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Mendeliome v0.8600 AP1G1 Danielle Ariti gene: AP1G1 was added
gene: AP1G1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Mode of pathogenicity for gene: AP1G1 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: AP1G1 was set to GREEN
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site.

Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality.

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature
Mendeliome v0.8600 SEMA3D Zornitza Stark Marked gene: SEMA3D as ready
Mendeliome v0.8598 SPTBN1 Belinda Chong changed review comment from: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature; to: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures (9/29); behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Mendeliome v0.8598 SPTBN4 Zornitza Stark Marked gene: SPTBN4 as ready
Mendeliome v0.8594 HMGB1 Zornitza Stark Marked gene: HMGB1 as ready
Mendeliome v0.8593 SPTBN1 Zornitza Stark Marked gene: SPTBN1 as ready
Mendeliome v0.8592 EDEM3 Seb Lunke Marked gene: EDEM3 as ready
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
Mendeliome v0.8587 GCNA Zornitza Stark Marked gene: GCNA as ready
Mendeliome v0.8586 TP73 Ee Ming Wong changed review comment from: - Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants)
- Epithelial cells from TP73 variant carriers showed reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls; to: - Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants)
- In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls
Mendeliome v0.8586 SPTBN1 Belinda Chong gene: SPTBN1 was added
gene: SPTBN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to PMID: 34211179; PMID: 33847457
Phenotypes for gene: SPTBN1 were set to Neurodevelopmental Syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
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
Mendeliome v0.8586 GCNA Ain Roesley gene: GCNA was added
gene: GCNA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GCNA was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GCNA were set to 33963445
Phenotypes for gene: GCNA were set to primary spermatogenic failure
Penetrance for gene: GCNA were set to unknown
Review for gene: GCNA was set to GREEN
Added comment: 7x probands all missense except 1 fs. Variants had <0.0005 MAF in gnomad v2 male cohort and absent in 5784 Dutch control cohort
no functional studies were done except for histology of Ser659Trp, revealing a Sertoli-cell only
Sources: Literature
Mendeliome v0.8586 ANK2 Zornitza Stark Marked gene: ANK2 as ready
Mendeliome v0.8585 ANK2 Zornitza Stark gene: ANK2 was added
gene: ANK2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 31983240; 22542183; 25363768; 27479843; 28554332; 30564305; 30755392; 31981491; 33004838; 33057194
Phenotypes for gene: ANK2 were set to Long QT syndrome 4, MIM# 600919; Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: ANK2 was set to GREEN
Added comment: Link with cardiac abnormalities such as LongQT is DISPUTED. More than 10 unrelated individuals reported with neurodevelopmental phenotype, comprising autism/ID and de novo truncating variants, in addition to many other individuals as part of large NDD cohorts. This association has been assessed as DEFINITIVE by ClinGen.
Sources: Expert Review
Mendeliome v0.8584 PRDX3 Zornitza Stark Marked gene: PRDX3 as ready
Mendeliome v0.8583 PRDX3 Hazel Phillimore changed review comment from: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote of a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRXD3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature; to: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote with a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRDX3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mendeliome v0.8583 PRDX3 Hazel Phillimore gene: PRDX3 was added
gene: PRDX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDX3 were set to PMID: 33889951
Phenotypes for gene: PRDX3 were set to cerebellar ataxia (early onset, mild to moderate, progressive)
Penetrance for gene: PRDX3 were set to unknown
Review for gene: PRDX3 was set to GREEN
Added comment: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote of a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRXD3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mendeliome v0.8583 GSC Zornitza Stark Marked gene: GSC as ready
Mendeliome v0.8583 GSC Zornitza Stark Phenotypes for gene: GSC were changed from to Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471
Mendeliome v0.8580 GSC Zornitza Stark reviewed gene: GSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 24290375; Phenotypes: Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8580 GNAI3 Zornitza Stark Marked gene: GNAI3 as ready
Mendeliome v0.8580 GNAI3 Zornitza Stark Phenotypes for gene: GNAI3 were changed from to Auriculocondylar syndrome 1, OMIM #602483
Mendeliome v0.8577 GNAI3 Zornitza Stark reviewed gene: GNAI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091; Phenotypes: Auriculocondylar syndrome 1, OMIM #602483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8577 EIF4A3 Zornitza Stark Marked gene: EIF4A3 as ready
Mendeliome v0.8574 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Neurodevelopmental disorder with gut dysmotility to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Complex neurocristinopathy
Mendeliome v0.8573 ERBB3 Zornitza Stark changed review comment from: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and neurodevelopmental disorder. Note variants in this gene have also recently been linked to Hirschsprung's disease.; to: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and other features of neurocristinopathy including short-segment HSCR, progressive axonal peripheral neuropathy, dysautonomia, hypopigmentation, deafness. Note variants in this gene have also recently been linked to Hirschsprung's disease.
Mendeliome v0.8573 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Neurodevelopmental disorder with gut dysmotility
Mendeliome v0.8571 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Added comment: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and neurodevelopmental disorder. Note variants in this gene have also recently been linked to Hirschsprung's disease.; Changed rating: GREEN; Changed publications: 17701904, 31752936, 33497358; Changed phenotypes: Lethal congenital contractural syndrome 2, MIM# 607598, Neurodevelopmental disorder with gut dysmotility
Mendeliome v0.8571 PDCL3 Zornitza Stark Marked gene: PDCL3 as ready
Mendeliome v0.8570 PDCL3 Zornitza Stark gene: PDCL3 was added
gene: PDCL3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PDCL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCL3 were set to 32621347
Phenotypes for gene: PDCL3 were set to Megacystis-microcolon
Review for gene: PDCL3 was set to AMBER
Added comment: Single publication (PMID 32621347): one family with two affected fetuses - one with megacystis and microcolon, and the other with megacystisis and bilateral diaphragmatic hernia (prune-belly phenotype). Compound het LOF variants in PDCL3 (one frameshift and one missense). Complete absence of PDLC3 expression demonstrated in one of the affected fetuses. No homozygous LOF PDCL3 variants in gnomAD. PCDL3 negatively modulates actin folding and is strongly expressed in smooth muscle of bladder and colon.
Sources: Expert Review
Mendeliome v0.8569 SGO1 Zornitza Stark Marked gene: SGO1 as ready
Mendeliome v0.8565 TYMP Zornitza Stark Marked gene: TYMP as ready
Mendeliome v0.8565 TYMP Zornitza Stark Phenotypes for gene: TYMP were changed from to Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041; MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy
Mendeliome v0.8562 TYMP Zornitza Stark reviewed gene: TYMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9924029, 14757860; Phenotypes: Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041, MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8562 ZNF687 Zornitza Stark Marked gene: ZNF687 as ready
Mendeliome v0.8559 GRHPR Zornitza Stark Marked gene: GRHPR as ready
Mendeliome v0.8559 GRHPR Zornitza Stark Phenotypes for gene: GRHPR were changed from to Hyperoxaluria, primary, type II, MIM# 260000; MONDO:0009824
Mendeliome v0.8556 GRHPR Zornitza Stark reviewed gene: GRHPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 10484776, 11030416, 24116921; Phenotypes: Hyperoxaluria, primary, type II, MIM# 260000, MONDO:0009824; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8556 AGXT Zornitza Stark Marked gene: AGXT as ready
Mendeliome v0.8556 AGXT Zornitza Stark Phenotypes for gene: AGXT were changed from to Hyperoxaluria, primary, type 1, MIM# 259900; MONDO:0009823
Mendeliome v0.8553 AGXT Zornitza Stark reviewed gene: AGXT: Rating: GREEN; Mode of pathogenicity: None; Publications: 2039493, 19479957; Phenotypes: Hyperoxaluria, primary, type 1, MIM# 259900, MONDO:0009823; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8553 HOGA1 Zornitza Stark Marked gene: HOGA1 as ready
Mendeliome v0.8553 HOGA1 Zornitza Stark Phenotypes for gene: HOGA1 were changed from to Hyperoxaluria, primary, type III MIM#613616
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 v0.8550 VPS45 Zornitza Stark Marked gene: VPS45 as ready
Mendeliome v0.8547 LAMTOR2 Zornitza Stark Marked gene: LAMTOR2 as ready
Mendeliome v0.8543 IKZF3 Zornitza Stark Marked gene: IKZF3 as ready
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
Mendeliome v0.8541 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Mendeliome v0.8541 HSD17B4 Zornitza Stark Phenotypes for gene: HSD17B4 were changed from to D-bifunctional protein deficiency, AR (MIM#261515); Perrault syndrome 1, AR (MIM#233400)
Mendeliome v0.8538 HSD17B4 Zornitza Stark reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8538 HSD17B4 Michelle Torres reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27790638; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8538 LCK Zornitza Stark Marked gene: LCK as ready
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 Marked gene: DOCK8 as ready
Mendeliome v0.8530 DOCK2 Zornitza Stark Marked gene: DOCK2 as ready
Mendeliome v0.8530 DOCK2 Zornitza Stark Phenotypes for gene: DOCK2 were changed from to Immunodeficiency 40 MIM# 616433; T/B-cell lymphopaenia; early-onset invasive herpes/viral/bacterial Infections; function defects in T/B/NK cells; immunodeficiency; defective IFN-mediated immunity; elevated IgM; normal IgG/IgA levels
Mendeliome v0.8527 DOCK2 Zornitza Stark reviewed gene: DOCK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26083206, 29204803, 33928462, 30826364, 30838481, 11518968; Phenotypes: Immunodeficiency 40 MIM# 616433, T/B-cell lymphopaenia, early-onset invasive herpes/viral/bacterial Infections, function defects in T/B/NK cells, immunodeficiency, defective IFN-mediated immunity, elevated IgM, normal IgG/IgA levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8527 DNMT3B Zornitza Stark Marked gene: DNMT3B as ready
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 v0.8524 TMPO Bryony Thompson Marked gene: TMPO as ready
Mendeliome v0.8523 TMPO Bryony Thompson reviewed gene: TMPO: Rating: RED; Mode of pathogenicity: None; Publications: 16247757; Phenotypes: Hypertrophic cardiomyopathy, dilated cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8523 SYNCRIP Zornitza Stark Marked gene: SYNCRIP as ready
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
Mendeliome v0.8521 MSN Zornitza Stark Marked gene: MSN as ready
Mendeliome v0.8518 JAGN1 Zornitza Stark Marked gene: JAGN1 as ready
Mendeliome v0.8515 ITGB2 Zornitza Stark Marked gene: ITGB2 as ready
Mendeliome v0.8512 CAMK4 Zornitza Stark Marked gene: CAMK4 as ready
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
Mendeliome v0.8510 FERMT3 Zornitza Stark Marked gene: FERMT3 as ready
Mendeliome v0.8506 CYBB Zornitza Stark Marked gene: CYBB as ready
Mendeliome v0.8503 CSF3R Zornitza Stark Marked gene: CSF3R as ready
Mendeliome v0.8497 DPYSL5 Zornitza Stark Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, MIM# 619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Mendeliome v0.8496 RRP7A Zornitza Stark Phenotypes for gene: RRP7A were changed from Microcephaly to Microcephaly 28, primary, autosomal recessive MIM#619453
Mendeliome v0.8495 RRP7A Zornitza Stark edited their review of gene: RRP7A: Changed phenotypes: Microcephaly 28, primary, autosomal recessive MIM#619453
Mendeliome v0.8495 CEBPE Zornitza Stark Marked gene: CEBPE as ready
Mendeliome v0.8492 NCF1 Zornitza Stark Marked gene: NCF1 as ready
Mendeliome v0.8487 COL25A1 Zornitza Stark edited their review of gene: COL25A1: Added comment: PMID: 2643702 - Patient: 273182 reported in DECIPHER, chet COL25A1 missense variants (listed as Likely Pathogenic). Phenotype includes Duane anomaly of the eye.

PMID: 31875546 - Mouse models, including Col25a1 KO and muscle-specific KO mice showed a significant reduction in the number of motor neurons in the cranial nerve nuclei, including the oculomotor, trochlear, trigeminal, and facial motor nuclei. Abnormalities in motor innervation of muscles of the head, such as the extraocular and masseter muscles, were also observed

PMID: 31875546 - Functional studies in human cell lines showed that the reported COL25A1 variants (G382R and G497X) impaired the interaction of COL25A1 with receptor protein tyrosine phosphatases, thereby reducing the ability to attract motor axons.; Changed rating: GREEN; Changed publications: 25500261, 26486031, 31875546, 26437029
Mendeliome v0.8485 STX3 Zornitza Stark changed review comment from: At least 5 unrelated families reported.; to: At least 5 unrelated families reported.

STX3 isoform B (STX3B) predominates in the retina, so mutations in the STX3 gene that affect both isoform A (STX3A) and STX3B cause both retinal and gastrointestinal disease (RDMVID), whereas mutations in STX3 affecting only the STX3A transcript cause only diarrhoea.
Mendeliome v0.8484 C1QA Zornitza Stark Marked gene: C1QA as ready
Mendeliome v0.8481 CIITA Zornitza Stark Marked gene: CIITA as ready
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 Marked gene: CD40LG as ready
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 Marked gene: CD3G as ready
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 v0.8472 WDR26 Zornitza Stark Marked gene: WDR26 as ready
Mendeliome v0.8470 WDR26 Zornitza Stark Phenotypes for gene: WDR26 were changed from to Skraban-Deardorff syndrome, MIM#617616
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 v0.8467 ABCD4 Zornitza Stark Marked gene: ABCD4 as ready
Mendeliome v0.8464 ABCD1 Zornitza Stark Marked gene: ABCD1 as ready
Mendeliome v0.8460 RAD21 Zornitza Stark reviewed gene: RAD21: Rating: GREEN; Mode of pathogenicity: None; Publications: 14638363, 32193685, 25575569; Phenotypes: Mungan syndrome, MIM# 611376: Barrett esophagus, megaduodenum, cardiac abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8460 CCBE1 Zornitza Stark Marked gene: CCBE1 as ready
Mendeliome v0.8457 CD27 Zornitza Stark Marked gene: CD27 as ready
Mendeliome v0.8454 ZNF148 Zornitza Stark Marked gene: ZNF148 as ready
Mendeliome v0.8453 RAC3 Zornitza Stark Marked gene: RAC3 as ready
Mendeliome v0.8452 PCLO Zornitza Stark Phenotypes for gene: PCLO were changed from to Pontocerebellar hypoplasia, type 3, MIM#608027
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
Mendeliome v0.8449 RAC3 Natalie Tan gene: RAC3 was added
gene: RAC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAC3 were set to PMID: 30293988; 29276006
Phenotypes for gene: RAC3 were set to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, MIM#618577
Review for gene: RAC3 was set to GREEN
Added comment: Multiple unrelated individuals with heterozygous missense variants and a concordant phenotype (severe intellectual disability with brain malformations). No functional studies to date.
Sources: Literature
Mendeliome v0.8449 CHRNA4 Zornitza Stark Marked gene: CHRNA4 as ready
Mendeliome v0.8445 SYP Elena Savva reviewed gene: SYP: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 23966691, 19377476; Phenotypes: Mental retardation, X-linked 96 MIM#300802; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8445 ZIC3 Zornitza Stark Marked gene: ZIC3 as ready
Mendeliome v0.8445 ZIC3 Zornitza Stark Phenotypes for gene: ZIC3 were changed from to Congenital heart defects, nonsyndromic, 1, X-linked (MIM#306955); Heterotaxy, visceral, 1, X-linked (MIM#306955); VACTERL association, X-linked, MIM# 314390
Mendeliome v0.8442 ZIC3 Zornitza Stark edited their review of gene: ZIC3: Changed phenotypes: Congenital heart defects, nonsyndromic, 1, X-linked (MIM#306955), Heterotaxy, visceral, 1, X-linked (MIM#306955), VACTERL association, X-linked, MIM# 314390
Mendeliome v0.8442 VPS13B Zornitza Stark Marked gene: VPS13B as ready
Mendeliome v0.8440 TULP1 Zornitza Stark Marked gene: TULP1 as ready
Mendeliome v0.8437 TOPORS Zornitza Stark Marked gene: TOPORS as ready
Mendeliome v0.8434 SUFU Zornitza Stark Marked gene: SUFU as ready
Mendeliome v0.8431 SUFU Zornitza Stark changed review comment from: Two unrelated families described with what are postulated to be hypomorphic bi-allelic variants in this gene and Joubert syndrome. Note gene also causes dominant Basal Cell Nevus Syndrome.; to: Two unrelated families described with what are postulated to be hypomorphic bi-allelic variants in this gene and Joubert syndrome.
Mendeliome v0.8431 SUFU Zornitza Stark edited their review of gene: SUFU: Added comment: Mono-allelic variants are also associated with Basal cell nevus syndrome/predisposition to medulloblastoma.; Changed rating: GREEN; Changed publications: 28965847, 19533801, 31485359; Changed phenotypes: Joubert syndrome 32, MIM#617757, Basal cell nevus syndrome, MIM# 109400; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8431 SCNN1G Zornitza Stark Marked gene: SCNN1G as ready
Mendeliome v0.8428 SCNN1G Zornitza Stark edited their review of gene: SCNN1G: Added comment: Variants resulting in constitutive activation of epithelial sodium channel activity have been demonstrated in the beta and gamma subunits as the cause of the autosomal dominant form of hypertension, Liddle syndrome, which is characterized by volume expansion, hypokalemia, and alkalosis.

Variants causing loss of epithelial sodium channel activity cause the converse phenotype of volume depletion, hyperkalaemia and acidosis characteristic of patients with pseudohypoaldosteronism type I.

Well established gene-disease associations.; Changed rating: GREEN; Changed phenotypes: Liddle syndrome 2, MIM# 618114, Pseudohypoaldosteronism, type I, MIM# 264350; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8428 SCLT1 Zornitza Stark Marked gene: SCLT1 as ready
Mendeliome v0.8428 SCLT1 Zornitza Stark Phenotypes for gene: SCLT1 were changed from to Orofaciodigital syndrome type IX; Senior-Loken syndrome; Bardet-Biedl syndrome
Mendeliome v0.8425 RPGR Zornitza Stark Marked gene: RPGR as ready
Mendeliome v0.8422 PRKCSH Zornitza Stark Marked gene: PRKCSH as ready
Mendeliome v0.8418 POC1B Zornitza Stark Marked gene: POC1B as ready
Mendeliome v0.8415 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Mendeliome v0.8412 PKHD1 Zornitza Stark Marked gene: PKHD1 as ready
Mendeliome v0.8410 MUC1 Zornitza Stark Marked gene: MUC1 as ready
Mendeliome v0.8410 MUC1 Zornitza Stark Phenotypes for gene: MUC1 were changed from to Medullary cystic kidney disease 1 (MIM#174000)
Mendeliome v0.8407 MUC1 Zornitza Stark edited their review of gene: MUC1: Added comment: Well established gene-disease association, but note main variant type not readily tractable by NGS.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed publications: Medullary cystic kidney disease 1 (MIM#174000); Changed phenotypes: Medullary cystic kidney disease 1 (MIM#174000); Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8407 KIF7 Zornitza Stark Marked gene: KIF7 as ready
Mendeliome v0.8404 KIAA0753 Zornitza Stark Marked gene: KIAA0753 as ready
Mendeliome v0.8401 KIAA0586 Zornitza Stark Marked gene: KIAA0586 as ready
Mendeliome v0.8398 IFT52 Zornitza Stark Marked gene: IFT52 as ready
Mendeliome v0.8395 IFT27 Zornitza Stark Marked gene: IFT27 as ready
Mendeliome v0.8395 IFT27 Zornitza Stark Phenotypes for gene: IFT27 were changed from to Bardet-Biedl syndrome 19, MIM#615996
Mendeliome v0.8392 POLG2 Zornitza Stark Marked gene: POLG2 as ready
Mendeliome v0.8389 PCDHGC4 Zornitza Stark Marked gene: PCDHGC4 as ready
Mendeliome v0.8388 PCDHGC4 Zornitza Stark gene: PCDHGC4 was added
gene: PCDHGC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to Intellectual disability; Seizures
Review for gene: PCDHGC4 was set to GREEN
Added comment: Eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty in eight families and seizures in four families. Four of the variants were LoF, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Mendeliome v0.8387 ATP6V0A4 Zornitza Stark Marked gene: ATP6V0A4 as ready
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 v0.8384 ICK Zornitza Stark Marked gene: ICK as ready
Mendeliome v0.8381 HNF1B Zornitza Stark Marked gene: HNF1B as ready
Mendeliome v0.8379 GDF1 Zornitza Stark Marked gene: GDF1 as ready
Mendeliome v0.8379 GDF1 Zornitza Stark Phenotypes for gene: GDF1 were changed from to Congenital heart defects, multiple types, 6 613854; Right atrial isomerism (Ivemark) 208530
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 v0.8376 EVC2 Zornitza Stark Marked gene: EVC2 as ready
Mendeliome v0.8373 EVC Zornitza Stark Marked gene: EVC as ready
Mendeliome v0.8370 DCDC2 Zornitza Stark Marked gene: DCDC2 as ready
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 v0.8367 CRELD1 Zornitza Stark Marked gene: CRELD1 as ready
Mendeliome v0.8367 CRELD1 Zornitza Stark Phenotypes for gene: CRELD1 were changed from to Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217
Mendeliome v0.8364 CRELD1 Zornitza Stark reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740159; Phenotypes: Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8364 CRB2 Zornitza Stark Marked gene: CRB2 as ready
Mendeliome v0.8361 CEP55 Zornitza Stark Marked gene: CEP55 as ready
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 v0.8358 CENPF Zornitza Stark Marked gene: CENPF as ready
Mendeliome v0.8355 C8orf37 Zornitza Stark Marked gene: C8orf37 as ready
Mendeliome v0.8355 C8orf37 Zornitza Stark Phenotypes for gene: C8orf37 were changed from to Bardet-Biedl syndrome 21, MIM#617406; Retinitis pigmentosa 64, MIM#614500
Mendeliome v0.8352 C2CD3 Zornitza Stark Marked gene: C2CD3 as ready
Mendeliome v0.8348 CHRM3 Zornitza Stark Marked gene: CHRM3 as ready
Mendeliome v0.8345 ARHGAP42 Zornitza Stark Marked gene: ARHGAP42 as ready
Mendeliome v0.8345 ARHGAP42 Zornitza Stark Gene: arhgap42 has been classified as Red List (Low Evidence).
Mendeliome v0.8345 ARHGAP42 Zornitza Stark gene: ARHGAP42 was added
gene: ARHGAP42 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGAP42 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARHGAP42 were set to 34232960
Phenotypes for gene: ARHGAP42 were set to Interstitial lung disease; systemic hypertension; immunological abnormalities
Review for gene: ARHGAP42 was set to RED
Added comment: Single individual reported with homozygous LoF variant, chILD disorder, systemic hypertension, and immunological findings.
Sources: Literature
Mendeliome v0.8344 KIAA0556 Zornitza Stark Marked gene: KIAA0556 as ready
Mendeliome v0.8339 LINGO4 Zornitza Stark Marked gene: LINGO4 as ready
Mendeliome v0.8338 ARFGEF3 Zornitza Stark Marked gene: ARFGEF3 as ready
Mendeliome v0.8338 ARFGEF3 Zornitza Stark Gene: arfgef3 has been classified as Green List (High Evidence).
Mendeliome v0.8338 ARFGEF3 Zornitza Stark Classified gene: ARFGEF3 as Green List (high evidence)
Mendeliome v0.8338 ARFGEF3 Zornitza Stark Gene: arfgef3 has been classified as Green List (High Evidence).
Mendeliome v0.8337 IMPDH2 Zornitza Stark Marked gene: IMPDH2 as ready
Mendeliome v0.8335 LINGO4 Laura Raiti gene: LINGO4 was added
gene: LINGO4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LINGO4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LINGO4 were set to PMID: 33098801
Phenotypes for gene: LINGO4 were set to Developmental Delay, Intellectual disability, speech disorder
Review for gene: LINGO4 was set to GREEN
Added comment: 3 unrelated individuals
1 x individual compound heterozygous for 2x missense variants:
c.679C>A; c.1262G>A p.Leu227Met; p.Arg421Gln comp het. Phenotype: infancy-onset
generalized dystonia; DD/hypo, ID, speech disorder (isolated plus non-MD symptoms) NDD

1 x individual homozygous for missense variant: c.679C>A p.Leu227Met Phenotype: DD/hypo, ID, speech disorder

1 x individual homozygous for missense variant: c.1673G>A p.Ser558Asn Phenotype: DD/hypo, ID, speech disorder
Sources: Literature
Mendeliome v0.8335 ARFGEF3 Laura Raiti gene: ARFGEF3 was added
gene: ARFGEF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARFGEF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF3 were set to PMID: 33098801
Phenotypes for gene: ARFGEF3 were set to Dystonia
Review for gene: ARFGEF3 was set to GREEN
Added comment: 3 x unrelated individuals
1 x de novo missense variant: c.6212T>C p.Met2071Thr, phenotype: infancy-onset generalized dystonia (isolated)
1x stop-gain variant c.1773T>G p.Tyr591* (inherited from mosaic mother), phenotype: infancy-onset generalized dystonia (isolated)
1 x de novo missense variant (Gene Matcher) c.250A>C p.Met84Leu childhood-onset generalized dystonia (isolated)
Sources: Literature
Mendeliome v0.8335 IMPDH2 Laura Raiti gene: IMPDH2 was added
gene: IMPDH2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IMPDH2 were set to PMID: 33098801
Phenotypes for gene: IMPDH2 were set to Dystonia
Review for gene: IMPDH2 was set to GREEN
Added comment: 6 unrelated individuals
1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein.
IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition.
1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified:
3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg)
1 x deletion: c.478_480delTCC (p.Ser160del)
The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair.
The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1.

