndrome followed by Lennox-Gastaut syndrome , the second patient had the variant p.(Arg190Pro) and DEE with migrating focal seizures. Both variants were absent gnomad and had supportive in silico support for pathogenicity. In an electrophisological model both KCNT2 R190P and KCNT2 R190H increased maximal current density and shifted toward more negative membrane potential values the activation curve of KCNT2 channels, consistent with gain of function effects. PMID: 29740868. Gururaj et al describe one male with de novo variant in KCNT2 p. (Phe240Leu) and early infantile epileptic encephalopathy. he variant was absent gnomad and supportive evidence of pathogenicity This variant was electrophysiologically modelled and revealed that the variant resulted in a 'change in function' demonstrating unusual altered selectivity in KNa channels.PMID: 29069600. Sources: Literature |
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| Mendeliome v0.324 | TANC2 |
Zornitza Stark gene: TANC2 was added gene: TANC2 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: TANC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TANC2 were set to 31616000 Phenotypes for gene: TANC2 were set to Intellectual disability; autism; epilepsy; dysmorphism Review for gene: TANC2 was set to GREEN Added comment: 19 families with potentially disruptive heterozygous TANC2 variants, including 16 likely gene-disrupting mutations and three intragenic microdeletions. Patients presented with autism, intellectual disability, delayed language and motor development, epilepsy, facial dysmorphism, with complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. No functional evidence of specific variants, but they show TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, and shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes. Sources: Literature |
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| Mendeliome v0.299 | PAK1 |
Zornitza Stark gene: PAK1 was added gene: PAK1 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: PAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAK1 were set to 31504246; 30290153 Phenotypes for gene: PAK1 were set to Intellectual developmental disorder with macrocephaly, seizures, and speech delay; OMIM #618158 Review for gene: PAK1 was set to GREEN Added comment: 2 unrelated individuals with de novo PAK1 mutations, with developmental delay, secondary macrocephaly, seizures, and ataxic gait. Enhanced phosphorylation of the PAK1 targets JNK and AKT shown in fibroblasts of one subject and of c-JUN in those of both subjects compared with control subjects. In fibroblasts of the 2 affected individuals, they observed a trend toward enhanced PAK1 kinase activity. By using co-immunoprecipitation and size-exclusion chromatography, they observed a significantly reduced dimerization for both PAK1 mutants compared with wild-type PAK1. 4 unrelated individuals with intellectual disability, macrocephaly and seizures, with de novo heterozygous missense variants in PAK1. Sources: Literature |
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| Mendeliome v0.281 | KDM3B |
Zornitza Stark gene: KDM3B was added gene: KDM3B was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: KDM3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KDM3B were set to 30929739 Phenotypes for gene: KDM3B were set to Intellectual disability; dysmorphic features; short stature Review for gene: KDM3B was set to GREEN Added comment: 14 unrelated individuals and 3 affected parents with varying degrees of ID, DD, short stature, dysmorphism, and de novo or inherited pathogenic variants in KDM3B. No functional studies. Sources: Literature |
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| Mendeliome v0.279 | GRIA2 |
Zornitza Stark gene: GRIA2 was added gene: GRIA2 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: GRIA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GRIA2 were set to 31300657 Phenotypes for gene: GRIA2 were set to Intellectual disability; autism; Rett-like features; epileptic encephalopathy Review for gene: GRIA2 was set to GREEN Added comment: 28 unrelated patients with ID, ASD, Rett-like features, seizures/EE, and de novo heterozygous GRIA2 mutations. In functional expression studies, mutations led to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Sources: Literature |
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| Mendeliome v0.273 | GABRA5 |
Zornitza Stark gene: GABRA5 was added gene: GABRA5 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: GABRA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GABRA5 were set to 31056671; 29961870 Phenotypes for gene: GABRA5 were set to Epileptic encephalopathy, early infantile, 79; OMIM #618559 Review for gene: GABRA5 was set to GREEN Added comment: 3 unrelated patients with de novo heterozygous missense mutations in GABRA5 gene. In vitro functional expression studies in HEK293 cells showed that the mutant subunit was expressed at the surface and incorporated into the channel, but the mutant channel was 10 times more sensitive to GABA compared to wildtype. This increased sensitization resulted in increased receptor desensitization to GABA, with a reduced maximal GABA-evoked current and impaired capacity to pass GABAergic chloride current. Sources: Literature |
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| Mendeliome v0.256 | DDX6 |
Zornitza Stark gene: DDX6 was added gene: DDX6 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: DDX6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DDX6 were set to 31422817 Phenotypes for gene: DDX6 were set to Intellectual developmental disorder with impaired language and dysmorphic facies, MIM#618653 Review for gene: DDX6 was set to GREEN Added comment: Five unrelated individuals reported with 5 different de novo heterozygous missense mutations in exon 11 of the DDX6 gene. All variants occurred at conserved residues in either the QxxR or V motifs within the second RecA-2 domain of the helicase core; this region is involved in RNA and/or ATP binding, suggesting functional consequences. Sources: Literature |
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| Mendeliome v0.251 | CSDE1 |
Zornitza Stark gene: CSDE1 was added gene: CSDE1 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: CSDE1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CSDE1 were set to 31579823 Phenotypes for gene: CSDE1 were set to Autism; intellectual disability; seizures; macrocephaly Review for gene: CSDE1 was set to GREEN Added comment: 18 families reported with high impact (stoppage/frameshift) variants in this gene. Eight de novo, eight inherited, two with undetermined inheritance. Functional data. Parents who had the variants were also affected, though generally more mildly. Sources: Literature |
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| Mendeliome v0.250 | CNTN6 |
Zornitza Stark gene: CNTN6 was added gene: CNTN6 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: CNTN6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CNTN6 were set to 30836150; 28641109; 29983269 Phenotypes for gene: CNTN6 were set to Intellectual disability; autism; Tourette syndrome; schizophrenia Review for gene: CNTN6 was set to RED Added comment: Conflicting evidence based on CNV data, no SNVs identified. Sources: Literature |
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| Mendeliome v0.233 | BRSK2 |
Zornitza Stark gene: BRSK2 was added gene: BRSK2 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: BRSK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BRSK2 were set to 30879638 Phenotypes for gene: BRSK2 were set to Intellectual disability; autism Review for gene: BRSK2 was set to GREEN Added comment: Nine unrelated individuals with heterozygous variants in this gene; six confirmed de novo (parents available). Sources: Literature |
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| Mendeliome v0.0 | REN |
Zornitza Stark gene: REN was added gene: REN was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: REN was set to Unknown |
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