The variant carriers shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing. Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2.
Sources: Literature
Mendeliome v0.8334 DYNC2H1 Zornitza Stark changed review comment from: More than 50 unrelated families reported.; to: More than 50 unrelated families reported with predominantly skeletal dysplasia.

Association with RP: - Five affected probands with homozygous and compound heterozygous missense and PTC variants - Associated with the NM_001080463.1 transcript (predominant isoform in retina from retinal organoid studies). PMID 32753734
Mendeliome v0.8334 STK36 Zornitza Stark Phenotypes for gene: STK36 were changed from Primary ciliary dyskinesia to Ciliary dyskinesia, primary, 46, MIM# 619436
Mendeliome v0.8333 STK36 Zornitza Stark edited their review of gene: STK36: Changed phenotypes: Ciliary dyskinesia, primary, 46, MIM# 619436
Mendeliome v0.8333 KIF20A Zornitza Stark Marked gene: KIF20A as ready
Mendeliome v0.8333 KIF20A Zornitza Stark gene: KIF20A was added
gene: KIF20A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF20A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF20A were set to 29357359
Phenotypes for gene: KIF20A were set to Cardiomyopathy, familial restrictive, 6, MIM# 619433
Review for gene: KIF20A was set to GREEN
Added comment: Single family reported, two affected sibs, perinatal lethal cardiomyopathy, compound het variants in this gene.
Sources: Literature
Mendeliome v0.8331 B2M Zornitza Stark Marked gene: B2M as ready
Mendeliome v0.8331 B2M Zornitza Stark Phenotypes for gene: B2M were changed from to Immunodeficiency 43 MIM# 241600; Sinopulmonary infections; Purple-red skin lesions; Decreased serum IgG; Decreased B cells; Absent β2m associated proteins MHC-I, CD1a, CD1b, and CD1c; MONDO:0009434; Amyloidosis, familial visceral, MIM# 105200
Mendeliome v0.8328 B2M Zornitza Stark reviewed gene: B2M: Rating: GREEN; Mode of pathogenicity: None; Publications: 4186801, 16549777, 25702838, 11118151, 6165007, 22693999; Phenotypes: Immunodeficiency 43 MIM# 241600, Sinopulmonary infections, Purple-red skin lesions, Decreased serum IgG, Decreased B cells, Absent β2m associated proteins MHC-I, CD1a, CD1b, and CD1c, MONDO:0009434, Amyloidosis, familial visceral, MIM# 105200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8328 AK2 Zornitza Stark Phenotypes for gene: AK2 were changed from Reticular dysgenesis, MIM# 267500 to Reticular dysgenesis, MIM# 267500; MONDO:0009973
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.
Mendeliome v0.8326 AK2 Zornitza Stark edited their review of gene: AK2: Changed phenotypes: Reticular dysgenesis, MIM# 267500, MONDO:0009973
Mendeliome v0.8326 TMEM126A Zornitza Stark Marked gene: TMEM126A as ready
Mendeliome v0.8323 MYC Zornitza Stark Marked gene: MYC as ready
Mendeliome v0.8318 ATG7 Zornitza Stark changed review comment from: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature; to: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Mendeliome v0.8318 ATG7 Zornitza Stark changed review comment from: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.
Sources: Literature; to: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Mendeliome v0.8318 ATG7 Zornitza Stark Marked gene: ATG7 as ready
Mendeliome v0.8317 ATG7 Zornitza Stark gene: ATG7 was added
gene: ATG7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to 34161705
Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, SCAR31, MIM#619422
Review for gene: ATG7 was set to GREEN
Added comment: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.
Sources: Literature
Mendeliome v0.8316 ADA Zornitza Stark Marked gene: ADA as ready
Mendeliome v0.8313 C2orf69 Zornitza Stark Marked gene: C2orf69 as ready
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
Mendeliome v0.8310 NYNRIN Zornitza Stark Marked gene: NYNRIN as ready
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
Mendeliome v0.8306 YARS Zornitza Stark Phenotypes for gene: YARS were changed from Charcot-Marie-Tooth disease, dominant intermediate C 608323; Bi-allelic variants: ID, deafness, nystagmus to Charcot-Marie-Tooth disease, dominant intermediate C, MIM# 608323; MONDO:0012012; Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, MIM# 619418
Mendeliome v0.8305 YARS Zornitza Stark edited their review of gene: YARS: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8305 YARS Zornitza Stark edited their review of gene: YARS: Changed phenotypes: Charcot-Marie-Tooth disease, dominant intermediate C, MIM# 608323, MONDO:0012012, Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, MIM# 619418
Mendeliome v0.8304 ZC3H14 Zornitza Stark edited their review of gene: ZC3H14: Added comment: PMID: 33710394
1 Finnish family with a hom splice variant, severe ID. Classed a VUS. No functional evidence; Changed publications: 21734151, 28666327, 33710394
Mendeliome v0.8304 ZC3H14 Zornitza Stark edited their review of gene: ZC3H14: Added comment: Two families and a mouse model.; Changed phenotypes: Mental retardation, autosomal recessive 56, OMIM# 617125
Mendeliome v0.8302 ATP1A2 Zornitza Stark Marked gene: ATP1A2 as ready
Mendeliome v0.8302 RNF2 Zornitza Stark Marked gene: RNF2 as ready
Mendeliome v0.8301 RING1 Zornitza Stark Marked gene: RING1 as ready
Mendeliome v0.8300 IRX5 Zornitza Stark Marked gene: IRX5 as ready
Mendeliome v0.8296 IRX6 Zornitza Stark Marked gene: IRX6 as ready
Mendeliome v0.8295 RAB3GAP1 Zornitza Stark Phenotypes for gene: RAB3GAP1 were changed from Warburg micro syndrome 1, MIM# 600118 to Warburg micro syndrome 1, MIM# 600118; Martsolf syndrome 2, MIM# 619420
Mendeliome v0.8293 RAB3GAP1 Zornitza Stark changed review comment from: Rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. Multiple families reported.; to: Warburg micro: Rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe ID, spastic diplegia, and hypogonadism. Multiple families reported.

Martsolf syndrome is characterised by cataracts, mild to severe ID, dysmorphic features. Two families reported.
Mendeliome v0.8293 RAB3GAP1 Zornitza Stark edited their review of gene: RAB3GAP1: Changed publications: 15696165, 20512159, 23420520, 23420520, 30730599; Changed phenotypes: Warburg micro syndrome 1, MIM# 600118, Martsolf syndrome 2, MIM# 619420
Mendeliome v0.8293 CXCR2 Zornitza Stark Marked gene: CXCR2 as ready
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
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
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
Mendeliome v0.8292 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition.

Cone dystrophy
-------------------
PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.; to: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of function/gene
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
Mendeliome v0.8292 IRX6 Eleanor Williams changed review comment from: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature; to: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature
Mendeliome v0.8292 SLCO2A1 Zornitza Stark Marked gene: SLCO2A1 as ready
Mendeliome v0.8290 HID1 Zornitza Stark Marked gene: HID1 as ready
Mendeliome v0.8289 HID1 Zornitza Stark gene: HID1 was added
gene: HID1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Review for gene: HID1 was set to GREEN
Added comment: 7 individuals from 6 unrelated families reported. Clinical features included: hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy
Sources: Literature
Mendeliome v0.8288 KIF1B Zornitza Stark Marked gene: KIF1B as ready
Mendeliome v0.8288 KIF1B Zornitza Stark Phenotypes for gene: KIF1B were changed from to Charcot-Marie-Tooth disease, type 2A1 MIM#118210; Hypotonia, coloboma, hypoplasia of the corpus callosum, severe neurodevelopmental delay
Mendeliome v0.8285 NUF2 Zornitza Stark Marked gene: NUF2 as ready
Mendeliome v0.8284 ERGIC3 Seb Lunke Marked gene: ERGIC3 as ready
Mendeliome v0.8283 FYCO1 Zornitza Stark Marked gene: FYCO1 as ready
Mendeliome v0.8283 FYCO1 Zornitza Stark Phenotypes for gene: FYCO1 were changed from to Cataract 18, MIM#610019
Mendeliome v0.8280 FYCO1 Zornitza Stark reviewed gene: FYCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32355443; Phenotypes: Cataract 18, MIM#610019; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8278 JPH3 Seb Lunke Marked gene: JPH3 as ready
Mendeliome v0.8277 MYT1 Zornitza Stark changed review comment from: Five unrelated individuals reported with variants in this gene and OAV spectrum.; to: Five unrelated individuals reported with variants in this gene and OAV spectrum.

Single individual reported with missense variant as part of an ID cohort, limited evidence for disease association.
Mendeliome v0.8277 JPH3 Seb Lunke Added comment: Comment on list classification: Only STRs disease causing, see separate STR list. No evidence for SNVs etc.
Mendeliome v0.8276 MYT1 Zornitza Stark Marked gene: MYT1 as ready
Mendeliome v0.8273 HEATR5B Seb Lunke Phenotypes for gene: HEATR5B were changed from pontocerebellar hypoplasia to pontocerebellar hypoplasia; intellectual disability; seizures
Mendeliome v0.8272 ATP1A2 Zornitza Stark Phenotypes for gene: ATP1A2 were changed from to Alternating hemiplegia of childhood 1, MIM#104290; Hydrops fetalis, microcephaly, arthrogryposis, extensive cortical malformations; Developmental and epileptic encephalopathy, polymicrogyria
Mendeliome v0.8269 ATP1A2 Zornitza Stark edited their review of gene: ATP1A2: Added comment: Association with alternating hemiplegia is well established.

PMID 31608932: Three individuals from two unrelated families reported with balleliic LoF variants in this gene and hydrops/congenital abnormalities. Mouse model is perinatal lethal.

PMID 33880529: six individuals with de novo missense variants reported and DD/EE/PMG.; Changed rating: GREEN; Changed publications: 31608932, 33880529; Changed phenotypes: Alternating hemiplegia of childhood 1, MIM#104290, Hydrops fetalis, microcephaly, arthrogryposis, extensive cortical malformations, Developmental and epileptic encephalopathy, polymicrogyria; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8269 HEATR5B Seb Lunke Marked gene: HEATR5B as ready
Mendeliome v0.8266 PITRM1 Zornitza Stark Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia-30 (SCAR30), MIM#619405; intellectual disability; cognitive decline; psychosis
Mendeliome v0.8265 PITRM1 Zornitza Stark edited their review of gene: PITRM1: Changed phenotypes: Spinocerebellar ataxia-30 (SCAR30), MIM#619405
Mendeliome v0.8265 VPS41 Zornitza Stark Phenotypes for gene: VPS41 were changed from Dystonia; intellectual disability to Spinocerebellar ataxia-29 (SCAR29), MIM#619389; Progressive neurodevelopmental disorder with ataxia, hypotonia, dystonia, intellectual disability and speech delay
Mendeliome v0.8264 IRX6 Eleanor Williams gene: IRX6 was added
gene: IRX6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IRX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IRX6 were set to 33891002
Phenotypes for gene: IRX6 were set to cone dystrophy, MONDO:0000455
Mode of pathogenicity for gene: IRX6 was set to Other
Review for gene: IRX6 was set to GREEN
Added comment: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature
Mendeliome v0.8264 EPHA7 Zornitza Stark Marked gene: EPHA7 as ready
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
Mendeliome v0.8262 DNM1 Zornitza Stark Marked gene: DNM1 as ready
Mendeliome v0.8259 GRK2 Zornitza Stark Marked gene: GRK2 as ready
Mendeliome v0.8257 WDR60 Zornitza Stark Marked gene: WDR60 as ready
Mendeliome v0.8254 WDR34 Zornitza Stark Marked gene: WDR34 as ready
Mendeliome v0.8251 WDR19 Zornitza Stark Marked gene: WDR19 as ready
Mendeliome v0.8248 TXNDC15 Zornitza Stark Marked gene: TXNDC15 as ready
Mendeliome v0.8245 TTC8 Zornitza Stark Marked gene: TTC8 as ready
Mendeliome v0.8245 TTC8 Zornitza Stark Phenotypes for gene: TTC8 were changed from to Bardet-Biedl syndrome 8, MIM# 615985
Mendeliome v0.8242 TTC8 Zornitza Stark reviewed gene: TTC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 14520415, 19797195; Phenotypes: Bardet-Biedl syndrome 8, MIM# 615985; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8242 TTC21B Zornitza Stark Marked gene: TTC21B as ready
Mendeliome v0.8239 TRAF3IP1 Zornitza Stark Marked gene: TRAF3IP1 as ready
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
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
Mendeliome v0.8229 TMEM67 Zornitza Stark Marked gene: TMEM67 as ready
Mendeliome v0.8226 TMEM67 Zornitza Stark edited their review of gene: TMEM67: Added comment: Bi-allelic variants in this gene are associated with a range of ciliopathies, including JBTS, Meckel syndrome and nephronophthisis. Multiple families with each.; Changed publications: 16415887, 17377820, 17160906, 19508969; Changed phenotypes: Joubert syndrome 6, MIM# 610688, Meckel syndrome 3, MIM# 607361, Nephronophthisis 11, MIM# 613550, COACH syndrome 1, MIM# 216360
Mendeliome v0.8226 XDH Zornitza Stark Marked gene: XDH as ready
Mendeliome v0.8223 TCTEX1D2 Zornitza Stark Marked gene: TCTEX1D2 as ready
Mendeliome v0.8220 TCTN3 Zornitza Stark Marked gene: TCTN3 as ready
Mendeliome v0.8217 TCTN3 Zornitza Stark changed review comment from: Rare cause of JBS, I can only find two families reported plus one with OFD. Ataxia specifically described in one of the JBS individuals.; to: Three unrelated families reported with JBTS phenotype. Variants in this gene are associated with other ciliopathies as well (OFD and Mohr-Majewski).
Mendeliome v0.8217 SDCCAG8 Zornitza Stark Marked gene: SDCCAG8 as ready
Mendeliome v0.8217 SDCCAG8 Zornitza Stark Phenotypes for gene: SDCCAG8 were changed from to Bardet-Biedl syndrome 16, MIM# 615993; MONDO:0014444; Senior-Loken syndrome 7, MIM# 613615; MONDO:0013326; Nephronophthisis
Mendeliome v0.8214 SDCCAG8 Zornitza Stark reviewed gene: SDCCAG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 20835237, 22626039, 22626039, 32432520, 31534065, 26968886; Phenotypes: Bardet-Biedl syndrome 16, MIM# 615993, MONDO:0014444, Senior-Loken syndrome 7, MIM# 613615, MONDO:0013326, Nephronophthisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8214 SBDS Zornitza Stark Marked gene: SBDS as ready
Mendeliome v0.8212 RPGRIP1L Zornitza Stark Marked gene: RPGRIP1L as ready
Mendeliome v0.8209 RPGRIP1L Zornitza Stark edited their review of gene: RPGRIP1L: Added comment: Bi-allelic variants in this gene are associated with a range of ciliopathies, including JBTS and Meckel syndrome. Mouse model.; Changed publications: 17558409, 17558407, 17960139, 26071364, 19574260, 29991045; Changed phenotypes: Joubert syndrome 7, MIM# 611560, Meckel syndrome 5, MIM# 611561, COACH syndrome 3, MIM# 619113, Nephronophthisis
Mendeliome v0.8209 NPHP4 Zornitza Stark Marked gene: NPHP4 as ready
Mendeliome v0.8206 NPHP1 Zornitza Stark Marked gene: NPHP1 as ready
Mendeliome v0.8203 TIE1 Zornitza Stark Marked gene: TIE1 as ready
Mendeliome v0.8202 TIE1 Zornitza Stark gene: TIE1 was added
gene: TIE1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TIE1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TIE1 were set to 32947856; 24764452
Phenotypes for gene: TIE1 were set to Lymphatic malformation 11, MIM# 619401
Review for gene: TIE1 was set to AMBER
Added comment: Three families reported, supportive animal model, though variants are missense and present at a low frequency in gnomad.
Sources: Literature
Mendeliome v0.8201 NUF2 Dean Phelan gene: NUF2 was added
gene: NUF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUF2 were set to PMID: 33721060
Phenotypes for gene: NUF2 were set to microcephaly; short stature; bilateral vocal cord paralysis; micrognathia; atrial septal defect
Review for gene: NUF2 was set to RED
Added comment: PMID: 33721060 - de novo missense variant identified in one male patient with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect.
Sources: Literature
Mendeliome v0.8201 ERGIC3 Elena Savva gene: ERGIC3 was added
gene: ERGIC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERGIC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC3 were set to PMID: 33710394; 31585110
Phenotypes for gene: ERGIC3 were set to Intellectual disability
Review for gene: ERGIC3 was set to AMBER
Added comment: PMID: 33710394 - two homozygous sibs with mild ID, a novel canonical splice (c.717+1G>A). Absent in gnomAD, no splice studies. Classed as a VUS.

PMID: 31585110 - 1 hom (p.Gln233Argfs*10) in a male 8yo with Growth retardation, Microcephaly, Learning disability, Facial dysmorphism, Abnormal pigmentation.
Sources: Literature
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
Mendeliome v0.8201 NEK8 Zornitza Stark Marked gene: NEK8 as ready
Mendeliome v0.8198 MKKS Zornitza Stark Marked gene: MKKS as ready
Mendeliome v0.8198 MKKS Zornitza Stark Phenotypes for gene: MKKS were changed from to Bardet-Biedl syndrome 6 (MIM#605231); McKusick-Kaufman syndrome, MIM# 236700; Retinitis pigmentosa
Mendeliome v0.8195 MKKS Zornitza Stark reviewed gene: MKKS: Rating: GREEN; Mode of pathogenicity: None; Publications: 10802661, 26900326, 10973251; Phenotypes: Bardet-Biedl syndrome 6 (MIM#605231), McKusick-Kaufman syndrome, MIM# 236700, Retinitis pigmentosa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8195 IQCB1 Zornitza Stark Marked gene: IQCB1 as ready
Mendeliome v0.8192 IFT80 Zornitza Stark Marked gene: IFT80 as ready
Mendeliome v0.8189 LZTFL1 Zornitza Stark Marked gene: LZTFL1 as ready
Mendeliome v0.8189 LZTFL1 Zornitza Stark Phenotypes for gene: LZTFL1 were changed from to Bardet-Biedl syndrome 17 (MIM#615994)
Mendeliome v0.8186 LZTFL1 Zornitza Stark reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22510444, 23692385, 27312011, 22072986; Phenotypes: Bardet-Biedl syndrome 17 (MIM#615994); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8186 TTC26 Zornitza Stark Marked gene: TTC26 as ready
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
Mendeliome v0.8183 IFT43 Zornitza Stark Marked gene: IFT43 as ready
Mendeliome v0.8180 IFT140 Zornitza Stark Marked gene: IFT140 as ready
Mendeliome v0.8177 ARHGEF9 Zornitza Stark Mode of inheritance for gene: ARHGEF9 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.8175 DYNC2H1 Zornitza Stark Marked gene: DYNC2H1 as ready
Mendeliome v0.8172 DDX59 Zornitza Stark Marked gene: DDX59 as ready
Mendeliome v0.8169 CEP83 Zornitza Stark Marked gene: CEP83 as ready
Mendeliome v0.8166 RNU12 Bryony Thompson Marked gene: RNU12 as ready
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
Mendeliome v0.8164 FHOD3 Zornitza Stark Marked gene: FHOD3 as ready
Mendeliome v0.8164 FHOD3 Zornitza Stark Phenotypes for gene: FHOD3 were changed from to Cardiomyopathy, familial hypertrophic, 28, MIM# 619402
Mendeliome v0.8161 FHOD3 Zornitza Stark reviewed gene: FHOD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32335906, 31742804, 30442288; Phenotypes: Cardiomyopathy, familial hypertrophic, 28, MIM# 619402; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8160 KCNJ16 Zornitza Stark Marked gene: KCNJ16 as ready
Mendeliome v0.8158 KLHL7 Zornitza Stark Marked gene: KLHL7 as ready
Mendeliome v0.8155 SLC34A3 Zornitza Stark Marked gene: SLC34A3 as ready
Mendeliome v0.8152 TNC Zornitza Stark Marked gene: TNC as ready
Mendeliome v0.8148 RIPK4 Zornitza Stark Marked gene: RIPK4 as ready
Mendeliome v0.8148 RIPK4 Zornitza Stark Phenotypes for gene: RIPK4 were changed from to Popliteal pterygium syndrome, Bartsocas-Papas type, MIM# 263650
Mendeliome v0.8145 RIPK4 Zornitza Stark reviewed gene: RIPK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940926, 22197489, 22197488; Phenotypes: Popliteal pterygium syndrome, Bartsocas-Papas type, MIM# 263650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8145 CEP290 Zornitza Stark Marked gene: CEP290 as ready
Mendeliome v0.8145 CEP290 Zornitza Stark Phenotypes for gene: CEP290 were changed from to Bardet-Biedl syndrome 14, MIM# 615991; Joubert syndrome 5 610188; Leber congenital amaurosis 10, MIM# 611755; Meckel syndrome 4, MIM# 611134; Senior-Loken syndrome 6, MIM# 610189
Mendeliome v0.8142 CEP290 Zornitza Stark reviewed gene: CEP290: Rating: GREEN; Mode of pathogenicity: None; Publications: 18327255, 20690115, 16682973, 16682970, 17564967, 16909394, 17564974; Phenotypes: Bardet-Biedl syndrome 14, MIM# 615991, Joubert syndrome 5 610188, Leber congenital amaurosis 10, MIM# 611755, Meckel syndrome 4, MIM# 611134, Senior-Loken syndrome 6, MIM# 610189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8142 CEP164 Zornitza Stark Marked gene: CEP164 as ready
Mendeliome v0.8142 CEP164 Zornitza Stark Phenotypes for gene: CEP164 were changed from to Bardet-Biedl syndrome; Nephronophthisis 15, MIM# 614845; Oro-facio-digital syndrome
Mendeliome v0.8139 CEP164 Zornitza Stark reviewed gene: CEP164: Rating: GREEN; Mode of pathogenicity: None; Publications: 34132027, 34013113, 32055034, 27708425, 22863007; Phenotypes: Bardet-Biedl syndrome, Nephronophthisis 15, MIM# 614845, Oro-facio-digital syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8139 CEP120 Zornitza Stark Marked gene: CEP120 as ready
Mendeliome v0.8136 CEP104 Zornitza Stark Marked gene: CEP104 as ready
Mendeliome v0.8133 C5orf42 Zornitza Stark Marked gene: C5orf42 as ready
Mendeliome v0.8130 C21orf2 Zornitza Stark changed review comment from: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported.

7 families also reported with isolated retinal dystrophy.; to: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported.

7 families also reported with isolated retinal dystrophy.

New HGNC approved name is CFAP410.
Mendeliome v0.8130 C21orf2 Zornitza Stark Marked gene: C21orf2 as ready
Mendeliome v0.8130 C21orf2 Zornitza Stark Phenotypes for gene: C21orf2 were changed from to Spondylometaphyseal dysplasia, axial, MIM# 602271; Retinal dystrophy with macular staphyloma, MIM# 617547
Mendeliome v0.8127 C21orf2 Zornitza Stark reviewed gene: C21orf2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26974433, 27548899, 28422394, 26294103, 23105016, 27548899; Phenotypes: Spondylometaphyseal dysplasia, axial, MIM# 602271, Retinal dystrophy with macular staphyloma, MIM# 617547; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8127 BBS9 Zornitza Stark Marked gene: BBS9 as ready
Mendeliome v0.8127 BBS9 Zornitza Stark Phenotypes for gene: BBS9 were changed from to Bardet-Biedl syndrome 9, MIM#615986; MONDO:0014437
Mendeliome v0.8124 BBS9 Zornitza Stark reviewed gene: BBS9: Rating: GREEN; Mode of pathogenicity: None; Publications: 16380913, 22353939, 32686083, 32037757; Phenotypes: Bardet-Biedl syndrome 9, MIM#615986, MONDO:0014437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8124 BBS7 Zornitza Stark Marked gene: BBS7 as ready
Mendeliome v0.8124 BBS7 Zornitza Stark Phenotypes for gene: BBS7 were changed from to Bardet-Biedl syndrome 7, MIM# 615984; MONDO:0014435
Mendeliome v0.8121 BBS7 Zornitza Stark reviewed gene: BBS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 12567324, 21937992, 19797195; Phenotypes: Bardet-Biedl syndrome 7, MIM# 615984, MONDO:0014435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8121 BBS5 Zornitza Stark Marked gene: BBS5 as ready
Mendeliome v0.8121 BBS5 Zornitza Stark Phenotypes for gene: BBS5 were changed from to Bardet-Biedl syndrome 5, MIM#615983; MONDO:0014434
Mendeliome v0.8118 BBS5 Zornitza Stark reviewed gene: BBS5: Rating: GREEN; Mode of pathogenicity: None; Publications: 19252258, 15137946, 10053027, 15637713; Phenotypes: Bardet-Biedl syndrome 5, MIM#615983, MONDO:0014434; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8118 BBS4 Zornitza Stark Marked gene: BBS4 as ready
Mendeliome v0.8118 BBS4 Zornitza Stark Phenotypes for gene: BBS4 were changed from to Bardet-Biedl syndrome 4, MIM#615982; MONDO:0014433
Mendeliome v0.8115 BBS4 Zornitza Stark reviewed gene: BBS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12016587, 11381270; Phenotypes: Bardet-Biedl syndrome 4, MIM#615982, MONDO:0014433; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8115 ARL6 Zornitza Stark Marked gene: ARL6 as ready
Mendeliome v0.8115 ARL6 Zornitza Stark Gene: arl6 has been classified as Green List (High Evidence).
Mendeliome v0.8115 ARL6 Zornitza Stark Phenotypes for gene: ARL6 were changed from to Bardet-Biedl syndrome 3, MIM# 600151; Retinitis pigmentosa 55, MIM# 613575
Mendeliome v0.8114 ARL6 Zornitza Stark Publications for gene: ARL6 were set to
Mendeliome v0.8113 ARL6 Zornitza Stark Mode of inheritance for gene: ARL6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8112 ARL6 Zornitza Stark reviewed gene: ARL6: Rating: GREEN; Mode of pathogenicity: None; Publications: 15258860, 32361989, 31888296, 25402481, 31736247, 19858128; Phenotypes: Bardet-Biedl syndrome 3, MIM# 600151, Retinitis pigmentosa 55, MIM# 613575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8111 SLCO2A1 Zornitza Stark Phenotypes for gene: SLCO2A1 were changed from to Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100; Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441
Mendeliome v0.8108 SLCO2A1 Zornitza Stark reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23509104, 27134495, 33852188, 22331663, 27134495]; Phenotypes: Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100, Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8108 NDUFB11 Zornitza Stark Phenotypes for gene: NDUFB11 were changed from Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); MONDO:0010494; Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); MONDO:0026721 to Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); MONDO:0010494; Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); MONDO:0026721; X-linked sideroblastic anaemia
Mendeliome v0.8106 PPP2R1A Zornitza Stark changed review comment from: Intellectual disability with variable other features, including CC abnormalities and microcephaly.; to: Intellectual disability with variable other features, including CC abnormalities and microcephaly/macrocephaly.
Mendeliome v0.8106 PPP2R1A Zornitza Stark Marked gene: PPP2R1A as ready
Mendeliome v0.8106 PPP2R1A Zornitza Stark Phenotypes for gene: PPP2R1A were changed from to Mental retardation, autosomal dominant 36, MIM#616362; Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605
Mendeliome v0.8103 PPP2R1A Zornitza Stark reviewed gene: PPP2R1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal dominant 36, MIM#616362, Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Marked gene: ARHGEF10 as ready
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Gene: arhgef10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Classified gene: ARHGEF10 as Amber List (moderate evidence)
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Gene: arhgef10 has been classified as Amber List (Moderate Evidence).
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 v0.8100 CLPB Zornitza Stark Marked gene: CLPB as ready
Mendeliome v0.8100 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271
Mendeliome v0.8097 CLPB Zornitza Stark reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25597510, 34140661; Phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8096 PON1 Zornitza Stark Marked gene: PON1 as ready
Mendeliome v0.8096 PON1 Zornitza Stark Phenotypes for gene: PON1 were changed from to {Coronary artery disease, susceptibility to}
Mendeliome v0.8094 PON1 Zornitza Stark reviewed gene: PON1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Coronary artery disease, susceptibility to}; Mode of inheritance: None
Mendeliome v0.8094 ABCB4 Zornitza Stark Marked gene: ABCB4 as ready
Mendeliome v0.8091 OAS1 Zornitza Stark Marked gene: OAS1 as ready
Mendeliome v0.8091 OAS1 Zornitza Stark Phenotypes for gene: OAS1 were changed from to Autoinflammatory immunodeficiency; infantile-onset pulmonary alveolar proteinosis; hypogammaglobulinaemia
Mendeliome v0.8087 OAS1 Zornitza Stark reviewed gene: OAS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34145065, 29455859; Phenotypes: Autoinflammatory immunodeficiency, infantile-onset pulmonary alveolar proteinosis, hypogammaglobulinaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8087 SLIT3 Zornitza Stark Marked gene: SLIT3 as ready
Mendeliome v0.8085 SOCS1 Zornitza Stark Phenotypes for gene: SOCS1 were changed from Common variable immunodeficiency; Early-onset autoimmunity to Autoinflammatory syndrome, familial, with or without immunodeficiency, MIM# 619375; Common variable immunodeficiency; Early-onset autoimmunity
Mendeliome v0.8084 SOCS1 Zornitza Stark edited their review of gene: SOCS1: Changed phenotypes: Autoinflammatory syndrome, familial, with or without immunodeficiency, MIM# 619375, Early-onset autoimmunity
Mendeliome v0.8083 IQGAP3 Zornitza Stark Marked gene: IQGAP3 as ready
Mendeliome v0.8083 IQGAP3 Zornitza Stark gene: IQGAP3 was added
gene: IQGAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IQGAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: IQGAP3 were set to Hereditary neuropathy
Review for gene: IQGAP3 was set to RED
Added comment: Single multiplex family, intronic variant, limited functional data.
Sources: Literature
Mendeliome v0.8082 TINF2 Zornitza Stark Marked gene: TINF2 as ready
Mendeliome v0.8079 TINF2 Zornitza Stark edited their review of gene: TINF2: Added comment: RS is a severe variant of DKC with early bone marrow failure and retinopathy. Well established gene-disease associations.; Changed publications: 18252230, 21477109, 18979121, 18669893, 21199492, 33097095; Changed phenotypes: Dyskeratosis congenita, autosomal dominant 3, MIM# 613990, Revesz syndrome, MIM# 268130
Mendeliome v0.8079 POPDC3 Zornitza Stark changed review comment from: 5 affected individuals from 3 unrelated families reported, supportive animal model data.
Sources: Literature; to: 5 affected individuals from 3 unrelated families reported, supportive animal model data. Presentation was between adolescence and 40s with proximal muscle weakness primarily affecting the lower limbs, resulting in increased falls and difficulty running. The disorder was slowly progressive, with later involvement of the upper limbs. MRI showed fatty replacement of the thigh muscles and medial gastrocnemius, with some paraspinal muscles also affected. Some patients had calf hypertrophy. Serum CK was markedly elevated.
Sources: Literature
Mendeliome v0.8079 POPDC3 Zornitza Stark Marked gene: POPDC3 as ready
Mendeliome v0.8078 POPDC3 Zornitza Stark gene: POPDC3 was added
gene: POPDC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POPDC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POPDC3 were set to 31610034
Phenotypes for gene: POPDC3 were set to Muscular dystrophy, limb-girdle, autosomal recessive 26, MIM# 618848
Review for gene: POPDC3 was set to GREEN
Added comment: 5 affected individuals from 3 unrelated families reported, supportive animal model data.
Sources: Literature
Mendeliome v0.8077 ACD Zornitza Stark Marked gene: ACD as ready
Mendeliome v0.8071 WRAP53 Zornitza Stark Marked gene: WRAP53 as ready
Mendeliome v0.8068 EP300 Zornitza Stark Marked gene: EP300 as ready
Mendeliome v0.8065 PARN Zornitza Stark Marked gene: PARN as ready
Mendeliome v0.8065 PARN Zornitza Stark Gene: parn has been classified as Green List (High Evidence).
Mendeliome v0.8065 PARN Zornitza Stark Phenotypes for gene: PARN were changed from to Dyskeratosis congenita, autosomal recessive 6, MIM# 616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, MIM# 616371
Mendeliome v0.8064 PARN Zornitza Stark Publications for gene: PARN were set to
Mendeliome v0.8063 PARN Zornitza Stark Mode of inheritance for gene: PARN was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8062 PARN Zornitza Stark reviewed gene: PARN: Rating: GREEN; Mode of pathogenicity: None; Publications: 25893599, 26342108, 25848748; Phenotypes: Dyskeratosis congenita, autosomal recessive 6, MIM# 616353, Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, MIM# 616371; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8062 KLF1 Zornitza Stark Marked gene: KLF1 as ready
Mendeliome v0.8059 SPAG17 Zornitza Stark Marked gene: SPAG17 as ready
Mendeliome v0.8059 SPAG17 Zornitza Stark gene: SPAG17 was added
gene: SPAG17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPAG17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPAG17 were set to 28548327
Phenotypes for gene: SPAG17 were set to Spermatogenic failure 55, MIM#619380
Review for gene: SPAG17 was set to RED
Added comment: Single family reported with two affected brothers, homozygous missense variant.
Sources: Literature
Mendeliome v0.8058 CATIP Zornitza Stark Marked gene: CATIP as ready
Mendeliome v0.8058 CATIP Zornitza Stark gene: CATIP was added
gene: CATIP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CATIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CATIP were set to 32503832
Phenotypes for gene: CATIP were set to Spermatogenic failure 54, MIM# 619379
Review for gene: CATIP was set to RED
Added comment: Homozygous missense variant reported in a single consanguineous family with 4 affecteds. Limited functional data.
Sources: Expert list
Mendeliome v0.8056 HAX1 Zornitza Stark Marked gene: HAX1 as ready
Mendeliome v0.8051 DNAJC30 Zornitza Stark Phenotypes for gene: DNAJC30 were changed from Leber Hereditary Optic Neuropathy to Leber Hereditary Optic Neuropathy, MIM#619382
Mendeliome v0.8050 DNAJC30 Zornitza Stark edited their review of gene: DNAJC30: Changed phenotypes: Leber Hereditary Optic Neuropathy, MIM#619382
Mendeliome v0.8049 ARCN1 Zornitza Stark Phenotypes for gene: ARCN1 were changed from to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164)
Mendeliome v0.8048 ARCN1 Zornitza Stark Publications for gene: ARCN1 were set to
Mendeliome v0.8047 ARCN1 Zornitza Stark Mode of inheritance for gene: ARCN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8046 ARCN1 Zornitza Stark reviewed gene: ARCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27476655, 33154040; Phenotypes: Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8046 NBEAL2 Zornitza Stark Marked gene: NBEAL2 as ready
Mendeliome v0.8043 GFI1 Zornitza Stark Marked gene: GFI1 as ready
Mendeliome v0.8040 SLC13A5 Zornitza Stark Marked gene: SLC13A5 as ready
Mendeliome v0.8037 GATA2 Zornitza Stark Marked gene: GATA2 as ready
Mendeliome v0.8034 GATA1 Zornitza Stark Marked gene: GATA1 as ready
Mendeliome v0.8032 ELANE Zornitza Stark Marked gene: ELANE as ready
Mendeliome v0.8029 EFL1 Zornitza Stark Marked gene: EFL1 as ready
Mendeliome v0.8026 CXCR4 Zornitza Stark Marked gene: CXCR4 as ready
Mendeliome v0.8023 CTC1 Zornitza Stark Marked gene: CTC1 as ready
Mendeliome v0.8020 ANKRD26 Zornitza Stark Marked gene: ANKRD26 as ready
Mendeliome v0.8017 AK2 Zornitza Stark Marked gene: AK2 as ready
Mendeliome v0.8017 AK2 Zornitza Stark Phenotypes for gene: AK2 were changed from to Reticular dysgenesis, MIM# 267500
Mendeliome v0.8014 AK2 Zornitza Stark reviewed gene: AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19043416; Phenotypes: Reticular dysgenesis, MIM# 267500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8014 ADA2 Zornitza Stark Marked gene: ADA2 as ready
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 v0.8011 IFT74 Zornitza Stark Phenotypes for gene: IFT74 were changed from Bardet-Biedl syndrome 20, MIM# 617119 to Bardet-Biedl syndrome 20, MIM# 617119; Joubert syndrome
Mendeliome v0.8009 IFT74 Zornitza Stark edited their review of gene: IFT74: Added comment: PMID 33531668: Identified IFT74 as a JBTS-associated gene in 3 unrelated families through WES. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants.; Changed publications: 27486776, 32144365, 33531668; Changed phenotypes: Bardet-Biedl syndrome 20, MIM# 617119, Joubert syndrome
Mendeliome v0.8009 RFX4 Zornitza Stark Marked gene: RFX4 as ready
Mendeliome v0.8008 RFX4 Zornitza Stark gene: RFX4 was added
gene: RFX4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX4 were set to 33658631
Phenotypes for gene: RFX4 were set to ID, ASD, ADHD
Review for gene: RFX4 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8007 RFX3 Zornitza Stark Marked gene: RFX3 as ready
Mendeliome v0.8006 RFX3 Zornitza Stark gene: RFX3 was added
gene: RFX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX3 were set to 33658631
Phenotypes for gene: RFX3 were set to ID, ASD, ADHD
Review for gene: RFX3 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8005 RFX7 Zornitza Stark Marked gene: RFX7 as ready
Mendeliome v0.8004 RFX7 Zornitza Stark gene: RFX7 was added
gene: RFX7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX7 were set to 33658631
Phenotypes for gene: RFX7 were set to ID, ASD, ADHD
Review for gene: RFX7 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8003 SEMA3F Zornitza Stark Marked gene: SEMA3F as ready
Mendeliome v0.8002 SEMA3F Zornitza Stark gene: SEMA3F was added
gene: SEMA3F was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEMA3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA3F were set to 33495532
Phenotypes for gene: SEMA3F were set to Hypogonadotropic hypogonadism
Review for gene: SEMA3F was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 10 individuals from 7 families with heterozygous SEMA3F missense variants. In 4 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Provide unequivocal human embryonic data showing the expression of SEMA3F along the developing human GnRH migratory pathway. SEMA3Fs harboring the P452T, T29M, and T724M missense variants showed impaired SEMA3F secretion in whole cell lysates.
Sources: Literature
Mendeliome v0.8001 PLXNA3 Zornitza Stark Marked gene: PLXNA3 as ready
Mendeliome v0.8000 PLXNA3 Zornitza Stark gene: PLXNA3 was added
gene: PLXNA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLXNA3 were set to 33495532
Phenotypes for gene: PLXNA3 were set to Hypogonadotropic hypogonadism
Review for gene: PLXNA3 was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 7 individuals from 5 families with hemizygous PLXNA3 missense variants. In 2 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Data provided with evidence that PLXNA3, a key component of the SEMA3F holoreceptor complex,31 is expressed by the human GnRH and olfactory/vomeronasal systems. S646P variant showed PLXNA3 localization exclusively in the ER, indicating that the variant S646P disrupts cell surface localization of PLXNA3.
Sources: Literature
Mendeliome v0.7999 DLG4 Zornitza Stark Phenotypes for gene: DLG4 were changed from Intellectual disability; Marfanoid habitus to Intellectual developmental disorder 62, MIM# 618793
Mendeliome v0.7997 DLG4 Zornitza Stark edited their review of gene: DLG4: Added comment: PMID 33597769: 53 patients (42 previously unpublished) with DLG4 variants. The clinical picture predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder.; Changed publications: 27479843, 25123844, 19617690, 29460436, 23020937, 28135719, 33597769; Changed phenotypes: Intellectual developmental disorder 62, MIM# 618793
Mendeliome v0.7997 GNAI1 Zornitza Stark Marked gene: GNAI1 as ready
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 v0.7994 FARSA Zornitza Stark Classified gene: FARSA as Green List (high evidence)
Mendeliome v0.7994 FARSA Zornitza Stark Gene: farsa has been classified as Green List (High Evidence).
Mendeliome v0.7993 FARSA Zornitza Stark edited their review of gene: FARSA: Added comment: Schuch et al. (2021) report 3 unrelated individuals with bi-allelic variants in FARSA. Identified through WES and variants segregated with disease. Functional evidence was obtained with reduced FARS1 enzyme activity levels in fibroblasts or EBV-transformed lymphoblastoid cell lines (EBV-LCLs) of patients. Common to all was a chronic interstitial lung disease starting early in life and characterized by bilateral ground-glass opacification on HR-CT, and cholesterol pneumonitis in lung histology. Additional abnormalities in other organ systems include liver disease, neurological manifestations, and growth restriction.; Changed rating: GREEN; Changed publications: 31355908, 33598926; Changed phenotypes: Rajab interstitial lung disease with brain calcifications 2, MIM# 619013
Mendeliome v0.7990 ZNF81 Zornitza Stark Marked gene: ZNF81 as ready
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
Mendeliome v0.7986 NIID Bryony Thompson Marked STR: NIID as ready
Mendeliome v0.7985 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[(66_517)]
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 7-60
Pathogenic repeat range: >=61-500
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Mendeliome v0.7983 TRPM6 Zornitza Stark Marked gene: TRPM6 as ready
Mendeliome v0.7981 CNTNAP1 Zornitza Stark Marked gene: CNTNAP1 as ready
Mendeliome v0.7978 GLDN Zornitza Stark Marked gene: GLDN as ready
Mendeliome v0.7975 ZBTB42 Zornitza Stark Marked gene: ZBTB42 as ready
Mendeliome v0.7974 ZBTB42 Zornitza Stark gene: ZBTB42 was added
gene: ZBTB42 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZBTB42 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB42 were set to 25055871
Phenotypes for gene: ZBTB42 were set to Lethal congenital contracture syndrome 6, MIM# 616248
Review for gene: ZBTB42 was set to AMBER
Added comment: Homozygous missense variant reported in a family with three stillbirths and a phenotype consistent with LCCS. Supportive zebrafish model.
Sources: Expert Review
Mendeliome v0.7973 MYBPC1 Zornitza Stark Marked gene: MYBPC1 as ready
Mendeliome v0.7973 MYBPC1 Zornitza Stark Phenotypes for gene: MYBPC1 were changed from to Arthrogryposis, distal, type 1B 614335; Lethal congenital contracture syndrome 4, MIM# 614915; Myopathy, congenital, with tremor MIM#618524
Mendeliome v0.7970 MYBPC1 Zornitza Stark reviewed gene: MYBPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20045868, 22610851, 23873045, 26661508, 31264822, 31025394; Phenotypes: Arthrogryposis, distal, type 1B 614335, Lethal congenital contracture syndrome 4, MIM# 614915, Myopathy, congenital, with tremor MIM#618524; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7970 ERBB3 Zornitza Stark Marked gene: ERBB3 as ready
Mendeliome v0.7970 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598 to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis
Mendeliome v0.7967 TRPM6 Kristin Rigbye reviewed gene: TRPM6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 1, intestinal (MIM#602014), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7967 MUSK Zornitza Stark Marked gene: MUSK as ready
Mendeliome v0.7964 DOK7 Zornitza Stark Marked gene: DOK7 as ready
Mendeliome v0.7961 TPM2 Zornitza Stark Marked gene: TPM2 as ready
Mendeliome v0.7961 TPM2 Zornitza Stark Phenotypes for gene: TPM2 were changed from to Arthrogryposis, distal, type 1A 108120; Arthrogryposis, distal, type 2B4 108120; CAP myopathy 2 609285; Nemaline myopathy 4, autosomal dominant 609285; Multiple pterygium syndrome
Mendeliome v0.7958 TPM2 Zornitza Stark reviewed gene: TPM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32092148, 27726070, 32092148, 24692096; Phenotypes: Arthrogryposis, distal, type 1A 108120, Arthrogryposis, distal, type 2B4 108120, CAP myopathy 2 609285, Nemaline myopathy 4, autosomal dominant 609285, Multiple pterygium syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7958 CHRNG Zornitza Stark Marked gene: CHRNG as ready
Mendeliome v0.7958 CHRNG Zornitza Stark Phenotypes for gene: CHRNG were changed from to Escobar syndrome, MIM# 265000; Multiple pterygium syndrome, lethal type, MIM# 253290; MONDO:0009926; MONDO:0009668
Mendeliome v0.7955 CHRNG Zornitza Stark reviewed gene: CHRNG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826520, 16826531, 22167768; Phenotypes: Escobar syndrome, MIM# 265000, Multiple pterygium syndrome, lethal type, MIM# 253290, MONDO:0009926, MONDO:0009668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7955 CD207 Zornitza Stark Marked gene: CD207 as ready
Mendeliome v0.7951 KIF17 Zornitza Stark Marked gene: KIF17 as ready
Mendeliome v0.7951 KIF17 Zornitza Stark gene: KIF17 was added
gene: KIF17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF17 were set to 33922911; 30458707; 28341548
Phenotypes for gene: KIF17 were set to Microphthalmia; Coloboma
Review for gene: KIF17 was set to RED
Added comment: Two siblings reported with MAC spectrum and homozygous missense variant in this gene. Some pre-existing data linking KIF17 to eye development.
Sources: Literature
Mendeliome v0.7950 SASH3 Zornitza Stark Marked gene: SASH3 as ready
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
Mendeliome v0.7946 FOXP1 Zornitza Stark reviewed gene: FOXP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26633542, 28741757; Phenotypes: Mental retardation with language impairment and with or without autistic features 613670; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7946 PARP6 Zornitza Stark Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Mendeliome v0.7945 PARP6 Zornitza Stark edited their review of gene: PARP6: Changed publications: 34067418
Mendeliome v0.7945 DNAH2 Zornitza Stark edited their review of gene: DNAH2: Added comment: PMID 32732226: compound het variants identified in a fetus with hydrops and complex congenital heart disease detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, heterotaxy, complex congenital heart disease, hypotrophic splenium, and common mesentery.; Changed publications: 30811583, 32732226; Changed phenotypes: Spermatogenic failure 45, MIM# 619094, Heterotaxy
Mendeliome v0.7945 MYBPC2 Zornitza Stark Marked gene: MYBPC2 as ready
Mendeliome v0.7945 MYBPC2 Zornitza Stark gene: MYBPC2 was added
gene: MYBPC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYBPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBPC2 were set to 32732226
Phenotypes for gene: MYBPC2 were set to Fetal akinesia; Hydrops; Hygroma; Multiple pterygium
Review for gene: MYBPC2 was set to RED
Added comment: Novel candidate gene identified in a fetus with fetal akinesia detected by ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, hygroma, multiple pterygium. A homozygous variant (c.3394G>A/ p.Glu1132Lys) in MYBPC2 was found by exome sequencing with concordant segregation among one affected sib and two unaffected sibs.
Sources: Literature
Mendeliome v0.7944 SCN7A Zornitza Stark Marked gene: SCN7A as ready
Mendeliome v0.7944 SCN7A Zornitza Stark gene: SCN7A was added
gene: SCN7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCN7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN7A were set to 32732226
Phenotypes for gene: SCN7A were set to Holoprosencephaly
Review for gene: SCN7A was set to RED
Added comment: Novel candidate gene identified in a fetus with holoprosencephaly detected by ultrasound. Autopsy showed multiple congenital abnormalities including IUGR, microcephaly, bilateral, ablepharon, corpus callosum agenesis, myelomeningocele, tracheal atresia, absent nipples, unilateral simian crease, and hypoplastic phalanges. Compound heterozygous variants including a truncating variant were found by exome sequencing with concordant segregation.
Sources: Literature
Mendeliome v0.7943 SPTBN5 Zornitza Stark Marked gene: SPTBN5 as ready
Mendeliome v0.7943 SPTBN5 Zornitza Stark gene: SPTBN5 was added
gene: SPTBN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTBN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN5 were set to 32732226; 28007035
Phenotypes for gene: SPTBN5 were set to Sacral agenesis; congenital anomalies
Review for gene: SPTBN5 was set to RED
Added comment: Identified as a candidate gene in a sacral agenesis cohort.

PMID 32732226: compound het variants identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis.
Sources: Literature
Mendeliome v0.7942 WDR91 Zornitza Stark Phenotypes for gene: WDR91 were changed from to Hydrocephalus; cerebellar hypoplasia; hygroma
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 v0.7938 WDR91 Zornitza Stark reviewed gene: WDR91: Rating: AMBER; Mode of pathogenicity: None; Publications: 34028500, 28860274, 32732226; Phenotypes: Hydrocephalus, cerebellar hypoplasia, hygroma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7938 PLEKHN1 Zornitza Stark Marked gene: PLEKHN1 as ready
Mendeliome v0.7938 PLEKHN1 Zornitza Stark gene: PLEKHN1 was added
gene: PLEKHN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEKHN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHN1 were set to 33884296
Phenotypes for gene: PLEKHN1 were set to Sensory Neuropathy
Review for gene: PLEKHN1 was set to RED
Added comment: Hom missense variant in single patient with severely reduced/absent pain and temperature sensation
Sources: Literature
Mendeliome v0.7937 ZNF3 Zornitza Stark Marked gene: ZNF3 as ready
Mendeliome v0.7937 SMPDL3A Seb Lunke changed review comment from: Hom missense variant in twin sisters with deverely reduced pain and temperature sensation
Sources: Literature; to: Hom missense variant in twin sisters with severely reduced pain and temperature sensation
Sources: Literature
Mendeliome v0.7937 ZNF3 Zornitza Stark gene: ZNF3 was added
gene: ZNF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF3 were set to 32732226
Phenotypes for gene: ZNF3 were set to Hydrocephalus; cleft palate; microphthalmia
Review for gene: ZNF3 was set to RED
Added comment: Novel candidate gene identified in a fetus with hydrocephaly and facial cleft detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including a median cleft palate, partial maxillar agenesis, bilateral severe microphthalmia, arhinencephaly, partial thalamic fusion. A homozygous truncating variant (c.396A>G/ p.*132Trpext*69) in ZNF3 was found by exome sequencing.
Sources: Literature
Mendeliome v0.7936 SMPDL3A Seb Lunke Marked gene: SMPDL3A as ready
Mendeliome v0.7936 WRAP73 Zornitza Stark Marked gene: WRAP73 as ready
Mendeliome v0.7936 SMPDL3A Seb Lunke gene: SMPDL3A was added
gene: SMPDL3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMPDL3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPDL3A were set to 33884296
Phenotypes for gene: SMPDL3A were set to Sensory Neuropathy
Added comment: Hom missense variant in twin sisters with deverely reduced pain and temperature sensation
Sources: Literature
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 v0.7932 SLC37A4 Zornitza Stark Marked gene: SLC37A4 as ready
Mendeliome v0.7929 TUBA1A Zornitza Stark Marked gene: TUBA1A as ready
Mendeliome v0.7929 TUBA1A Zornitza Stark Phenotypes for gene: TUBA1A were changed from to Lissencephaly 3, MIM# 611603; Congenital fibrosis of the extraocular muscles, AD
Mendeliome v0.7926 COL9A3 Zornitza Stark Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome; Deafness to Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome AR; Deafness AD; Peripheral vitreoretinal degeneration and retinal detachment, AD
Mendeliome v0.7921 ANGPTL8 Zornitza Stark Marked gene: ANGPTL8 as ready
Mendeliome v0.7920 SRCAP Zornitza Stark Marked gene: SRCAP as ready
Mendeliome v0.7920 SRCAP Zornitza Stark Phenotypes for gene: SRCAP were changed from to Floating-Harbor syndrome MIM#136140; Neurodevelopmental disorder, non-Floating Harbor
Mendeliome v0.7917 SRCAP Zornitza Stark reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Floating-Harbor syndrome MIM#136140, Neurodevelopmental disorder, non-Floating Harbor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7917 ADAMTSL2 Zornitza Stark Marked gene: ADAMTSL2 as ready
Mendeliome v0.7917 ADAMTSL2 Zornitza Stark Phenotypes for gene: ADAMTSL2 were changed from to Geleophysic dysplasia 1, MIM# 231050; Dermatosparaxic Ehlers Danlos syndrome
Mendeliome v0.7914 ADAMTSL2 Zornitza Stark reviewed gene: ADAMTSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33369194, 26879370, 21415077; Phenotypes: Geleophysic dysplasia 1, MIM# 231050, Dermatosparaxic Ehlers Danlos syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7914 UNC45A Zornitza Stark Phenotypes for gene: UNC45A were changed from Cholestasis; Diarrhoea; Bone fragility; Impaired hearing to Osteootohepatoenteric syndrome, MIM# 619377; Cholestasis; Diarrhoea; Bone fragility; Impaired hearing
Mendeliome v0.7913 UNC45A Zornitza Stark edited their review of gene: UNC45A: Changed phenotypes: Osteootohepatoenteric syndrome, MIM# 619377, Cholestasis, Diarrhoea, Bone fragility, Impaired hearing
Mendeliome v0.7912 HS3ST6 Zornitza Stark Marked gene: HS3ST6 as ready
Mendeliome v0.7912 HS3ST6 Zornitza Stark gene: HS3ST6 was added
gene: HS3ST6 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HS3ST6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HS3ST6 were set to 33508266
Phenotypes for gene: HS3ST6 were set to Hereditary angioedema-8 (HAE8), MIM#619367
Review for gene: HS3ST6 was set to RED
Added comment: Three affected individuals from a single family reported, missense variant, no functional data.
Sources: Expert list
Mendeliome v0.7911 MYOF Zornitza Stark Marked gene: MYOF as ready
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
Mendeliome v0.7910 KNG1 Zornitza Stark Marked gene: KNG1 as ready
Mendeliome v0.7910 KNG1 Zornitza Stark Phenotypes for gene: KNG1 were changed from to Hereditary angioedema-6 (HAE6), MIM#619363
Mendeliome v0.7906 KNG1 Zornitza Stark reviewed gene: KNG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31087670, 33114181; Phenotypes: Hereditary angioedema-6 (HAE6), MIM#619363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7906 ANGPT1 Zornitza Stark Marked gene: ANGPT1 as ready
Mendeliome v0.7906 ANGPT1 Zornitza Stark Phenotypes for gene: ANGPT1 were changed from Hereditary angioedema to Hereditary angioedema-5 (HAE5), MIM#619361
Mendeliome v0.7905 ANGPT1 Zornitza Stark reviewed gene: ANGPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary angioedema-5 (HAE5), MIM#619361; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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.
Mendeliome v0.7905 PLG Zornitza Stark Marked gene: PLG as ready
Mendeliome v0.7905 PLG Zornitza Stark Phenotypes for gene: PLG were changed from to Hereditary angioedema-4 (HAE4), MIM#619360; Plasminogen deficiency, type I, MIM# 217090
Mendeliome v0.7902 PLG Zornitza Stark reviewed gene: PLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 28795768, 29548426, 29987869, 9242524, 10233898; Phenotypes: Hereditary angioedema-4 (HAE4), MIM#619360, Plasminogen deficiency, type I, MIM# 217090; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7901 PRKD1 Zornitza Stark Phenotypes for gene: PRKD1 were changed from Congenital heart defects and ectodermal dysplasia, 617364 to Congenital heart defects and ectodermal dysplasia, 617364; Congenital heart disease, autosomal recessive
Mendeliome v0.7897 PRKD1 Zornitza Stark edited their review of gene: PRKD1: Added comment: Additional publications supporting association with bi-allelic disease:

PMID: 33919081: Three sisters with pulmonary stenosis, truncus arteriosis, and atrial septal defect were homozygous for c.265-1G>T. Their asymptomatic father was also homozygous, however he had two affected sisters (not genotyped), raising the possibility that PRKD1 may undergo autosomal recessive inheritance mode with gender limitation. PMID: 25713110: Two sisters with truncus arteriosis were homozygous for R618X.; Changed publications: 27479907, 32817298, 25713110, 33919081; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7897 ATXN2L Seb Lunke Marked gene: ATXN2L as ready
Mendeliome v0.7895 LTBP1 Seb Lunke Marked gene: LTBP1 as ready
Mendeliome v0.7893 SLC30A5 Seb Lunke Marked gene: SLC30A5 as ready
Mendeliome v0.7893 CADM3 Seb Lunke Marked gene: CADM3 as ready
Mendeliome v0.7893 CADM3 Seb Lunke Added comment: Comment when marking as ready: Three families, but evidence not that great and missing segregation, so stays amber.
Mendeliome v0.7892 PGM2L1 Sue White Marked gene: PGM2L1 as ready
Mendeliome v0.7891 BCAS3 Sue White Marked gene: BCAS3 as ready
Mendeliome v0.7891 TUBA1A Kristin Rigbye edited their review of gene: TUBA1A: Changed phenotypes: Congenital fibrosis of the extraocular muscles, AD
Mendeliome v0.7891 TUBA1A Kristin Rigbye reviewed gene: TUBA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30677308; Phenotypes: Congenital fibrosis of the extraocular muscles; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
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
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 COL9A3 Kristin Rigbye reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33633367; Phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy, AD, MIM# 600969, Stickler syndrome, AR, Deafness, AD, Peripheral vitreoretinal degeneration and retinal detachment, AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7891 CADM3 Teresa Zhao gene: CADM3 was added
gene: CADM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CADM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CADM3 were set to PMID: 33889941
Phenotypes for gene: CADM3 were set to Charcot-Marie-Tooth disease
Review for gene: CADM3 was set to AMBER
Added comment: Three families reported with the same missense variant in CADM3 p.Tyr172Cys (one family de novo), with mice work to show reduced expression of the mutant protein in axons and abnormal axonal organization.
Sources: Literature
Mendeliome v0.7891 ANGPTL8 Dean Phelan gene: ANGPTL8 was added
gene: ANGPTL8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANGPTL8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPTL8 were set to PMID: 33909604
Phenotypes for gene: ANGPTL8 were set to Low serum triglycerides; Coronary artery disease
Review for gene: ANGPTL8 was set to RED
Added comment: PMID: 33909604 - Population studies showed PTV are associated with both lipid levels and coronary artery disease.
Sources: Literature
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
Mendeliome v0.7891 KCNB1 Zornitza Stark Marked gene: KCNB1 as ready
Mendeliome v0.7891 KCNB1 Zornitza Stark Phenotypes for gene: KCNB1 were changed from to Epileptic encephalopathy, early infantile, 26, MIM# 616056
Mendeliome v0.7888 KCNB1 Zornitza Stark reviewed gene: KCNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31600826, 31513310; Phenotypes: Epileptic encephalopathy, early infantile, 26, MIM# 616056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7888 SYT1 Zornitza Stark Marked gene: SYT1 as ready
Mendeliome v0.7885 UBTF Zornitza Stark Marked gene: UBTF as ready
Mendeliome v0.7882 ZEB2 Zornitza Stark Marked gene: ZEB2 as ready
Mendeliome v0.7881 SLC9A6 Zornitza Stark Marked gene: SLC9A6 as ready
Mendeliome v0.7881 SLC9A6 Zornitza Stark Phenotypes for gene: SLC9A6 were changed from to Mental retardation, X-linked syndromic, Christianson type, MIM# 300243; MONDO:0010278
Mendeliome v0.7878 SLC9A6 Zornitza Stark reviewed gene: SLC9A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 18342287, 19377476, 25044251, 33278113, 32569089, 31879735; Phenotypes: Mental retardation, X-linked syndromic, Christianson type, MIM# 300243, MONDO:0010278; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7878 RPL3L Zornitza Stark Phenotypes for gene: RPL3L were changed from Neonatal dilated cardiomyopathy to Cardiomyopathy, dilated, 2D, MIM# 619371; Neonatal dilated cardiomyopathy
Mendeliome v0.7877 RPL3L Zornitza Stark reviewed gene: RPL3L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 2D, MIM# 619371, Neonatal dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7875 SATB2 Zornitza Stark Marked gene: SATB2 as ready
Mendeliome v0.7872 MEF2C Zornitza Stark Phenotypes for gene: MEF2C were changed from Chromosome 5q14.3 deletion syndrome, 613443; Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, 613443 to Chromosome 5q14.3 deletion syndrome, 613443; Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, 613443; MONDO:0013266
Mendeliome v0.7870 MEF2C Zornitza Stark reviewed gene: MEF2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 19876902, 19471318, 19592390, 19592390, 20513142, 34055696, 34022131; Phenotypes: Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, MIM# 613443, MONDO:0013266 Edit; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7870 MBD5 Zornitza Stark Marked gene: MBD5 as ready
Mendeliome v0.7870 MBD5 Zornitza Stark Phenotypes for gene: MBD5 were changed from to Mental retardation, autosomal dominant 1, MIM# 156200; MONDO:0007974
Mendeliome v0.7867 MBD5 Zornitza Stark reviewed gene: MBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 18812405, 21981781, 23708187, 22726846, 33912662; Phenotypes: Mental retardation, autosomal dominant 1, MIM# 156200, MONDO:0007974; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7867 IQSEC2 Zornitza Stark Phenotypes for gene: IQSEC2 were changed from Mental retardation, X-linked 1/78, MIM#309530 to Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656; Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347
Mendeliome v0.7865 IQSEC2 Zornitza Stark reviewed gene: IQSEC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33368194, 20473311, 23674175; Phenotypes: Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656, Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.7865 EEF1A2 Zornitza Stark Phenotypes for gene: EEF1A2 were changed from Epileptic encephalopathy, early infantile, 33, MIM# 616409; Mental retardation, autosomal dominant 38, MIM# 616393 to Mental retardation, autosomal dominant 38, MIM# 616393; MONDO:0014617; Developmental and epileptic encephalopathy 33, MIM# 616409; MONDO:0014625
Mendeliome v0.7863 EEF1A2 Zornitza Stark reviewed gene: EEF1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24697219, 32196822, 32160274, 32062104, 31893083; Phenotypes: Mental retardation, autosomal dominant 38, MIM# 616393, MONDO:0014617, Developmental and epileptic encephalopathy 33, MIM# 616409, MONDO:0014625; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7863 MASP1 Zornitza Stark Marked gene: MASP1 as ready
Mendeliome v0.7860 BRPF1 Zornitza Stark Marked gene: BRPF1 as ready
Mendeliome v0.7857 TRAF7 Zornitza Stark Marked gene: TRAF7 as ready
Mendeliome v0.7857 TRAF7 Zornitza Stark Phenotypes for gene: TRAF7 were changed from to Cardiac, facial, and digital anomalies with developmental delay, MIM# 618164
Mendeliome v0.7854 TRAF7 Zornitza Stark reviewed gene: TRAF7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32376980; Phenotypes: Cardiac, facial, and digital anomalies with developmental delay, MIM# 618164; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7854 UBE3B Zornitza Stark Marked gene: UBE3B as ready
Mendeliome v0.7850 HSPG2 Zornitza Stark reviewed gene: HSPG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11101850, 16927315, 11279527; Phenotypes: Schwartz-Jampel syndrome, type 1, MIM# 255800, MONDO:0009717, Dyssegmental dysplasia, Silverman-Handmaker type, MIM# 224410, MONDO:0009140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7850 HLA-DRB1 Zornitza Stark Marked gene: HLA-DRB1 as ready
Mendeliome v0.7849 HLA-DRA Zornitza Stark Marked gene: HLA-DRA as ready
Mendeliome v0.7848 HLA-C Zornitza Stark Marked gene: HLA-C as ready
Mendeliome v0.7847 HLA-B Zornitza Stark Marked gene: HLA-B as ready
Mendeliome v0.7846 HLA-A Zornitza Stark Marked gene: HLA-A as ready
Mendeliome v0.7845 TAF6 Zornitza Stark Marked gene: TAF6 as ready
Mendeliome v0.7842 ANGPT2 Zornitza Stark Phenotypes for gene: ANGPT2 were changed from Primary lymphoedema to Lymphatic malformation-10, MIM#619369; Primary lymphoedema
Mendeliome v0.7841 ANGPT2 Zornitza Stark edited their review of gene: ANGPT2: Changed phenotypes: Lymphatic malformation-10, MIM#619369, Primary lymphoedema
Mendeliome v0.7841 SLC24A5 Zornitza Stark Marked gene: SLC24A5 as ready
Mendeliome v0.7838 SLC45A2 Zornitza Stark Marked gene: SLC45A2 as ready
Mendeliome v0.7835 TYR Zornitza Stark Marked gene: TYR as ready
Mendeliome v0.7833 TYRP1 Zornitza Stark Marked gene: TYRP1 as ready
Mendeliome v0.7830 MC1R Zornitza Stark Marked gene: MC1R as ready
Mendeliome v0.7826 LRMDA Zornitza Stark Marked gene: LRMDA as ready
Mendeliome v0.7823 SERPINF2 Zornitza Stark Marked gene: SERPINF2 as ready
Mendeliome v0.7820 SERPINE1 Zornitza Stark Marked gene: SERPINE1 as ready
Mendeliome v0.7817 TBXA2R Zornitza Stark Marked gene: TBXA2R as ready
Mendeliome v0.7813 P2RY12 Zornitza Stark Marked gene: P2RY12 as ready
Mendeliome v0.7810 MCFD2 Zornitza Stark Marked gene: MCFD2 as ready
Mendeliome v0.7807 LMAN1 Zornitza Stark Marked gene: LMAN1 as ready
Mendeliome v0.7804 ITGA2B Zornitza Stark Marked gene: ITGA2B as ready
Mendeliome v0.7801 LMOD1 Zornitza Stark Marked gene: LMOD1 as ready
Mendeliome v0.7797 POU4F1 Bryony Thompson Marked gene: POU4F1 as ready
Mendeliome v0.7796 POU4F1 Bryony Thompson gene: POU4F1 was added
gene: POU4F1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POU4F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU4F1 were set to 33783914; 8876243
Phenotypes for gene: POU4F1 were set to Ataxia; intention tremor; hypotonia
Review for gene: POU4F1 was set to GREEN
Added comment: 4 unrelated probands presenting with paediatric onset ataxia, intention tremor, and hypotonia, with de novo loss of function variants, and supporting null mouse model.
Sources: Literature
Mendeliome v0.7795 HPS6 Zornitza Stark Marked gene: HPS6 as ready
Mendeliome v0.7792 HPS4 Zornitza Stark Marked gene: HPS4 as ready
Mendeliome v0.7789 HPS3 Zornitza Stark Marked gene: HPS3 as ready
Mendeliome v0.7786 HPS1 Zornitza Stark Marked gene: HPS1 as ready
Mendeliome v0.7783 GP9 Zornitza Stark Marked gene: GP9 as ready
Mendeliome v0.7783 GP9 Zornitza Stark Phenotypes for gene: GP9 were changed from to Bernard-Soulier syndrome, type C, MIM# 231200
Mendeliome v0.7780 GP9 Zornitza Stark reviewed gene: GP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 8049428, 33553065, 32030720, 31484196; Phenotypes: Bernard-Soulier syndrome, type C, MIM# 231200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7780 GP6 Zornitza Stark Marked gene: GP6 as ready
Mendeliome v0.7777 GP1BB Zornitza Stark Marked gene: GP1BB as ready
Mendeliome v0.7777 GP1BB Zornitza Stark Phenotypes for gene: GP1BB were changed from to Bernard-Soulier syndrome, type B, MIM# 231200; Macrothrombocytopaenia
Mendeliome v0.7774 GP1BB Zornitza Stark reviewed gene: GP1BB: Rating: GREEN; Mode of pathogenicity: None; Publications: 8703016, 9116284, 10887115, 33813986, 33657022, 33216977, 31997307, 1730088, 11222377; Phenotypes: Bernard-Soulier syndrome, type B, MIM# 231200, Macrothrombocytopaenia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7774 CREB3L3 Zornitza Stark Marked gene: CREB3L3 as ready
Mendeliome v0.7773 PSMC3 Zornitza Stark Phenotypes for gene: PSMC3 were changed from Deafness; cataract to Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v0.7772 PSMC3 Zornitza Stark edited their review of gene: PSMC3: Changed phenotypes: Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v0.7772 PSMC3 Zornitza Stark edited their review of gene: PSMC3: Changed phenotypes: Feafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v0.7772 SCNN1B Zornitza Stark Marked gene: SCNN1B as ready
Mendeliome v0.7770 FGB Zornitza Stark Marked gene: FGB as ready
Mendeliome v0.7767 FGB Zornitza Stark changed review comment from: Inherited disorders of fibrinogen affect either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenemia) of the circulating fibrinogen or both.

Afibrinogenaemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenaemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial haemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. First-trimester pregnancy loss is common. Both arterial and venous thromboembolic complications have been reported. Hypofibrinogenaemia is a milder disorder. Well established gene-disease association.; to: Inherited disorders of fibrinogen affect either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenemia) of the circulating fibrinogen or both.

Afibrinogenaemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenaemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial haemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. First-trimester pregnancy loss is common. Both arterial and venous thromboembolic complications have been reported. Hypofibrinogenaemia is a milder disorder.

Well established gene-disease association.
Mendeliome v0.7767 F9 Zornitza Stark Marked gene: F9 as ready
Mendeliome v0.7764 F8 Zornitza Stark Marked gene: F8 as ready
Mendeliome v0.7761 F7 Zornitza Stark Marked gene: F7 as ready
Mendeliome v0.7758 F5 Zornitza Stark Marked gene: F5 as ready
Mendeliome v0.7756 F13A1 Zornitza Stark Marked gene: F13A1 as ready
Mendeliome v0.7753 F10 Zornitza Stark Marked gene: F10 as ready
Mendeliome v0.7750 F10 Zornitza Stark commented on gene: F10: Factor X deficiency shows variable phenotypic severity. Affected individuals can manifest prolonged nasal and mucosal haemorrhage, menorrhagia, haematuria, and occasionally haemarthrosis. More than 20 unrelated families reported.
Mendeliome v0.7750 MCM7 Zornitza Stark Marked gene: MCM7 as ready
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
Mendeliome v0.7749 DTNBP1 Zornitza Stark Marked gene: DTNBP1 as ready
Mendeliome v0.7746 BLOC1S3 Zornitza Stark Marked gene: BLOC1S3 as ready
Mendeliome v0.7743 AP3B1 Zornitza Stark Marked gene: AP3B1 as ready
Mendeliome v0.7740 LHCGR Zornitza Stark Marked gene: LHCGR as ready
Mendeliome v0.7736 NEB Zornitza Stark Phenotypes for gene: NEB were changed from Nemaline myopathy 2, autosomal recessive 256030 to Nemaline myopathy 2, autosomal recessive 256030; MONDO:0009725; Arthrogryposis multiplex congenita 6, MIM# 619334
Mendeliome v0.7735 NEB Zornitza Stark reviewed gene: NEB: Rating: GREEN; Mode of pathogenicity: None; Publications: 10051637, 22367672, 26578207, 33376055; Phenotypes: Arthrogryposis multiplex congenita 6, MIM# 619334; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7735 GEMIN5 Zornitza Stark Marked gene: GEMIN5 as ready
Mendeliome v0.7734 GEMIN5 Zornitza Stark gene: GEMIN5 was added
gene: GEMIN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333
Review for gene: GEMIN5 was set to GREEN
Added comment: Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy. 30 individuals from 22 unrelated families reported.
Sources: Literature
Mendeliome v0.7733 ANO6 Zornitza Stark Marked gene: ANO6 as ready
Mendeliome v0.7730 KLHL3 Zornitza Stark Marked gene: KLHL3 as ready
Mendeliome v0.7727 KCNJ5 Zornitza Stark Marked gene: KCNJ5 as ready
Mendeliome v0.7725 HSD11B2 Zornitza Stark Marked gene: HSD11B2 as ready
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 v0.7722 CLCN2 Zornitza Stark Marked gene: CLCN2 as ready
Mendeliome v0.7719 CACNA1D Zornitza Stark Marked gene: CACNA1D as ready
Mendeliome v0.7719 CACNA1D Zornitza Stark Phenotypes for gene: CACNA1D were changed from to Primary aldosteronism, seizures, and neurologic abnormalities, MIM# 615474; MONDO:0014200; Sinoatrial node dysfunction and deafness, MIM# 614896
Mendeliome v0.7716 CACNA1D Zornitza Stark reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 23913001, 32336187, 30698561, 21131953, 15357422, 22678062; Phenotypes: Primary aldosteronism, seizures, and neurologic abnormalities, MIM# 615474, MONDO:0014200, Sinoatrial node dysfunction and deafness, MIM# 614896; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7716 CACNA1H Zornitza Stark Marked gene: CACNA1H as ready
Mendeliome v0.7713 COX16 Zornitza Stark Phenotypes for gene: COX16 were changed from Hypertrophic cardiomyopathy; encephalopathy; severe fatal lactic acidosis to Mitochondrial complex IV deficiency, nuclear type 22, MIM# 619355; Hypertrophic cardiomyopathy; encephalopathy; severe fatal lactic acidosis
Mendeliome v0.7712 COX16 Zornitza Stark reviewed gene: COX16: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 22, MIM# 619355; Mode of inheritance: None
Mendeliome v0.7709 NFU1 Zornitza Stark Marked gene: NFU1 as ready
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 v0.7706 RAB11B Zornitza Stark Marked gene: RAB11B as ready
Mendeliome v0.7703 UFSP2 Zornitza Stark Marked gene: UFSP2 as ready
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.
Mendeliome v0.7700 KLHL13 Zornitza Stark Marked gene: KLHL13 as ready
Mendeliome v0.7699 PRX Zornitza Stark Marked gene: PRX as ready
Mendeliome v0.7699 PRX Zornitza Stark Phenotypes for gene: PRX were changed from to Charcot-Marie-Tooth disease, type 4F, MIM# 614895; Dejerine-Sottas disease, MIM# 145900
Mendeliome v0.7696 PRX Zornitza Stark reviewed gene: PRX: Rating: GREEN; Mode of pathogenicity: None; Publications: 11133365, 11157804, 15197604, 21079185, 22847150, 10839370, 32460404, 31523542, 31426691; Phenotypes: Charcot-Marie-Tooth disease, type 4F, MIM# 614895, Dejerine-Sottas disease, MIM# 145900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7696 PLEKHG5 Zornitza Stark Marked gene: PLEKHG5 as ready
Mendeliome v0.7696 PLEKHG5 Zornitza Stark Phenotypes for gene: PLEKHG5 were changed from to Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376; Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067
Mendeliome v0.7693 PLEKHG5 Zornitza Stark reviewed gene: PLEKHG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564964, 23777631, 23844677, 33492783, 33275839, 33220101, 23777631; Phenotypes: Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376, Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7693 NEFL Zornitza Stark Marked gene: NEFL as ready
Mendeliome v0.7693 NEFL Zornitza Stark Phenotypes for gene: NEFL were changed from to Charcot-Marie-Tooth disease, dominant intermediate G, MIM# 617882; Charcot-Marie-Tooth disease, type 1F, MIM# 607734; Charcot-Marie-Tooth disease, type 2E 607684
Mendeliome v0.7690 NEFL Zornitza Stark reviewed gene: NEFL: Rating: GREEN; Mode of pathogenicity: None; Publications: 10841809, 12393795, 14733962, 24887401, 25877835, 20039262, 12566280, 29191368, 28902413; Phenotypes: Charcot-Marie-Tooth disease, dominant intermediate G, MIM# 617882, Charcot-Marie-Tooth disease, type 1F, MIM# 607734, Charcot-Marie-Tooth disease, type 2E 607684; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7690 ADNP Zornitza Stark Marked gene: ADNP as ready
Mendeliome v0.7687 CHUK Zornitza Stark Marked gene: CHUK as ready
Mendeliome v0.7687 CHUK Zornitza Stark Phenotypes for gene: CHUK were changed from to Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339; Cocoon syndrome, MIM# 613630; AEC-like syndrome
Mendeliome v0.7683 CHUK Zornitza Stark reviewed gene: CHUK: Rating: AMBER; Mode of pathogenicity: None; Publications: 25691407, 20961246, 10195895, 10195896, 29523099, 28513979; Phenotypes: Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339, Cocoon syndrome, MIM# 613630, AEC-like syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7682 PARP6 Zornitza Stark Mode of inheritance for gene: PARP6 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7681 PARP6 Zornitza Stark edited their review of gene: PARP6: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7681 PARP6 Zornitza Stark Marked gene: PARP6 as ready
Mendeliome v0.7681 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Mendeliome v0.7681 PARP6 Zornitza Stark Classified gene: PARP6 as Green List (high evidence)
Mendeliome v0.7681 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Mendeliome v0.7680 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PARP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Mendeliome v0.7679 MAPKBP1 Zornitza Stark Marked gene: MAPKBP1 as ready
Mendeliome v0.7676 SLC6A6 Zornitza Stark Phenotypes for gene: SLC6A6 were changed from Early retinal degeneration; cardiomyopathy to Hypotaurinaemic retinal degeneration and cardiomyopathy (HTRDC), MIM#145350; Early retinal degeneration; cardiomyopathy
Mendeliome v0.7675 DNAJB2 Zornitza Stark Marked gene: DNAJB2 as ready
Mendeliome v0.7675 DNAJB2 Zornitza Stark Phenotypes for gene: DNAJB2 were changed from to Spinal muscular atrophy, distal, autosomal recessive, 5, MIM# 614881; MONDO:0014866
Mendeliome v0.7672 DNAJB2 Zornitza Stark reviewed gene: DNAJB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22522442, 25274842, 33369814, 22522442; Phenotypes: Spinal muscular atrophy, distal, autosomal recessive, 5, MIM# 614881, MONDO:0014866; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7672 ATP7A Zornitza Stark Phenotypes for gene: ATP7A were changed from Occipital horn syndrome, 304150; X-linked recessive Menkes disease, 309400 Spinal muscular atrophy, distal, X-linked 3, 300489 to Menkes disease MIM#309400; Occipital horn syndrome MIM#304150; Spinal muscular atrophy, distal, X-linked 3, MIM# 300489
Mendeliome v0.7670 ATP7A Zornitza Stark reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20170900, 33137485, 31969342, 31558336; Phenotypes: Menkes disease MIM#309400, Occipital horn syndrome MIM#304150, Spinal muscular atrophy, distal, X-linked 3, MIM# 300489; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
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.
Mendeliome v0.7670 TRPV6 Zornitza Stark Marked gene: TRPV6 as ready
Mendeliome v0.7670 TRPV6 Zornitza Stark Phenotypes for gene: TRPV6 were changed from to Hyperparathyroidism, transient neonatal, MIM# 618188; Early onset chronic pancreatitis susceptibility
Mendeliome v0.7667 TRPV6 Zornitza Stark reviewed gene: TRPV6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32383311, 31930989, 29861107; Phenotypes: Hyperparathyroidism, transient neonatal, MIM# 618188, Early onset chronic pancreatitis susceptibility; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7667 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; spastic paraparesis and bilateral cataracts to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; Cataracts, spastic paraparesis, and speech delay, MIM#619338
Mendeliome v0.7666 FAR1 Zornitza Stark edited their review of gene: FAR1: Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, Cataracts, spastic paraparesis, and speech delay, MIM#619338
Mendeliome v0.7664 RETREG1 Zornitza Stark Marked gene: RETREG1 as ready
Mendeliome v0.7664 RETREG1 Zornitza Stark Phenotypes for gene: RETREG1 were changed from to Neuropathy, hereditary sensory and autonomic, type IIB, MIM# 613115; MONDO:0013142
Mendeliome v0.7661 RETREG1 Zornitza Stark reviewed gene: RETREG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19838196, 24327336, 31737055, 31596031; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IIB, MIM# 613115, MONDO:0013142; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7661 SBF1 Zornitza Stark Marked gene: SBF1 as ready
Mendeliome v0.7661 SBF1 Zornitza Stark Phenotypes for gene: SBF1 were changed from to Charcot-Marie-Tooth disease, type 4B3 , MIM#615284; MONDO:0014117
Mendeliome v0.7658 SBF1 Zornitza Stark reviewed gene: SBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23749797, 23749797, 32444983, 30039846, 28005197; Phenotypes: Charcot-Marie-Tooth disease, type 4B3 , MIM#615284, MONDO:0014117; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7658 SBF2 Zornitza Stark Marked gene: SBF2 as ready
Mendeliome v0.7658 SBF2 Zornitza Stark Phenotypes for gene: SBF2 were changed from to Charcot-Marie-Tooth disease, type 4B2 , MIM#604563
Mendeliome v0.7655 SBF2 Zornitza Stark reviewed gene: SBF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12554688, 15477569, 12687498, 15304601, 31772832, 31070812; Phenotypes: Charcot-Marie-Tooth disease, type 4B2 , MIM#604563; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7655 SCN10A Zornitza Stark Marked gene: SCN10A as ready
Mendeliome v0.7652 TBC1D2B Zornitza Stark Phenotypes for gene: TBC1D2B were changed from Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality to Neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO), MIM#619323; Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Mendeliome v0.7651 TBC1D2B Zornitza Stark edited their review of gene: TBC1D2B: Changed phenotypes: Neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO), MIM#619323, Global developmental delay, Intellectual disability, Seizures, Gingival overgrowth, Behavioral abnormality, Abnormality of the mandible, Abnormality of brain morphology, Abnormality of the eye, Hearing abnormality
Mendeliome v0.7651 COL5A1 Zornitza Stark Marked gene: COL5A1 as ready
Mendeliome v0.7651 COL5A1 Zornitza Stark Phenotypes for gene: COL5A1 were changed from to Ehlers-Danlos syndrome, classic type, 1, MIM# 130000; Fibromuscular dysplasia, multifocal, MIM# 619329
Mendeliome v0.7648 COL5A1 Zornitza Stark reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 32938213; Phenotypes: Ehlers-Danlos syndrome, classic type, 1, MIM# 130000, Fibromuscular dysplasia, multifocal, MIM# 619329; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7648 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208; Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome; Febrile seizures; Arthrogryposis multiplex congenita to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208; Developmental and epileptic encephalopathy 6B, non-Dravet, MIM# 619317; Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome; Febrile seizures; Arthrogryposis multiplex congenita
Mendeliome v0.7647 SCN1A Zornitza Stark edited their review of gene: SCN1A: Changed phenotypes: Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208, Developmental and epileptic encephalopathy 6B, non-Dravet, MIM# 619317, Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome, Febrile seizures, Arthrogryposis multiplex congenita
Mendeliome v0.7646 DKC1 Zornitza Stark Marked gene: DKC1 as ready
Mendeliome v0.7646 DKC1 Zornitza Stark Phenotypes for gene: DKC1 were changed from to Dyskeratosis congenita, X-linked 305000; Hoyeraal-Hreidarsson Syndrome
Mendeliome v0.7643 DKC1 Zornitza Stark reviewed gene: DKC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31269755, 26951492, 29081935, 25940403; Phenotypes: Dyskeratosis congenita, X-linked 305000, Hoyeraal-Hreidarsson Syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7643 THOC2 Zornitza Stark Marked gene: THOC2 as ready
Mendeliome v0.7643 THOC2 Zornitza Stark Phenotypes for gene: THOC2 were changed from to Mental retardation, X-linked 12/35 MIM#300957
Mendeliome v0.7640 FGA Zornitza Stark Marked gene: FGA as ready
Mendeliome v0.7640 FGA Zornitza Stark Phenotypes for gene: FGA were changed from to Afibrinogenemia, congenital (MIM#202400), AR; Amyloidosis, familial visceral (MIM#105200), AD
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 v0.7637 GRHL2 Zornitza Stark Marked gene: GRHL2 as ready
Mendeliome v0.7634 ST14 Zornitza Stark Marked gene: ST14 as ready
Mendeliome v0.7631 CPE Zornitza Stark Marked gene: CPE as ready
Mendeliome v0.7630 CPE Zornitza Stark gene: CPE was added
gene: CPE was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Review for gene: CPE was set to AMBER
Added comment: Four affected individuals from two unrelated families reported, bi-allelic LoF variants.
Sources: Expert Review
Mendeliome v0.7629 CELSR1 Zornitza Stark Marked gene: CELSR1 as ready
Mendeliome v0.7627 SLC2A4RG Zornitza Stark Marked gene: SLC2A4RG as ready
Mendeliome v0.7626 SLCO1B1 Zornitza Stark Marked gene: SLCO1B1 as ready
Mendeliome v0.7626 SLCO1B1 Zornitza Stark Added comment: Comment when marking as ready: Not a monogenic disorder.
Mendeliome v0.7623 SIAH1 Zornitza Stark Phenotypes for gene: SIAH1 were changed from Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia to Buratti-Harel syndrome, MIM# 619314; Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Mendeliome v0.7622 SIAH1 Zornitza Stark reviewed gene: SIAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Buratti-Harel syndrome, MIM# 619314; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7622 SMARCA5 Zornitza Stark Marked gene: SMARCA5 as ready
Mendeliome v0.7622 SMARCA5 Zornitza Stark Gene: smarca5 has been classified as Green List (High Evidence).
Mendeliome v0.7622 SMARCA5 Zornitza Stark Classified gene: SMARCA5 as Green List (high evidence)
Mendeliome v0.7622 SMARCA5 Zornitza Stark Gene: smarca5 has been classified as Green List (High Evidence).
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
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.
Mendeliome v0.7618 LEMD2 Zornitza Stark Phenotypes for gene: LEMD2 were changed from progeroid disorder to Marbach-Rustad progeroid syndrome, OMIM# 619322; progeroid disorder
Mendeliome v0.7617 LEMD2 Zornitza Stark reviewed gene: LEMD2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Marbach-Rustad progeroid syndrome, OMIM# 619322; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v0.7615 SLC5A7 Zornitza Stark Marked gene: SLC5A7 as ready
Mendeliome v0.7615 SLC5A7 Zornitza Stark Phenotypes for gene: SLC5A7 were changed from to Neuronopathy, distal hereditary motor, type VIIA, MIM# 158580; MONDO:0008024; Myasthenic syndrome, congenital, 20, presynaptic, MIM# 617143
Mendeliome v0.7612 SLC5A7 Zornitza Stark reviewed gene: SLC5A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 23141292, 15173594, 29782645, 29582019, 27569547, 29189923, 30172469; Phenotypes: Neuronopathy, distal hereditary motor, type VIIA, MIM# 158580, MONDO:0008024, Myasthenic syndrome, congenital, 20, presynaptic, MIM# 617143; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7612 MCM10 Zornitza Stark Phenotypes for gene: MCM10 were changed from Susceptibility to CMV; Restrictive cardiomyopathy to Immunodeficiency-80 with or without congenital cardiomyopathy (IMD80), MIM#619313; Susceptibility to CMV; Restrictive cardiomyopathy
Mendeliome v0.7611 MCM10 Zornitza Stark edited their review of gene: MCM10: Changed phenotypes: Immunodeficiency-80 with or without congenital cardiomyopathy (IMD80), MIM#619313, Susceptibility to CMV, Restrictive cardiomyopathy
Mendeliome v0.7611 NR3C2 Zornitza Stark Marked gene: NR3C2 as ready
Mendeliome v0.7608 SCNN1A Zornitza Stark Marked gene: SCNN1A as ready
Mendeliome v0.7608 SCNN1A Zornitza Stark Phenotypes for gene: SCNN1A were changed from to Liddle syndrome 3 618126, MIM# AD, MONDO:0029132; Bronchiectasis with or without elevated sweat chloride 2, MIM# 613021 AD, MONDO:0013087; Pseudohypoaldosteronism, type I, MIM# 264350 AR, MIM#0009917
Mendeliome v0.7605 SCNN1A Zornitza Stark reviewed gene: SCNN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31301676, 28710092, 19462466, 19017867; Phenotypes: Liddle syndrome 3 618126, MIM# AD, MONDO:0029132, Bronchiectasis with or without elevated sweat chloride 2, MIM# 613021 AD, MONDO:0013087, Pseudohypoaldosteronism, type I, MIM# 264350 AR, MIM#0009917; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7605 SPTLC1 Zornitza Stark Marked gene: SPTLC1 as ready
Mendeliome v0.7605 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from to Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v0.7602 SPTLC2 Zornitza Stark Marked gene: SPTLC2 as ready
Mendeliome v0.7602 SPTLC2 Zornitza Stark Phenotypes for gene: SPTLC2 were changed from to Neuropathy, hereditary sensory and autonomic, type IC, 613640; MONDO:0013337; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v0.7599 ZPR1 Zornitza Stark Marked gene: ZPR1 as ready
Mendeliome v0.7598 SPEN Zornitza Stark Marked gene: SPEN as ready
Mendeliome v0.7598 SPEN Zornitza Stark Phenotypes for gene: SPEN were changed from Intellectual disability; autism; congenital anomalies to Radio-Tartaglia syndrome, MIM# 619312; Intellectual disability; autism; congenital anomalies
Mendeliome v0.7596 SPEN Zornitza Stark reviewed gene: SPEN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Radio-Tartaglia syndrome, MIM# 619312; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7596 AFF3 Zornitza Stark Marked gene: AFF3 as ready
Mendeliome v0.7593 KDR Zornitza Stark Marked gene: KDR as ready
Mendeliome v0.7593 KDR Zornitza Stark Phenotypes for gene: KDR were changed from to Pulmonary hypertension; Haemangioma, capillary infantile, somatic 602089
Mendeliome v0.7590 KDR Zornitza Stark reviewed gene: KDR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31980491, 29650961, 18931684; Phenotypes: Pulmonary hypertension, Haemangioma, capillary infantile, somatic 602089; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7590 TRIM2 Zornitza Stark Marked gene: TRIM2 as ready
Mendeliome v0.7590 TRIM2 Zornitza Stark Phenotypes for gene: TRIM2 were changed from to Charcot-Marie-Tooth disease, type 2R, MIM# 615490; MONDO:0014208
Mendeliome v0.7587 TRIM2 Zornitza Stark reviewed gene: TRIM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23562820, 25893792, 18687884, 32815244, 32205255, 25893792; Phenotypes: Charcot-Marie-Tooth disease, type 2R, MIM# 615490, MONDO:0014208; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7587 RAB7A Zornitza Stark Marked gene: RAB7A as ready
Mendeliome v0.7587 RAB7A Zornitza Stark Phenotypes for gene: RAB7A were changed from to Charcot-Marie-Tooth disease, type 2B, MIM# 600882; MONDO:0010949
Mendeliome v0.7584 RAB7A Zornitza Stark reviewed gene: RAB7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 12545426, 17060578, 32326241, 29130394, 25614874; Phenotypes: Charcot-Marie-Tooth disease, type 2B, MIM# 600882, MONDO:0010949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7584 PRDM12 Zornitza Stark Marked gene: PRDM12 as ready
Mendeliome v0.7584 PRDM12 Zornitza Stark Phenotypes for gene: PRDM12 were changed from to Neuropathy, hereditary sensory and autonomic, type VIII, MIM# 616488; MONDO:0014662
Mendeliome v0.7581 PRDM12 Zornitza Stark reviewed gene: PRDM12: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005867, 33789102, 33010785, 32828702; Phenotypes: Neuropathy, hereditary sensory and autonomic, type VIII, MIM# 616488, MONDO:0014662; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7581 FIP1L1 Zornitza Stark Marked gene: FIP1L1 as ready
Mendeliome v0.7580 THBS2 Zornitza Stark Marked gene: THBS2 as ready
Mendeliome v0.7580 THBS2 Zornitza Stark Phenotypes for gene: THBS2 were changed from to {Lumbar disc herniation, susceptibility to} 603932
Mendeliome v0.7578 THBS2 Zornitza Stark reviewed gene: THBS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Lumbar disc herniation, susceptibility to} 603932; Mode of inheritance: None
Mendeliome v0.7578 ADIPOQ Zornitza Stark Marked gene: ADIPOQ as ready
Mendeliome v0.7578 ADIPOQ Zornitza Stark Added comment: Comment when marking as ready: No evidence for association with Mendelian disease.
Mendeliome v0.7575 INTU Zornitza Stark Marked gene: INTU as ready
Mendeliome v0.7572 NGF Zornitza Stark Marked gene: NGF as ready
Mendeliome v0.7572 NGF Zornitza Stark Phenotypes for gene: NGF were changed from to Neuropathy, hereditary sensory and autonomic, type V, MIM# 608654; MONDO:0012092
Mendeliome v0.7569 NGF Zornitza Stark reviewed gene: NGF: Rating: GREEN; Mode of pathogenicity: None; Publications: 14976160, 20978020, 33884296, 32693191, 31685654, 30296891; Phenotypes: Neuropathy, hereditary sensory and autonomic, type V, MIM# 608654, MONDO:0012092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7569 SPEG Zornitza Stark Phenotypes for gene: SPEG were changed from Centronuclear myopathy 5, MIM# 615959 to Centronuclear myopathy 5, MIM# 615959; Dilated cardiomyopathy
Mendeliome v0.7567 SPEG Zornitza Stark edited their review of gene: SPEG: Added comment: PMIDs 32925938;33794647: Reports of early onset isolated DCM, as well as cardiomyopathy in the context of skeletal myopathy.; Changed publications: 25087613, 31625632, 30412272, 30157964, 29614691, 29474540, 28624463, 26578207, 25087613, 32925938, 33794647; Changed phenotypes: Centronuclear myopathy 5, MIM# 615959, Dilated cardiomyopathy
Mendeliome v0.7567 NDUFB3 Zornitza Stark Marked gene: NDUFB3 as ready
Mendeliome v0.7567 NDUFB3 Zornitza Stark Phenotypes for gene: NDUFB3 were changed from to Mitochondrial complex I deficiency, nuclear type 25, MIM# 618246; MONDO:0032629
Mendeliome v0.7564 NDUFB3 Zornitza Stark reviewed gene: NDUFB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27091925; Phenotypes: Mitochondrial complex I deficiency, nuclear type 25, MIM# 618246, MONDO:0032629; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7564 NDUFB3 Elena Savva reviewed gene: NDUFB3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22499348; Phenotypes: Mitochondrial complex I deficiency, nuclear type 25, MIM#618246; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7563 EXOSC1 Zornitza Stark Phenotypes for gene: EXOSC1 were changed from Pontocerebellar hypoplasia to Pontocerebellar hypoplasia, type 1F, MIM# 619304
Mendeliome v0.7562 EXOSC1 Zornitza Stark edited their review of gene: EXOSC1: Changed phenotypes: Pontocerebellar hypoplasia, type 1F, MIM# 619304
Mendeliome v0.7562 SLC25A46 Zornitza Stark Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505 to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Pontocerebellar hypoplasia, type 1E, MIM# 619303
Mendeliome v0.7561 SLC25A46 Zornitza Stark changed review comment from: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus.

At least 10 unrelated families reported, supportive functional data.; to: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus. New disease entity added by OMIM in 2021 to reflect this more severe end of the spectrum.

At least 10 unrelated families reported, supportive functional data.
Mendeliome v0.7561 SLC25A46 Zornitza Stark edited their review of gene: SLC25A46: Changed phenotypes: Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505, Pontocerebellar hypoplasia, type 1E, MIM# 619303
Mendeliome v0.7559 EXOC2 Zornitza Stark Phenotypes for gene: EXOC2 were changed from Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology to Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia, MIM# 619306; Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology
Mendeliome v0.7558 EXOC2 Zornitza Stark edited their review of gene: EXOC2: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia, MIM# 619306, Global developmental delay, Intellectual disability, Abnormality of the face, Abnormality of brain morphology
Mendeliome v0.7558 SPI1 Zornitza Stark Marked gene: SPI1 as ready
Mendeliome v0.7557 SPI1 Zornitza Stark gene: SPI1 was added
gene: SPI1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPI1 were set to 33951726
Phenotypes for gene: SPI1 were set to Agammaglobulinaemia
Review for gene: SPI1 was set to GREEN
Added comment: Six unrelated individuals reported, four with de novo variants, two unphased. Some functional data.
Sources: Literature
Mendeliome v0.7556 NDRG1 Zornitza Stark Marked gene: NDRG1 as ready
Mendeliome v0.7556 NDRG1 Zornitza Stark Phenotypes for gene: NDRG1 were changed from to Charcot Marie Tooth disease, type 4D, 601455; MONDO:0011085; Auditory neuropathy
Mendeliome v0.7553 NDRG1 Zornitza Stark reviewed gene: NDRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10831399, 24136616, 33334662, 29724652, 29174527, 28776325; Phenotypes: Charcot Marie Tooth disease, type 4D, 601455, MONDO:0011085, Auditory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7553 MTMR2 Zornitza Stark Marked gene: MTMR2 as ready
Mendeliome v0.7553 MTMR2 Zornitza Stark Phenotypes for gene: MTMR2 were changed from to Charcot-Marie-Tooth disease, type 4B1, 601382; MONDO:0011066
Mendeliome v0.7550 MTMR2 Zornitza Stark reviewed gene: MTMR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10802647, 16249189, 33653949, 32586600, 32488727, 31680794; Phenotypes: Charcot-Marie-Tooth disease, type 4B1, 601382, MONDO:0011066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7550 TMEM222 Zornitza Stark Marked gene: TMEM222 as ready
Mendeliome v0.7549 TMEM222 Zornitza Stark gene: TMEM222 was added
gene: TMEM222 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: TMEM222 was set to GREEN
Added comment: Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants. The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17.
Sources: Literature
Mendeliome v0.7548 CHD5 Zornitza Stark Marked gene: CHD5 as ready
Mendeliome v0.7546 MME Zornitza Stark Marked gene: MME as ready
Mendeliome v0.7546 MME Zornitza Stark Phenotypes for gene: MME were changed from to Charcot-Marie-Tooth disease, axonal, type 2T, MIM# 617017; MONDO:0014866; Spinocerebellar ataxia 43 MIM#617018
Mendeliome v0.7543 MME Zornitza Stark reviewed gene: MME: Rating: GREEN; Mode of pathogenicity: None; Publications: 26991897, 27588448, 33144514, 31429185, 27583304; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2T, MIM# 617017, MONDO:0014866, Spinocerebellar ataxia 43 MIM#617018; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7543 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant to Mental retardation, autosomal recessive 45, MIM#615979; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant
Mendeliome v0.7541 FBXO31 Zornitza Stark changed review comment from: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.
Sources: Expert list; to: AR intellectual disability: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.
Sources: Expert list
Mendeliome v0.7541 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Added comment: PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP.; Changed rating: GREEN; Changed publications: 24623383, 33675180, 32989326; Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Spastic-dystonic cerebral palsy, de novo dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7541 RCAN1 Zornitza Stark Marked gene: RCAN1 as ready
Mendeliome v0.7539 ZNFX1 Zornitza Stark Marked gene: ZNFX1 as ready
Mendeliome v0.7536 STXBP3 Zornitza Stark Marked gene: STXBP3 as ready
Mendeliome v0.7535 STXBP3 Zornitza Stark gene: STXBP3 was added
gene: STXBP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STXBP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STXBP3 were set to 33891011
Phenotypes for gene: STXBP3 were set to Very Early Onset Inflammatory Bowel Disease; Bilateral Sensorineural Hearing Loss; Immune Dysregulation
Review for gene: STXBP3 was set to GREEN
Added comment: 10 individuals from 5 families reported.
Sources: Literature
Mendeliome v0.7534 IL21R Zornitza Stark Marked gene: IL21R as ready
Mendeliome v0.7531 SCD Zornitza Stark Marked gene: SCD as ready
Mendeliome v0.7530 DPYSL5 Zornitza Stark Marked gene: DPYSL5 as ready
Mendeliome v0.7529 SIN3B Zornitza Stark Marked gene: SIN3B as ready
Mendeliome v0.7523 JAG2 Zornitza Stark Marked gene: JAG2 as ready
Mendeliome v0.7522 NEPRO Zornitza Stark Marked gene: NEPRO as ready
Mendeliome v0.7521 LRSAM1 Zornitza Stark Marked gene: LRSAM1 as ready
Mendeliome v0.7521 LRSAM1 Zornitza Stark Phenotypes for gene: LRSAM1 were changed from to Charcot-Marie-Tooth disease, axonal, type 2P, MIM# 614436; MONDO:0013753
Mendeliome v0.7518 LRSAM1 Zornitza Stark reviewed gene: LRSAM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20865121, 22012984, 22781092, 27686364, 33568173, 33414056, 30996334; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2P, MIM# 614436, MONDO:0013753; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7518 LITAF Zornitza Stark Marked gene: LITAF as ready
Mendeliome v0.7518 LITAF Zornitza Stark Phenotypes for gene: LITAF were changed from to Charcot-Marie-Tooth disease, type 1C, MIM# 601098; MONDO:0010995
Mendeliome v0.7515 LITAF Zornitza Stark reviewed gene: LITAF: Rating: GREEN; Mode of pathogenicity: None; Publications: 12525712, 19541485, 23359569, 32665875, 28211240; Phenotypes: Charcot-Marie-Tooth disease, type 1C, MIM# 601098, MONDO:0010995; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7515 SLC3A1 Zornitza Stark Marked gene: SLC3A1 as ready
Mendeliome v0.7512 LSM7 Bryony Thompson Marked gene: LSM7 as ready
Mendeliome v0.7511 LSM7 Bryony Thompson gene: LSM7 was added
gene: LSM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to DOI:https://doi.org/10.1016/j.xhgg.2021.100034
Phenotypes for gene: LSM7 were set to Leukodystrophy; foetal death
Review for gene: LSM7 was set to AMBER
Added comment: Homozygous variant (p.Asp41Asn) identified in a child with leukodystrophy and a homozygous variant (p.Arg69Pro) identified in an individual that died in utero. In vitro and in vivo (zebrafish) assays supporting pathogenicity of the 2 variants.
Sources: Literature
Mendeliome v0.7510 PTPN4 Bryony Thompson Marked gene: PTPN4 as ready
Mendeliome v0.7509 PTPN4 Bryony Thompson gene: PTPN4 was added
gene: PTPN4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability; developmental delay
Review for gene: PTPN4 was set to GREEN
Added comment: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Mendeliome v0.7508 SLC3A1 Michelle Torres reviewed gene: SLC3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25964309; Phenotypes: Cystinuria (MIM#220100) AD, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7507 POLR3K Zornitza Stark Marked gene: POLR3K as ready
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
Mendeliome v0.7505 SAG Zornitza Stark Marked gene: SAG as ready
Mendeliome v0.7502 YWHAG Zornitza Stark Marked gene: YWHAG as ready
Mendeliome v0.7502 YWHAG Zornitza Stark Added comment: Comment when marking as ready: Developmental and epileptic encephalopathy-56 (DEE56) is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by impaired intellectual development, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia
Mendeliome v0.7498 OCRL Zornitza Stark Marked gene: OCRL as ready
Mendeliome v0.7491 NEK1 Zornitza Stark Marked gene: NEK1 as ready
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.
Mendeliome v0.7488 PDGFRB Eleanor Williams reviewed gene: PDGFRB: Rating: ; Mode of pathogenicity: None; Publications: 33450762; Phenotypes: Ocular pterygium-digital keloid dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7488 INF2 Zornitza Stark Marked gene: INF2 as ready
Mendeliome v0.7488 INF2 Zornitza Stark Phenotypes for gene: INF2 were changed from to Charcot-Marie-Tooth disease, dominant intermediate E, MIM# 614455; Glomerulosclerosis, focal segmental, 5, MIM# 613237
Mendeliome v0.7485 INF2 Zornitza Stark reviewed gene: INF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22187985, 30680856, 25943269, 20023659; Phenotypes: Charcot-Marie-Tooth disease, dominant intermediate E, MIM# 614455, Glomerulosclerosis, focal segmental, 5, MIM# 613237; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7485 MED25 Zornitza Stark changed review comment from: Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in mental retardation, as well as variable eye, brain, cardiac, and palatal abnormalities.

7 individuals from 4 families reported initially, founder variant p.Tyr39Cys. Over 20 individuals reported since, including other variants.; to: Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in intellectual disability, as well as variable eye, brain, cardiac, and palatal abnormalities.

7 individuals from 4 families reported initially, founder variant p.Tyr39Cys. Over 20 individuals reported since, including other variants.
Mendeliome v0.7485 MED25 Zornitza Stark Marked gene: MED25 as ready
Mendeliome v0.7485 MED25 Zornitza Stark Phenotypes for gene: MED25 were changed from to Basel-Vanagait-Smirin-Yosef syndrome, MIM# 616449; Congenital cataract-microcephaly-naevus flammeus syndrome MONDO:0014643
Mendeliome v0.7482 MED25 Zornitza Stark reviewed gene: MED25: Rating: GREEN; Mode of pathogenicity: None; Publications: 25792360, 32816121; Phenotypes: Basel-Vanagait-Smirin-Yosef syndrome, MIM# 616449, Congenital cataract-microcephaly-naevus flammeus syndrome MONDO:0014643; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7482 HSPB1 Zornitza Stark Marked gene: HSPB1 as ready
Mendeliome v0.7482 HSPB1 Zornitza Stark Phenotypes for gene: HSPB1 were changed from to Charcot Marie Tooth disease, axonal, type 2F, 606595; MONDO:0011687; Neuropathy, distal hereditary motor, type IIB, 608634; MONDO:0012080
Mendeliome v0.7479 HSPB1 Zornitza Stark reviewed gene: HSPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21785432, 15122254, 18832141, 32639100, 32334137; Phenotypes: Charcot Marie Tooth disease, axonal, type 2F, 606595, MONDO:0011687, Neuropathy, distal hereditary motor, type IIB, 608634, MONDO:0012080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7479 HINT1 Zornitza Stark Marked gene: HINT1 as ready
Mendeliome v0.7479 HINT1 Zornitza Stark Phenotypes for gene: HINT1 were changed from to Neuromyotonia and axonal neuropathy, autosomal recessive, MIM# 137200; Gamstorp-Wohlfart syndrome, MONDO:0007646
Mendeliome v0.7476 HINT1 Zornitza Stark reviewed gene: HINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22961002, 33663550, 33404983, 31848916; Phenotypes: Neuromyotonia and axonal neuropathy, autosomal recessive, MIM# 137200, Gamstorp-Wohlfart syndrome, MONDO:0007646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7476 GNB4 Zornitza Stark Marked gene: GNB4 as ready
Mendeliome v0.7476 GNB4 Zornitza Stark Phenotypes for gene: GNB4 were changed from to Charcot-Marie-Tooth disease, dominant intermediate F, MIM# 615185; MONDO:0014074
Mendeliome v0.7473 GNB4 Zornitza Stark reviewed gene: GNB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23434117, 28642160, 27908631; Phenotypes: Charcot-Marie-Tooth disease, dominant intermediate F, MIM# 615185, MONDO:0014074; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7473 GJB1 Zornitza Stark Marked gene: GJB1 as ready
Mendeliome v0.7473 GJB1 Zornitza Stark Phenotypes for gene: GJB1 were changed from to Charcot-Marie-Tooth neuropathy, X-linked dominant, 1, MIM# 302800; MONDO:0010549; reversible posterior leukoencephalopathy
Mendeliome v0.7470 NEPRO Chern Lim gene: NEPRO was added
gene: NEPRO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, MIM618853
Review for gene: NEPRO was set to AMBER
Added comment: PMIDs 26633546, 29620724: 2 families with the same homozygous missense variant, haplotype analysis confirmed the founder nature of the variant.

PMID 31250547: 1 family with homozygous novel missense

All 5 affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. No functional studies.
Sources: Literature
Mendeliome v0.7470 GJB1 Zornitza Stark reviewed gene: GJB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8266101, 17100997, 17353473, 31842800; Phenotypes: Charcot-Marie-Tooth neuropathy, X-linked dominant, 1, MIM# 302800, MONDO:0010549, reversible posterior leukoencephalopathy; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.7470 FGD4 Zornitza Stark Marked gene: FGD4 as ready
Mendeliome v0.7470 FGD4 Zornitza Stark Phenotypes for gene: FGD4 were changed from to Charcot Marie Tooth disease, type 4H, 609311; MONDO:0012250
Mendeliome v0.7467 FGD4 Zornitza Stark reviewed gene: FGD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564959, 31152969, 28847448, 28543957; Phenotypes: Charcot Marie Tooth disease, type 4H, 609311, MONDO:0012250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7467 COX6A1 Zornitza Stark Marked gene: COX6A1 as ready
Mendeliome v0.7467 COX6A1 Zornitza Stark Phenotypes for gene: COX6A1 were changed from to Charcot Marie Tooth disease, recessive intermediate D, MIM# 616039; MONDO:0014467
Mendeliome v0.7464 COX6A1 Zornitza Stark reviewed gene: COX6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152455, 26302975, 25152455; Phenotypes: Charcot Marie Tooth disease, recessive intermediate D, MIM# 616039, MONDO:0014467; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7464 JAG2 Belinda Chong gene: JAG2 was added
gene: JAG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: JAG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAG2 were set to PMID: 33861953
Phenotypes for gene: JAG2 were set to muscular dystrophy
Review for gene: JAG2 was set to GREEN
Added comment: Whole-exome sequencing identified 13 families with rare homozygous or compound heterozygous JAG2 variants. Bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy.
Sources: Literature
Mendeliome v0.7464 VPS41 Kristin Rigbye changed review comment from: "Five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function."; to: "Five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function."

"Affected individuals were born after uneventful pregnancies and presented in most cases early in life with developmental delay. Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation. Likewise, nystagmus was commonly described. In addition, all affected individuals displayed intellectual disability and speech delay. Two siblings further presented with therapy-resistant epilepsy. No major dysmorphic features were found. In two individuals, retinal pigment alterations were noticed. Brain MRI revealed mild cerebellar atrophy and vermian atrophy without other major structural abnormalities in most affected individuals while in one case (Subject 9) bilateral hyperintensities at the nucleus caudatus area were noted. No hearing or vision problems were noted and in cases where nerve conduction studies were performed, these were normal. Transmission electron microscopy (TEM) on peripheral blood lymphocytes from Subject 2 and lymphoblastoid cells from Subject 3 revealed more multilayered vesicles compared to control cells."
Mendeliome v0.7464 SIN3B Elena Savva gene: SIN3B was added
gene: SIN3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIN3B were set to PMID: 33811806
Phenotypes for gene: SIN3B were set to Syndromic intellectual disability/autism spectrum disorder
Review for gene: SIN3B was set to GREEN
Added comment: PMID: 33811806
- 9 affected patients, all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
- CNVs encompassing the gene have been found
Sources: Literature
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
Mendeliome v0.7464 CDC40 Zornitza Stark Phenotypes for gene: CDC40 were changed from Pontocerebellar hypoplasia; microcephaly; seizures to Pontocerebellar hypoplasia, type 15, MIM# 619302; microcephaly; seizures
Mendeliome v0.7463 CDC40 Zornitza Stark edited their review of gene: CDC40: Changed phenotypes: Pontocerebellar hypoplasia, type 15, MIM# 619302, microcephaly, seizures
Mendeliome v0.7463 PPIL1 Zornitza Stark Phenotypes for gene: PPIL1 were changed from Pontocerebellar hypoplasia; microcephaly; seizures to Pontocerebellar hypoplasia, type 14, MIM# 619301; microcephaly; seizures
Mendeliome v0.7462 PPIL1 Zornitza Stark edited their review of gene: PPIL1: Changed phenotypes: Pontocerebellar hypoplasia, type 14, MIM# 619301, microcephaly, seizures
Mendeliome v0.7462 BICD2 Zornitza Stark Marked gene: BICD2 as ready
Mendeliome v0.7462 BICD2 Zornitza Stark Phenotypes for gene: BICD2 were changed from to Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM# 615290; MONDO:0014121; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, MIM# 618291
Mendeliome v0.7459 BICD2 Zornitza Stark reviewed gene: BICD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23664116, 23664119, 23664120, 27751653, 28635954, 30054298, 29528393; Phenotypes: Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM# 615290, MONDO:0014121, Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, MIM# 618291; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7459 SMARCA2 Zornitza Stark Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome, MIM#619293
Mendeliome v0.7457 KCNQ5 Zornitza Stark Marked gene: KCNQ5 as ready
Mendeliome v0.7457 KCNQ5 Zornitza Stark Phenotypes for gene: KCNQ5 were changed from to Mental retardation, autosomal dominant 46, MIM# 617601
Mendeliome v0.7454 KCNQ5 Zornitza Stark reviewed gene: KCNQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 28669405, 30359776; Phenotypes: Mental retardation, autosomal dominant 46, MIM# 617601; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7454 KCNK9 Zornitza Stark Marked gene: KCNK9 as ready
Mendeliome v0.7454 KCNK9 Zornitza Stark Phenotypes for gene: KCNK9 were changed from to Birk-Barel syndrome, MIM# 612292; MONDO:0012856
Mendeliome v0.7451 KCNK9 Zornitza Stark reviewed gene: KCNK9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28333430, 27151206, 24980697, 18678320; Phenotypes: Birk-Barel syndrome, MIM# 612292, MONDO:0012856; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.7451 KCNK9 Ain Roesley reviewed gene: KCNK9: Rating: GREEN; Mode of pathogenicity: None; Publications: 18678320, 27151206; Phenotypes: Birk-Barel syndrome (MIM#612292); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.7451 ATL1 Zornitza Stark edited their review of gene: ATL1: Changed phenotypes: Neuropathy, hereditary sensory, type ID , MIM#613708, MONDO:0013381, Spastic paraplegia 3A, MIM 182600, Hereditary spastic paraplegia, AR
Mendeliome v0.7451 ATL1 Zornitza Stark Marked gene: ATL1 as ready
Mendeliome v0.7451 ATL1 Zornitza Stark Phenotypes for gene: ATL1 were changed from Neuropathy, hereditary sensory, type ID , MIM#613708; MONDO:0013381 to Neuropathy, hereditary sensory, type ID , MIM#613708; MONDO:0013381; Spastic paraplegia 3A, MIM 182600; Hereditary spastic paraplegia, AR
Mendeliome v0.7450 ATL1 Zornitza Stark Phenotypes for gene: ATL1 were changed from to Neuropathy, hereditary sensory, type ID , MIM#613708; MONDO:0013381
Mendeliome v0.7447 ATL1 Zornitza Stark reviewed gene: ATL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21194679, 24604904, 22340599, 16401858, 16537571, 17657515, 28396731, 24473461, 26888483; Phenotypes: Neuropathy, hereditary sensory, type ID , MIM#613708, MONDO:0013381; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7447 COQ2 Zornitza Stark Marked gene: COQ2 as ready
Mendeliome v0.7447 COQ2 Zornitza Stark Phenotypes for gene: COQ2 were changed from to Coenzyme Q10 deficiency, primary, 1, MIM# 607426; MONDO:0011829
Mendeliome v0.7444 COQ2 Zornitza Stark reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16400613, 17332895, 17855635; Phenotypes: Coenzyme Q10 deficiency, primary, 1, MIM# 607426, MONDO:0011829; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7444 COA6 Zornitza Stark Marked gene: COA6 as ready
Mendeliome v0.7444 COA6 Zornitza Stark Phenotypes for gene: COA6 were changed from to Mitochondrial complex IV deficiency, nuclear type 13, MIM# 616501; Cardioencephalomyopathy, fatal infantile, MONDO:0014668
Mendeliome v0.7441 COA6 Zornitza Stark reviewed gene: COA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 24549041, 25339201, 31851937, 26160915; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 13, MIM# 616501, Cardioencephalomyopathy, fatal infantile, MONDO:0014668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7441 CARS2 Zornitza Stark Marked gene: CARS2 as ready
Mendeliome v0.7441 CARS2 Zornitza Stark Gene: cars2 has been classified as Green List (High Evidence).
Mendeliome v0.7441 CARS2 Zornitza Stark Phenotypes for gene: CARS2 were changed from to Combined oxidative phosphorylation deficiency 27, MIM# 616672; MONDO:0014728
Mendeliome v0.7440 CARS2 Zornitza Stark Publications for gene: CARS2 were set to
Mendeliome v0.7439 CARS2 Zornitza Stark Mode of inheritance for gene: CARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7438 CARS2 Zornitza Stark reviewed gene: CARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25361775, 25787132, 30139652; Phenotypes: Combined oxidative phosphorylation deficiency 27, MIM# 616672, MONDO:0014728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7438 PPP2R5C Zornitza Stark Marked gene: PPP2R5C as ready
Mendeliome v0.7437 PPP2R5C Sue White gene: PPP2R5C was added
gene: PPP2R5C was added to Mendeliome. Sources: Research
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PPP2R5C were set to macrocephaly; intellectual disability
Penetrance for gene: PPP2R5C were set to Complete
Review for gene: PPP2R5C was set to AMBER
Added comment: Emerging unpublished evidence of monoallelic missense variants causing intellectual disability and macrocephaly
Sources: Research
Mendeliome v0.7436 SLX4 Zornitza Stark Marked gene: SLX4 as ready
Mendeliome v0.7432 SGCE Zornitza Stark Marked gene: SGCE as ready
Mendeliome v0.7429 PRKRA Zornitza Stark Marked gene: PRKRA as ready
Mendeliome v0.7426 KMT2B Zornitza Stark Marked gene: KMT2B as ready
Mendeliome v0.7423 CIZ1 Zornitza Stark Marked gene: CIZ1 as ready
Mendeliome v0.7419 NPAS2 Zornitza Stark Marked gene: NPAS2 as ready
Mendeliome v0.7415 NPAS2 Alison Compton changed review comment from: The brothers with NOA from consanguineous Turkish family, homozygous NM_002518.3(NPAS2) c.1363C>G; p.(Pro455Ala) variant identified. Heterozygous in mother, and fertile brother and sister. Not present in 1000 Genomes, EVS or gnomAD. Predicted to be “benign” by Polyphen2, and "neutral" by both SIFT and Mutation taster. Not predicted to in a functional domain. Not listed as a disease-gene in OMIM, no other 'pathogenic' or 'likely pathogenic' variants listed in ClinVar. Paper did not include any functional work.; to: Three brothers with NOA from consanguineous Turkish family, homozygous NM_002518.3(NPAS2) c.1363C>G; p.(Pro455Ala) variant identified. Found to be heterozygous in mother, and fertile brother and sister. Not present in 1000 Genomes, EVS or gnomAD. Predicted to be “benign” by Polyphen2, and "neutral" by both SIFT and Mutation taster. Not predicted to be within a functional domain. Gene not listed as a disease-gene in OMIM, no other 'pathogenic' or 'likely pathogenic' variants listed in ClinVar. Publication did not include any functional work as support.
Mendeliome v0.7415 PNKD Zornitza Stark Marked gene: PNKD as ready
Mendeliome v0.7415 PNKD Zornitza Stark Phenotypes for gene: PNKD were changed from to Paroxysmal nonkinesigenic dyskinesia 1, MIM# 118800; MONDO:0007326
Mendeliome v0.7412 PNKD Zornitza Stark reviewed gene: PNKD: Rating: GREEN; Mode of pathogenicity: None; Publications: 15262732, 15496428, 15824259, 19124534, 21487022; Phenotypes: Paroxysmal nonkinesigenic dyskinesia 1, MIM# 118800, MONDO:0007326; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7412 MECR Zornitza Stark Marked gene: MECR as ready
Mendeliome v0.7409 HPCA Zornitza Stark Marked gene: HPCA as ready
Mendeliome v0.7406 GNAL Zornitza Stark Marked gene: GNAL as ready
Mendeliome v0.7403 ADCY5 Zornitza Stark Marked gene: ADCY5 as ready
Mendeliome v0.7399 XPNPEP3 Zornitza Stark edited their review of gene: XPNPEP3: Added comment: PMID 20179356: two families with 5 individuals reported. Functional data, including animal models, supportive evidence for involvement in ciliary function.

PMID 32660933: Additional case reported.; Changed rating: GREEN; Changed publications: 20179356, 32660933
Mendeliome v0.7399 THAP1 Zornitza Stark Marked gene: THAP1 as ready
Mendeliome v0.7395 CHST11 Zornitza Stark Marked gene: CHST11 as ready
Mendeliome v0.7394 CHST11 Zornitza Stark gene: CHST11 was added
gene: CHST11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CHST11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHST11 were set to 26436107; 29514872
Phenotypes for gene: CHST11 were set to Osteochondrodysplasia, brachydactyly, and overlapping malformed digits, MIM# 618167
Review for gene: CHST11 was set to AMBER
Added comment: Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum.

Two unrelated families reported, note one had a homozygous deletion. One family had 10 affected individuals.
Sources: Expert Review
Mendeliome v0.7392 PSMB8 Zornitza Stark Marked gene: PSMB8 as ready
Mendeliome v0.7388 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Added comment: PMID 33807164: third unrelated family reported with CTD phenotype, single affected individual with bi-alllelic LoF variant, cutis laxa and multiple herniations.; Changed publications: 32006683, 31792352, 33807164
Mendeliome v0.7388 PPARG Zornitza Stark Marked gene: PPARG as ready
Mendeliome v0.7388 PPARG Zornitza Stark Gene: pparg has been classified as Green List (High Evidence).
Mendeliome v0.7388 PPARG Zornitza Stark Phenotypes for gene: PPARG were changed from to Lipodystrophy, familial partial, type 3, MIM# 604367; MONDO:0011448
Mendeliome v0.7387 PPARG Zornitza Stark Publications for gene: PPARG were set to
Mendeliome v0.7386 PPARG Zornitza Stark Mode of inheritance for gene: PPARG was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7385 PPARG Zornitza Stark reviewed gene: PPARG: Rating: GREEN; Mode of pathogenicity: None; Publications: 10622252, 12453919, 11788685, 31863320; Phenotypes: Lipodystrophy, familial partial, type 3, MIM# 604367, MONDO:0011448; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7385 POLD1 Zornitza Stark Marked gene: POLD1 as ready
Mendeliome v0.7385 POLD1 Zornitza Stark Phenotypes for gene: POLD1 were changed from to Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381; MONDO:0014157
Mendeliome v0.7382 POLD1 Zornitza Stark reviewed gene: POLD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23770608, 33618333, 33369179, 32826474, 30023403, 29199204, 28791128; Phenotypes: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381, MONDO:0014157; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7382 PLIN1 Zornitza Stark Marked gene: PLIN1 as ready
Mendeliome v0.7382 PLIN1 Zornitza Stark Phenotypes for gene: PLIN1 were changed from to Lipodystrophy, familial partial, type 4, MIM# 613877
Mendeliome v0.7378 PLIN1 Zornitza Stark reviewed gene: PLIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21345103, 31504636, 30020498, 25114292; Phenotypes: Lipodystrophy, familial partial, type 4, MIM# 613877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7378 PCYT1A Zornitza Stark Marked gene: PCYT1A as ready
Mendeliome v0.7374 KCNJ6 Zornitza Stark changed review comment from: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth.

Three unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model.; to: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth.

Four unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model. One of the individuals did not have lipodystrophy but had a prominent hyperkinetic movement disorder.
Mendeliome v0.7374 KCNJ6 Zornitza Stark Marked gene: KCNJ6 as ready
Mendeliome v0.7371 EIF4G1 Zornitza Stark Marked gene: EIF4G1 as ready
Mendeliome v0.7371 EIF4G1 Zornitza Stark Phenotypes for gene: EIF4G1 were changed from to {Parkinson disease 18} 614251
Mendeliome v0.7367 EIF4G1 Zornitza Stark reviewed gene: EIF4G1: Rating: RED; Mode of pathogenicity: None; Publications: 21907011, 23408866, 25368108; Phenotypes: {Parkinson disease 18} 614251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7367 CIDEC Zornitza Stark Marked gene: CIDEC as ready
Mendeliome v0.7367 CIDEC Zornitza Stark Phenotypes for gene: CIDEC were changed from to Lipodystrophy, familial partial, type 5, MIM# 615238
Mendeliome v0.7363 CIDEC Zornitza Stark reviewed gene: CIDEC: Rating: RED; Mode of pathogenicity: None; Publications: 20049731; Phenotypes: Lipodystrophy, familial partial, type 5, MIM# 615238; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7363 SAG Teresa Zhao reviewed gene: SAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 22419846, 9452120; Phenotypes: Oguchi disease-1 (MIM#258100), AR, Retinitis pigmentosa 47 (MIM#613758); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7363 LIG3 Zornitza Stark changed review comment from: Three unrelated families and functional data.
Sources: Literature; to: Seven individuals from three unrelated families and functional data, variable ages of onset from early childhood to late adolescence.
Sources: Literature
Mendeliome v0.7363 LIG3 Zornitza Stark Marked gene: LIG3 as ready
Mendeliome v0.7362 LIG3 Zornitza Stark gene: LIG3 was added
gene: LIG3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy
Review for gene: LIG3 was set to GREEN
Added comment: Three unrelated families and functional data.
Sources: Literature
Mendeliome v0.7361 HNRNPDL Bryony Thompson Marked gene: HNRNPDL as ready
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
Mendeliome v0.7359 JMJD1C Zornitza Stark Marked gene: JMJD1C as ready
Mendeliome v0.7358 JMJD1C Zornitza Stark gene: JMJD1C was added
gene: JMJD1C was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JMJD1C were set to 26181491; 32996679
Phenotypes for gene: JMJD1C were set to Intellectual disability
Review for gene: JMJD1C was set to GREEN
Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity.

Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679).

Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype.
Sources: Expert Review
Mendeliome v0.7357 CAVIN1 Zornitza Stark Marked gene: CAVIN1 as ready
Mendeliome v0.7354 CAV1 Zornitza Stark Marked gene: CAV1 as ready
Mendeliome v0.7354 CAV1 Zornitza Stark Phenotypes for gene: CAV1 were changed from to Lipodystrophy, familial partial, type 7, autosomal dominant MIM# 606721; Lipodystrophy, congenital generalized, type 3, autosomal recessive, MIM# 612526
Mendeliome v0.7351 CAV1 Zornitza Stark reviewed gene: CAV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18237401, 25898808, 11739396, 18211975, 27717241, 26176221, 33836561, 33776068, 32502478, 22474227, 28768485; Phenotypes: Lipodystrophy, familial partial, type 7, autosomal dominant MIM# 606721, Lipodystrophy, congenital generalized, type 3, autosomal recessive, MIM# 612526; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7351 AFF4 Zornitza Stark Marked gene: AFF4 as ready
Mendeliome v0.7347 DNAJB13 Zornitza Stark changed review comment from: Additional individual identified by VCGS laboratory, homozygous LoF variant.; to: Additional individual identified by VCGS laboratory, homozygous LoF variant and PCD.
Mendeliome v0.7347 DNAJB13 Zornitza Stark changed review comment from: Additional individual identified by VCGS laboratory.; to: Additional individual identified by VCGS laboratory, homozygous LoF variant.
Mendeliome v0.7347 GCGR Zornitza Stark Marked gene: GCGR as ready
Mendeliome v0.7344 MED27 Zornitza Stark Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, MIM# 619286
Mendeliome v0.7343 MED27 Zornitza Stark reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, MIM# 619286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7343 ABCB6 Zornitza Stark Marked gene: ABCB6 as ready
Mendeliome v0.7343 ABCB6 Zornitza Stark Phenotypes for gene: ABCB6 were changed from to Pseudohyperkalemia, familial, 2, due to red cell leak, MIM# 609153; Microphthalmia, isolated, with coloboma 7, MIM# 614497; Dyschromatosis universalis hereditaria 3, MIM# 615402
Mendeliome v0.7340 ABCB6 Zornitza Stark reviewed gene: ABCB6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23180570; Phenotypes: Pseudohyperkalemia, familial, 2, due to red cell leak, MIM# 609153, Microphthalmia, isolated, with coloboma 7, MIM# 614497, Dyschromatosis universalis hereditaria 3, MIM# 615402; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7340 ABCA1 Zornitza Stark Marked gene: ABCA1 as ready
Mendeliome v0.7340 PRDM15 Zornitza Stark Marked gene: PRDM15 as ready
Mendeliome v0.7339 PRDM15 Zornitza Stark gene: PRDM15 was added
gene: PRDM15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM15 were set to 31950080
Phenotypes for gene: PRDM15 were set to Steroid resistant nephrotic syndrome; Holoprosencephaly
Review for gene: PRDM15 was set to AMBER
Added comment: Four consanguineous families reported with same homozygous variant, C844Y, shown to be LoF. Syndromic SRNS including HPE, brain malformations, polydactyly, congenital heart disease. Mouse model, extensive functional data focused on the brain phenotype. Two additional homozygous missense identified with isolated SRNS.
Sources: Literature
Mendeliome v0.7338 ZIC2 Zornitza Stark Marked gene: ZIC2 as ready
Mendeliome v0.7335 TGIF1 Zornitza Stark Marked gene: TGIF1 as ready
Mendeliome v0.7332 SIX3 Zornitza Stark Marked gene: SIX3 as ready
Mendeliome v0.7329 DISP1 Zornitza Stark Marked gene: DISP1 as ready
Mendeliome v0.7325 TBX3 Zornitza Stark Marked gene: TBX3 as ready
Mendeliome v0.7325 TBX3 Zornitza Stark Phenotypes for gene: TBX3 were changed from to Ulnar-mammary syndrome, MIM# 181450; MONDO:0008411
Mendeliome v0.7322 TBX3 Zornitza Stark reviewed gene: TBX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9207801, 19938096, 28145909; Phenotypes: Ulnar-mammary syndrome, MIM# 181450, MONDO:0008411; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7322 SALL1 Zornitza Stark Marked gene: SALL1 as ready
Mendeliome v0.7317 HELLS Zornitza Stark Marked gene: HELLS as ready
Mendeliome v0.7314 ZBTB24 Zornitza Stark Marked gene: ZBTB24 as ready
Mendeliome v0.7311 CDCA7 Zornitza Stark Marked gene: CDCA7 as ready
Mendeliome v0.7307 XPC Zornitza Stark Marked gene: XPC as ready
Mendeliome v0.7304 XPA Zornitza Stark Marked gene: XPA as ready
Mendeliome v0.7301 RMI2 Zornitza Stark Marked gene: RMI2 as ready
Mendeliome v0.7297 RAD51 Zornitza Stark Marked gene: RAD51 as ready
Mendeliome v0.7294 POLH Zornitza Stark Marked gene: POLH as ready
Mendeliome v0.7294 POLH Zornitza Stark Phenotypes for gene: POLH were changed from to Xeroderma pigmentosum, variant type, MIM# 278750; MONDO:0010214
Mendeliome v0.7291 POLH Zornitza Stark reviewed gene: POLH: Rating: GREEN; Mode of pathogenicity: None; Publications: 10385124, 10398605; Phenotypes: Xeroderma pigmentosum, variant type, MIM# 278750, MONDO:0010214; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7291 NEUROD2 Zornitza Stark Phenotypes for gene: NEUROD2 were changed from Epileptic encephalopathy, early infantile, 72, MIM# 618374 to Epileptic encephalopathy, early infantile, 72, MIM# 618374; Intellectual disability
Mendeliome v0.7289 NEUROD2 Zornitza Stark edited their review of gene: NEUROD2: Added comment: Additional two individuals reported with de novo variants and predominantly ID phenotype.; Changed publications: 33438828, 30323019; Changed phenotypes: Epileptic encephalopathy, early infantile, 72, MIM# 618374
Mendeliome v0.7289 MRE11 Zornitza Stark Marked gene: MRE11 as ready
Mendeliome v0.7286 MPLKIP Zornitza Stark Marked gene: MPLKIP as ready
Mendeliome v0.7283 PIK3CD Zornitza Stark Marked gene: PIK3CD as ready
Mendeliome v0.7280 GTF2H5 Zornitza Stark Marked gene: GTF2H5 as ready
Mendeliome v0.7277 GTF2E2 Zornitza Stark Marked gene: GTF2E2 as ready
Mendeliome v0.7273 FANCL Zornitza Stark Marked gene: FANCL as ready
Mendeliome v0.7270 FANCI Zornitza Stark Marked gene: FANCI as ready
Mendeliome v0.7267 FANCG Zornitza Stark Marked gene: FANCG as ready
Mendeliome v0.7264 FANCF Zornitza Stark Marked gene: FANCF as ready
Mendeliome v0.7261 FANCE Zornitza Stark Marked gene: FANCE as ready
Mendeliome v0.7258 MDM2 Zornitza Stark Marked gene: MDM2 as ready
Mendeliome v0.7254 NDUFB11 Zornitza Stark Phenotypes for gene: NDUFB11 were changed from Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); MONDO:0010494; Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021) to Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); MONDO:0010494; Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); MONDO:0026721
Mendeliome v0.7253 NDUFB11 Zornitza Stark Phenotypes for gene: NDUFB11 were changed from Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021) to Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); MONDO:0010494; Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021)
Mendeliome v0.7252 NDUFB11 Zornitza Stark Marked gene: NDUFB11 as ready
Mendeliome v0.7252 NDUFB11 Zornitza Stark Phenotypes for gene: NDUFB11 were changed from to Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021)
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).
Mendeliome v0.7249 NDUFB11 Kristin Rigbye reviewed gene: NDUFB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 28050600, 27488349, 30423443, 27488349; Phenotypes: Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952), Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.7249 FANCC Zornitza Stark Marked gene: FANCC as ready
Mendeliome v0.7242 FANCB Zornitza Stark Marked gene: FANCB as ready
Mendeliome v0.7239 SMG8 Zornitza Stark Phenotypes for gene: SMG8 were changed from Intellectual disability to Alzahrani-Kuwahara syndrome, MIM# 619268; Intellectual disability
Mendeliome v0.7238 SMG8 Zornitza Stark reviewed gene: SMG8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alzahrani-Kuwahara syndrome, MIM# 619268; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7238 FANCA Zornitza Stark Marked gene: FANCA as ready
Mendeliome v0.7235 ERCC8 Zornitza Stark Marked gene: ERCC8 as ready
Mendeliome v0.7231 GP1BA Zornitza Stark Marked gene: GP1BA as ready
Mendeliome v0.7231 GP1BA Zornitza Stark Phenotypes for gene: GP1BA were changed from to Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS); von Willebrand disease, platelet-type, (MIM#177820), AD (VWD); MONDO:0008332; Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS); MONDO:0007930
Mendeliome v0.7229 GP1BA Zornitza Stark reviewed gene: GP1BA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS), von Willebrand disease, platelet-type, (MIM#177820), AD (VWD), MONDO:0008332, Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS), MONDO:0007930; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7229 GP1BA Ain Roesley reviewed gene: GP1BA: Rating: GREEN; Mode of pathogenicity: None; Publications: 24934643; Phenotypes: Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS), von Willebrand disease, platelet-type, (MIM#177820), AD (VWD), Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7227 ERCC4 Zornitza Stark Marked gene: ERCC4 as ready
Mendeliome v0.7224 ERCC3 Zornitza Stark Marked gene: ERCC3 as ready
Mendeliome v0.7220 SDHA Zornitza Stark Phenotypes for gene: SDHA were changed from to Mitochondrial complex II deficiency, nuclear type 1, MIM# 252011; Cardiomyopathy, dilated, 1GG, MIM# 613642; Neurodegeneration with ataxia and late-onset optic atrophy, MIM# 619259; Paragangliomas 5 , MIM#614165
Mendeliome v0.7219 SDHA Zornitza Stark Marked gene: SDHA as ready
Mendeliome v0.7217 SDHA Zornitza Stark reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: None; Publications: 10976639, 27683074, 7550341, 22972948, 20551992, 21752896; Phenotypes: Mitochondrial complex II deficiency, nuclear type 1, MIM# 252011, Cardiomyopathy, dilated, 1GG, MIM# 613642, Neurodegeneration with ataxia and late-onset optic atrophy, MIM# 619259, Paragangliomas 5 , MIM#614165; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7217 SLC19A1 Zornitza Stark Marked gene: SLC19A1 as ready
Mendeliome v0.7216 ERCC2 Zornitza Stark Marked gene: ERCC2 as ready
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 v0.7212 NDUFA8 Zornitza Stark Phenotypes for gene: NDUFA8 were changed from NDUFA8-related mitochondrial disease; Developmental delay; microcehaly; seizures to Mitochondrial complex I deficiency, nuclear type 37, MIM# 619272; Developmental delay; microcehaly; seizures
Mendeliome v0.7209 NDUFA8 Zornitza Stark commented on gene: NDUFA8: Second family reported with pair of affected siblings and homozygous missense variant, some functional data.
Mendeliome v0.7209 NDUFA8 Zornitza Stark edited their review of gene: NDUFA8: Changed rating: AMBER; Changed publications: 32385911, 33153867; Changed phenotypes: Mitochondrial complex I deficiency, nuclear type 37, MIM# 619272, Developmental delay, microcehaly, seizures
Mendeliome v0.7206 KCNH1 Zornitza Stark Marked gene: KCNH1 as ready
Mendeliome v0.7206 KCNH1 Zornitza Stark Phenotypes for gene: KCNH1 were changed from to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Mendeliome v0.7203 KCNH1 Zornitza Stark reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811134; Phenotypes: Temple-Baraitser syndrome, OMIM:611816, Zimmermann-Laband syndrome 1, OMIM:135500, Intellectual disability, Encephalopathy without features of TBS/ZLS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v0.7201 EMC10 Zornitza Stark Phenotypes for gene: EMC10 were changed from Intellectual disability to Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264
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 v0.7199 ITGB3 Zornitza Stark Marked gene: ITGB3 as ready
Mendeliome v0.7194 UNC50 Zornitza Stark Marked gene: UNC50 as ready
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
Mendeliome v0.7192 PLCH1 Zornitza Stark Marked gene: PLCH1 as ready
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
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
Mendeliome v0.7191 DDX11 Zornitza Stark Marked gene: DDX11 as ready
Mendeliome v0.7191 DDX11 Zornitza Stark Phenotypes for gene: DDX11 were changed from to Warsaw breakage syndrome, MIM# 613398; MONDO:0013252
Mendeliome v0.7188 DDX11 Zornitza Stark reviewed gene: DDX11: Rating: GREEN; Mode of pathogenicity: None; Publications: 20137776, 23033317, 30216658; Phenotypes: Warsaw breakage syndrome, MIM# 613398, MONDO:0013252; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7188 PDIA6 Zornitza Stark Marked gene: PDIA6 as ready
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
Mendeliome v0.7186 EXOSC1 Zornitza Stark Marked gene: EXOSC1 as ready
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
Mendeliome v0.7185 MED12 Zornitza Stark Phenotypes for gene: MED12 were changed from Ohdo syndrome, X-linked MIM#300895; Lujan-Fryns syndrome MIM#309520; Opitz-Kaveggia syndrome MIM#305450 to Ohdo syndrome, X-linked MIM#300895; Lujan-Fryns syndrome MIM#309520; Opitz-Kaveggia syndrome MIM#305450; Hardikar syndrome, OMIM #612726
Mendeliome v0.7183 MED12 Zornitza Stark reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33244166; Phenotypes: Hardikar syndrome, OMIM #612726; Mode of inheritance: Other
Mendeliome v0.7183 UBE4A Zornitza Stark Marked gene: UBE4A as ready
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
Mendeliome v0.7181 MAPKAPK5 Zornitza Stark Marked gene: MAPKAPK5 as ready
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
Mendeliome v0.7179 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; spastic paraparesis and bilateral cataracts
Mendeliome v0.7178 FAR1 Zornitza Stark Publications for gene: FAR1 were set to 25439727
Mendeliome v0.7177 FAR1 Zornitza Stark Mode of inheritance for gene: FAR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7176 FAR1 Zornitza Stark Classified gene: FAR1 as Green List (high evidence)
Mendeliome v0.7176 FAR1 Zornitza Stark Gene: far1 has been classified as Green List (High Evidence).
Mendeliome v0.7175 FAR1 Zornitza Stark edited their review of gene: FAR1: Added comment: PMID33239752: 12 patients with paediatric onset spastic paraparesis and bilateral congenital/juvenile cataracts. Most also had speech and gross motor developmental delay and truncal hypotonia. Exome sequencing identified de novo variants affecting the Arg480 residue in FAR1 (p.Arg480Cys/His/Leu). Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.; Changed rating: GREEN; Changed publications: 25439727, 33239752; Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, spastic paraparesis and bilateral cataracts; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7175 GRIA3 Zornitza Stark Marked gene: GRIA3 as ready
Mendeliome v0.7172 FAT1 Ee Ming Wong changed review comment from: - 5 consanguineous families with homozygous frameshift mutations in FAN1
- FAN1 KO mice had microphthalmia, with fully penetrant coloboma which was not observed in heterozygous mice
- in human retinal pigment epithelium (RPE) cells, FAN1 knockdown resulted in compromised early cell-cell junction integrity and filament organisation; to: - 5 consanguineous families with homozygous frameshift mutations in FAT1
- FAT1 KO mice had microphthalmia, with fully penetrant coloboma which was not observed in heterozygous mice
- in human retinal pigment epithelium (RPE) cells, FAT1 knockdown resulted in compromised early cell-cell junction integrity and filament organisation
Mendeliome v0.7172 SLC17A5 Zornitza Stark Marked gene: SLC17A5 as ready
Mendeliome v0.7169 SLC17A5 Zornitza Stark edited their review of gene: SLC17A5: Added comment: Sialic acid storage diseases are autosomal recessive neurodegenerative disorders that may present as a severe infantile form or a slowly progressive adult form, which is prevalent in Finland and referred to as Salla disease. p.Arg39Cys is a founder Finnish variant. Multiple families reported.; Changed publications: 10581036, 10947946; Changed phenotypes: Salla disease 604369, MONDO:0011449, Sialic acid storage disorder, infantile 269920, MONDO:0010027
Mendeliome v0.7169 SGSH Zornitza Stark Marked gene: SGSH as ready
Mendeliome v0.7169 SGSH Zornitza Stark Phenotypes for gene: SGSH were changed from to Mucopolysaccharidosis type IIIA (Sanfilippo A), MIM# 252900; MONDO:0009655
Mendeliome v0.7166 SGSH Zornitza Stark reviewed gene: SGSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7493035, 9158154, 9401012, 9554748; Phenotypes: Mucopolysaccharidosis type IIIA (Sanfilippo A), MIM# 252900, MONDO:0009655; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7166 SMPD1 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Niemann-Pick disease (NPD) refers to a group of disorders that present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings.

Well established gene-disease association.
Mendeliome v0.7166 SMPD1 Zornitza Stark Marked gene: SMPD1 as ready
Mendeliome v0.7163 TPP1 Zornitza Stark Phenotypes for gene: TPP1 were changed from Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270 to Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; MONDO:0008769; Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270; MONDO:0012235
Mendeliome v0.7161 TPP1 Zornitza Stark reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9295267, 18684116, 23418007, 26224725, 31283065; Phenotypes: Ceroid lipofuscinosis, neuronal, 2, MIM# 204500, MONDO:0008769, Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270, MONDO:0012235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7161 PSAP Zornitza Stark changed review comment from: Well established gene-disease association for bi-allelic variants. Early-onset PD reported with mono-allelic variants.; to: Well established gene-disease association for bi-allelic variants. Early-onset PD reported with mono-allelic variants.

The PSAP gene encodes saposins A, B, C and D. Variants resulting in PSAP null allele can be shared in patients with the deficit of other saposins (A-D) or whole prosaposin. The patient's phenotype depends then on the nature of the second allele - atypical Gaucher disease in case of saposin A, MLD in case of saposin B, and Krabbe disease in case of saposin C impairing mutations. The clinically most severe prosaposin deficit is caused by the presence of two PSAP null alleles.
Mendeliome v0.7161 PSAP Zornitza Stark Phenotypes for gene: PSAP were changed from Parkinson disease, AD; Combined SAP deficiency 611721; Gaucher disease, atypical, MIM# 610539; Krabbe disease, atypical, MIM# 611722; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900 to Parkinson disease, AD; Combined SAP deficiency, MIM# 611721; Encephalopathy due to prosaposin deficiency, MONDO:0012719; Krabbe disease, atypical, MIM# 611722; MONDO:0012720; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900; MONDO:0009590; Gaucher disease, atypical, MIM# 610539; MONDO:0012517
Mendeliome v0.7160 PPT1 Zornitza Stark Marked gene: PPT1 as ready
Mendeliome v0.7157 NEU1 Zornitza Stark Marked gene: NEU1 as ready
Mendeliome v0.7154 NAGLU Zornitza Stark Phenotypes for gene: NAGLU were changed from Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920; Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491 to Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920; MONDO:0009656; Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491; MONDO:0014665
Mendeliome v0.7153 NAGLU Zornitza Stark Marked gene: NAGLU as ready
Mendeliome v0.7153 NAGLU Zornitza Stark Phenotypes for gene: NAGLU were changed from to Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920; Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491
Mendeliome v0.7150 NAGLU Zornitza Stark reviewed gene: NAGLU: Rating: GREEN; Mode of pathogenicity: None; Publications: 25818867, 8650226; Phenotypes: Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920, Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7148 MIA3 Zornitza Stark Marked gene: MIA3 as ready
Mendeliome v0.7147 MIA3 Zornitza Stark changed review comment from: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability.

Four affected siblings reported. Mouse model has absence of bone mineralization.
Sources: Expert list; to: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability.

Four affected siblings reported, homozygous variant affecting splicing. Mouse model has absence of bone mineralization.
Sources: Expert list
Mendeliome v0.7147 MIA3 Zornitza Stark gene: MIA3 was added
gene: MIA3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIA3 were set to 32101163; 33778321
Phenotypes for gene: MIA3 were set to Ondontochondrodysplasia 2 with hearing loss and diabetes , MIM#619269
Review for gene: MIA3 was set to AMBER
Added comment: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability.

Four affected siblings reported. Mouse model has absence of bone mineralization.
Sources: Expert list
Mendeliome v0.7146 MFSD8 Zornitza Stark Phenotypes for gene: MFSD8 were changed from Ceroid lipofuscinosis, neuronal, 7 610951; Macular dystrophy with central cone involvement 616170 to Ceroid lipofuscinosis, neuronal, 7, MIM# 610951; MONDO:0012588; Macular dystrophy with central cone involvement, MIM# 616170; MONDO:0014515
Mendeliome v0.7144 MFSD8 Zornitza Stark reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564970, 19201763, 25227500; Phenotypes: Ceroid lipofuscinosis, neuronal, 7, MIM# 610951, MONDO:0012588, Macular dystrophy with central cone involvement, MIM# 616170, MONDO:0014515; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7144 MCOLN1 Zornitza Stark Marked gene: MCOLN1 as ready
Mendeliome v0.7142 MANBA Zornitza Stark Marked gene: MANBA as ready
Mendeliome v0.7140 MAN2B1 Zornitza Stark Marked gene: MAN2B1 as ready
Mendeliome v0.7138 LIPA Zornitza Stark Marked gene: LIPA as ready
Mendeliome v0.7135 LAMP2 Zornitza Stark changed review comment from: XLD. Vacuolar cardiomyopathy and myopathy. Gene encodes lysosome-associated membrane protein-2.; to: XLD. Gene encodes lysosome-associated membrane protein-2.

Danon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease) with 'normal acid maltase' or alpha-glucosidase, however, it may be more accurately classified as a lysosomal disorder.
Mendeliome v0.7135 LAMP2 Zornitza Stark Marked gene: LAMP2 as ready
Mendeliome v0.7133 IDUA Zornitza Stark Phenotypes for gene: IDUA were changed from Mucopolysaccharidosis Ih (MIM#607014); Mucopolysaccharidosis Ih/s (MIM#607015); Mucopolysaccharidosis Is (MIM#6070) to Mucopolysaccharidosis Ih (MIM#607014); Mucopolysaccharidosis Ih/s (MIM#607015); Mucopolysaccharidosis Is (MIM#6070); Mucopolysaccharidosis type 1, MONDO:0001586
Mendeliome v0.7132 IDUA Zornitza Stark reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis type 1, MONDO:0001586; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7132 IDS Zornitza Stark Marked gene: IDS as ready
Mendeliome v0.7132 IDS Zornitza Stark Phenotypes for gene: IDS were changed from to Mucopolysaccharidosis II, MIM# 309900; MONDO:0010674; Hunter syndrome
Mendeliome v0.7129 IDS Zornitza Stark reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9921913, 9762601, 8940265, 1901826; Phenotypes: Mucopolysaccharidosis II, MIM# 309900, MONDO:0010674, Hunter syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7128 VWA1 Alison Yeung Marked gene: VWA1 as ready
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
Mendeliome v0.7126 TSPOAP1 Tiong Tan Marked gene: TSPOAP1 as ready
Mendeliome v0.7125 CLDN11 Alison Yeung Marked gene: CLDN11 as ready
Mendeliome v0.7124 GIPC1 Dean Phelan reviewed gene: GIPC1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33374016; Phenotypes: Oculopharyngodistal myopathy 2 (MIM#618940); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7123 SYK Alison Yeung Marked gene: SYK as ready
Mendeliome v0.7122 NCDN Alison Yeung Marked gene: NCDN as ready
Mendeliome v0.7121 TSPOAP1 Ain Roesley gene: TSPOAP1 was added
gene: TSPOAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TSPOAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSPOAP1 were set to 33539324
Phenotypes for gene: TSPOAP1 were set to Dystonia, intellectual disability and cerebellar atrophy
Penetrance for gene: TSPOAP1 were set to unknown
Review for gene: TSPOAP1 was set to GREEN
Added comment: 7 affecteds from 3 families (1 consanguineous)
2x null, 1x missense

Affecteds with the null variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy while those with the missense p.(Gly1808Ser) presented with isolated adult-onset focal dystonia (mild cognitive impairment noted)

mice KO models were investigated
Sources: Literature
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
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
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
Mendeliome v0.7121 SLC5A5 Zornitza Stark Marked gene: SLC5A5 as ready
Mendeliome v0.7118 SLC45A1 Zornitza Stark Marked gene: SLC45A1 as ready
Mendeliome v0.7114 MESP1 Zornitza Stark Marked gene: MESP1 as ready
Mendeliome v0.7113 MESP1 Zornitza Stark gene: MESP1 was added
gene: MESP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MESP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MESP1 were set to 28677747; 28050627; 27185833; 26694203
Phenotypes for gene: MESP1 were set to Congenital heart disease
Review for gene: MESP1 was set to AMBER
Added comment: Rare/novel variants reported in at least 7 unrelated individuals with congenital heart disease, in-silicos conflicting, familial segregation only available for some (one de novo, three inherited, others unresolved). Functional data implicates gene in cardiac development.
Sources: Expert list
Mendeliome v0.7112 HYAL1 Zornitza Stark Marked gene: HYAL1 as ready
Mendeliome v0.7112 HYAL1 Zornitza Stark Phenotypes for gene: HYAL1 were changed from to Mucopolysaccharidosis type IX, MIM# 601492; MONDO:0011093
Mendeliome v0.7108 HYAL1 Zornitza Stark reviewed gene: HYAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 10339581, 18344557, 21559944; Phenotypes: Mucopolysaccharidosis type IX, MIM# 601492, MONDO:0011093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7108 HGSNAT Zornitza Stark Phenotypes for gene: HGSNAT were changed from Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930 MONDO:0009657 Retinitis pigmentosa 73, MIM# 616544 MONDO:0014687 to Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930; MONDO:0009657; Retinitis pigmentosa 73, MIM# 616544; MONDO:0014687
Mendeliome v0.7106 HGSNAT Zornitza Stark Phenotypes for gene: HGSNAT were changed from Mucopolysaccharidosis type IIIC (Sanfilippo C) (MIM #252930); Retinitis pigmentosa 73 (MIM # 616544) to Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930 MONDO:0009657 Retinitis pigmentosa 73, MIM# 616544 MONDO:0014687
Mendeliome v0.7105 HEXB Zornitza Stark Marked gene: HEXB as ready
Mendeliome v0.7102 GUSB Zornitza Stark Marked gene: GUSB as ready
Mendeliome v0.7102 GUSB Zornitza Stark Phenotypes for gene: GUSB were changed from to Mucopolysaccharidosis VII, MIM# 253220; MONDO:0009662
Mendeliome v0.7100 GUSB Zornitza Stark reviewed gene: GUSB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis VII, MIM# 253220, MONDO:0009662; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7100 GNS Zornitza Stark Marked gene: GNS as ready
Mendeliome v0.7100 GNS Zornitza Stark Phenotypes for gene: GNS were changed from to Mucopolysaccharidosis type IIID, MIM# 252940; Sanfilippo syndrome type D, MONDO:0009658
Mendeliome v0.7097 GNS Zornitza Stark reviewed gene: GNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12573255, 12624138, 31536183, 25851924; Phenotypes: Mucopolysaccharidosis type IIID, MIM# 252940, Sanfilippo syndrome type D, MONDO:0009658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7097 GNPTG Zornitza Stark Marked gene: GNPTG as ready
Mendeliome v0.7094 CHD7 Zornitza Stark Marked gene: CHD7 as ready
Mendeliome v0.7094 CHD7 Zornitza Stark Phenotypes for gene: CHD7 were changed from to Hypogonadotropic hypogonadism 5 with or without anosmia MIM#612370; CHARGE syndrome MIM#214800
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 v0.7091 ALDH1A2 Bryony Thompson Phenotypes for gene: ALDH1A2 were changed from to congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; dysmorphic features
Mendeliome v0.7088 NDUFA12 Bryony Thompson reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23 MIM#618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7088 ALDH1A2 Bryony Thompson Marked gene: ALDH1A2 as ready
Mendeliome v0.7086 ALDH1A2 Bryony Thompson reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33565183, 10192400; Phenotypes: congenital heart defects, diaphragmatic eventration, pulmonary hypoplasia, dysmorphic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7086 MMP20 Bryony Thompson Marked gene: MMP20 as ready
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
Mendeliome v0.7081 NDUFB7 Bryony Thompson Marked gene: NDUFB7 as ready
Mendeliome v0.7080 NDUFB7 Bryony Thompson gene: NDUFB7 was added
gene: NDUFB7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDUFB7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFB7 were set to 33502047; 27626371
Phenotypes for gene: NDUFB7 were set to Congenital lactic acidosis; hypertrophic cardiomyopathy
Review for gene: NDUFB7 was set to AMBER
Added comment: Single patient with a homozygous variant impacting RNA splicing (c.113-10C>G) with intrauterine growth restriction and anaemia, which displayed postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome. Also, a supporting knockout cell line model demonstrating impaired complex I assembly.
Sources: Literature
Mendeliome v0.7079 CELA3B Bryony Thompson Marked gene: CELA3B as ready
Mendeliome v0.7078 CDH11 Zornitza Stark Marked gene: CDH11 as ready
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
Mendeliome v0.7074 SLC10A1 Zornitza Stark Marked gene: SLC10A1 as ready
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
Mendeliome v0.7072 GALNS Zornitza Stark Marked gene: GALNS as ready
Mendeliome v0.7072 GALNS Zornitza Stark Phenotypes for gene: GALNS were changed from to Mucopolysaccharidosis IVA, MIM# 253000; MONDO:0009659
Mendeliome v0.7069 GALNS Zornitza Stark reviewed gene: GALNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9298823; Phenotypes: Mucopolysaccharidosis IVA, MIM# 253000, MONDO:0009659; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7069 GALC Zornitza Stark Marked gene: GALC as ready
Mendeliome v0.7065 FUCA1 Zornitza Stark Marked gene: FUCA1 as ready
Mendeliome v0.7062 CTSD Zornitza Stark Marked gene: CTSD as ready
Mendeliome v0.7059 CCDC88C Zornitza Stark Phenotypes for gene: CCDC88C were changed from Spinocerebellar ataxia 40, MIM#616053; Hydrocephalus, nonsyndromic, autosomal recessive 236600; Eearly-onset pure hereditary spastic paraplegia to Spinocerebellar ataxia 40, MIM#616053; Hydrocephalus, nonsyndromic, autosomal recessive 236600; Early-onset pure hereditary spastic paraplegia
Mendeliome v0.7058 CCDC88C Zornitza Stark Phenotypes for gene: CCDC88C were changed from Spinocerebellar ataxia 40, MIM#616053; Hydrocephalus, nonsyndromic, autosomal recessive 236600 AR to Spinocerebellar ataxia 40, MIM#616053; Hydrocephalus, nonsyndromic, autosomal recessive 236600; Eearly-onset pure hereditary spastic paraplegia
Mendeliome v0.7056 CCDC88C Paul De Fazio changed review comment from: Heterozygous missense variant (gnomad: 1 het) reported in a 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. In contrast to previous reports, she developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. Functional studies showed the varaint induced JNK hyper-phosphorylation and enhanced apoptosis. 4 unaffected family members did not have the variant.

This phenotype appears to be sufficiently dissimilar to the 2 previously reported SCA families to not constitute a 3rd supporting report in that context.; to: Heterozygous missense variant (gnomad: 1 het) reported in a 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. In contrast to previous reports, she developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. Functional studies showed the varaint induced JNK hyper-phosphorylation and enhanced apoptosis. 4 unaffected family members did not have the variant.

NB: Rated Amber as this phenotype appears to be sufficiently dissimilar to the 2 previously reported SCA families to not constitute a 3rd supporting report in that context. Gene remains Green for the AR ID phenotype.
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 v0.7055 NMNAT1 Zornitza Stark Phenotypes for gene: NMNAT1 were changed from to Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260; Leber congenital amaurosis 9, MIM# 608553
Mendeliome v0.7053 NMNAT1 Zornitza Stark Marked gene: NMNAT1 as ready
Mendeliome v0.7053 NMNAT1 Zornitza Stark reviewed gene: NMNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32533184, 33668384, 22842230, 22842229; Phenotypes: Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260, Leber congenital amaurosis 9, MIM# 608553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7052 ZMPSTE24 Zornitza Stark Marked gene: ZMPSTE24 as ready
Mendeliome v0.7048 EDN1 Zornitza Stark Marked gene: EDN1 as ready
Mendeliome v0.7048 EDN1 Zornitza Stark Phenotypes for gene: EDN1 were changed from to Auriculocondylar syndrome 3, MIM# 615706
Mendeliome v0.7044 EDN1 Zornitza Stark reviewed gene: EDN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23315542, 23913798, 24268655; Phenotypes: Auriculocondylar syndrome 3, MIM# 615706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7044 CLN5 Zornitza Stark Marked gene: CLN5 as ready
Mendeliome v0.7041 CLN3 Zornitza Stark Marked gene: CLN3 as ready
Mendeliome v0.7038 ARSB Zornitza Stark Marked gene: ARSB as ready
Mendeliome v0.7038 ARSB Zornitza Stark Gene: arsb has been classified as Green List (High Evidence).
Mendeliome v0.7038 ARSB Zornitza Stark Phenotypes for gene: ARSB were changed from to Mucopolysaccharidosis type VI (Maroteaux-Lamy), MIM# 253200; MONDO:0009661
Mendeliome v0.7037 ARSB Zornitza Stark Publications for gene: ARSB were set to
Mendeliome v0.7036 ARSB Zornitza Stark Mode of inheritance for gene: ARSB was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7035 ARSB Zornitza Stark reviewed gene: ARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 11668612; Phenotypes: Mucopolysaccharidosis type VI (Maroteaux-Lamy), MIM# 253200, MONDO:0009661; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7035 AGA Zornitza Stark Marked gene: AGA as ready
Mendeliome v0.7035 AGA Zornitza Stark Phenotypes for gene: AGA were changed from to Aspartylglucosaminuria, MIM# 208400; MONDO:0008830
Mendeliome v0.7032 AGA Zornitza Stark edited their review of gene: AGA: Added comment: Aspartylglucosaminuria (AGU) is a severe autosomal recessive lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. Multiple families and mouse model.; Changed publications: 1703489, 1904874, 8064811, 8946839; Changed phenotypes: Aspartylglucosaminuria, MIM# 208400, MONDO:0008830
Mendeliome v0.7032 ATCAY Zornitza Stark Marked gene: ATCAY as ready
Mendeliome v0.7032 ATCAY Zornitza Stark Phenotypes for gene: ATCAY were changed from to Ataxia, cerebellar, Cayman type, MIM# 601238; MONDO:0011025
Mendeliome v0.7029 ATCAY Zornitza Stark edited their review of gene: ATCAY: Added comment: Report of a variant c.599_605del, p.Pro200Profs*20 (PMID 29449188), which is in addition to the previously reported linked variants in the Cayman population (c.965+3G > T & p.S301R)(PMID 29449188). Mouse and zebra fish models share phenotypic features with humans with Ataxia, cerebellar, Cayman type (OMIM:601238)(PMID 14556008; 26343454).; Changed rating: GREEN; Changed publications: 14556008, 29449188, 23226316, 26343454; Changed phenotypes: Ataxia, cerebellar, Cayman type, MIM# 601238, MONDO:0011025
Mendeliome v0.7029 COPB1 Zornitza Stark Phenotypes for gene: COPB1 were changed from Severe intellectual disability; variable microcephaly; cataracts to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Mendeliome v0.7028 COPB1 Zornitza Stark edited their review of gene: COPB1: Changed phenotypes: Baralle-Macken syndrome, MIM# 619255, Severe intellectual disability, variable microcephaly, cataracts
Mendeliome v0.7028 ARAP3 Zornitza Stark Marked gene: ARAP3 as ready
Mendeliome v0.7028 ARAP3 Zornitza Stark Gene: arap3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7028 ARAP3 Zornitza Stark Classified gene: ARAP3 as Amber List (moderate evidence)
Mendeliome v0.7028 ARAP3 Zornitza Stark Gene: arap3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7027 ARAP3 Zornitza Stark gene: ARAP3 was added
gene: ARAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARAP3 were set to 32908855
Phenotypes for gene: ARAP3 were set to Lymphoedema
Review for gene: ARAP3 was set to AMBER
Added comment: Three unrelated families reported with rare missense variants in this gene as part of a lymphoedema cohort. However, incomplete information regarding segregation and no supporting functional data.
Sources: Literature
Mendeliome v0.7026 RORC Zornitza Stark changed review comment from: Association with lymphoedema: Two individuals reported with LoF variants as part of a large cohort. Note gene is depleted for LoF in gnomad, and bi-allelic variants have been associated with immunodeficiency.; to: Association with lymphoedema: Two individuals reported with LoF variants as part of a large cohort. Note gene is depleted for LoF in gnomad, and bi-allelic variants have been associated with immunodeficiency. Moderate evidence for gene-disease association.
Mendeliome v0.7026 RORC Zornitza Stark edited their review of gene: RORC: Added comment: Association with lymphoedema: Two individuals reported with LoF variants as part of a large cohort. Note gene is depleted for LoF in gnomad, and bi-allelic variants have been associated with immunodeficiency.; Changed publications: 26160376, 32960152; Changed phenotypes: Immunodeficiency 42, MIM# 616622, Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, MONDO:0014710, Lymphoedema; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7026 RORC Zornitza Stark Marked gene: RORC as ready
Mendeliome v0.7023 IL17RC Zornitza Stark Marked gene: IL17RC as ready
Mendeliome v0.7018 IL17RA Zornitza Stark Marked gene: IL17RA as ready
Mendeliome v0.7017 CARD9 Zornitza Stark Marked gene: CARD9 as ready
Mendeliome v0.7017 CARD9 Zornitza Stark Gene: card9 has been classified as Green List (High Evidence).
Mendeliome v0.7017 CARD9 Zornitza Stark Phenotypes for gene: CARD9 were changed from to Candidiasis, familial, 2, autosomal recessive, MIM# 212050; Predisposition to invasive fungal disease, MONDO:0008905
Mendeliome v0.7016 CARD9 Zornitza Stark Publications for gene: CARD9 were set to
Mendeliome v0.7015 CARD9 Zornitza Stark Mode of inheritance for gene: CARD9 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7014 CARD9 Zornitza Stark reviewed gene: CARD9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19864672, 23335372, 24131138, 33789983, 33558980, 33180249; Phenotypes: Candidiasis, familial, 2, autosomal recessive, MIM# 212050, Predisposition to invasive fungal disease, MONDO:0008905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7014 CYP24A1 Zornitza Stark Marked gene: CYP24A1 as ready
Mendeliome v0.7009 ABCB7 Zornitza Stark Marked gene: ABCB7 as ready
Mendeliome v0.7006 PORCN Zornitza Stark Marked gene: PORCN as ready
Mendeliome v0.7004 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7004 PRIM1 Zornitza Stark Marked gene: PRIM1 as ready
Mendeliome v0.7003 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7003 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7003 PRIM1 Zornitza Stark gene: PRIM1 was added
gene: PRIM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to 33060134
Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950
Review for gene: PRIM1 was set to AMBER
Added comment: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7001 TTC5 Zornitza Stark Phenotypes for gene: TTC5 were changed from Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system to Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism , MIM#619244; Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system
Mendeliome v0.7000 TTC5 Zornitza Stark edited their review of gene: TTC5: Changed phenotypes: Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism , MIM#619244, Central hypotonia, Global developmental delay, Intellectual disability, Abnormality of nervous system morphology, Microcephaly, Abnormality of the face, Behavioral abnormality, Abnormality of the genitourinary system
Mendeliome v0.7000 MCM10 Zornitza Stark Phenotypes for gene: MCM10 were changed from Susceptibility to CMV to Susceptibility to CMV; Restrictive cardiomyopathy
Mendeliome v0.6998 MCM10 Zornitza Stark edited their review of gene: MCM10: Added comment: PMID 33712616: second family reported, three affected sibs with restrictive cardiomyopathy and hypoplasia of the spleen and thymus. Functional data suggested that MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion.; Changed publications: 32865517, 33712616; Changed phenotypes: Susceptibility to CMV, Restrictive cardiomyopathy
Mendeliome v0.6998 CYBA Zornitza Stark Marked gene: CYBA as ready
Mendeliome v0.6995 NUP37 Zornitza Stark Phenotypes for gene: NUP37 were changed from Nephrotic syndrome to Nephrotic syndrome; Microcephaly 24, primary, autosomal recessive, MIM# 618179
Mendeliome v0.6994 NUP37 Zornitza Stark edited their review of gene: NUP37: Changed phenotypes: Nephrotic syndrome, Microcephaly 24, primary, autosomal recessive, MIM# 618179
Mendeliome v0.6994 COPB2 Zornitza Stark Marked gene: COPB2 as ready
Mendeliome v0.6994 COPB2 Zornitza Stark gene: COPB2 was added
gene: COPB2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COPB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB2 were set to 29036432
Phenotypes for gene: COPB2 were set to Microcephaly 19, primary, autosomal recessive, MIM# 617800
Review for gene: COPB2 was set to RED
Added comment: Two sibs with homozygous missense variant in this gene, mice homozygous for this variant had normal brain size however. Mice compound het for null allele and missense variant had some brain features, suggesting the missense variant is hypomorphic.
Sources: Expert list
Mendeliome v0.6993 WDR62 Zornitza Stark Marked gene: WDR62 as ready
Mendeliome v0.6993 WDR62 Zornitza Stark Phenotypes for gene: WDR62 were changed from to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317; MONDO:0011435
Mendeliome v0.6990 WDR62 Zornitza Stark reviewed gene: WDR62: Rating: GREEN; Mode of pathogenicity: None; Publications: 20890279, 20729831, 20890278, 21496009, 21834044, 22775483, 32677750, 31788460; Phenotypes: Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317, MONDO:0011435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6990 TRMT10A Zornitza Stark Marked gene: TRMT10A as ready
Mendeliome v0.6987 TRAIP Zornitza Stark Marked gene: TRAIP as ready
Mendeliome v0.6983 TOP3A Zornitza Stark Marked gene: TOP3A as ready
Mendeliome v0.6980 STIL Zornitza Stark Marked gene: STIL as ready
Mendeliome v0.6980 STIL Zornitza Stark Phenotypes for gene: STIL were changed from to Microcephaly 7, primary, autosomal recessive, MIM# 612703; MONDO:0012989
Mendeliome v0.6977 STIL Zornitza Stark reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: 19215732, 22989186, 25218063, 33132204, 32677750, 29230157; Phenotypes: Microcephaly 7, primary, autosomal recessive, MIM# 612703, MONDO:0012989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6975 STAMBP Zornitza Stark Marked gene: STAMBP as ready
Mendeliome v0.6975 STAMBP Zornitza Stark Phenotypes for gene: STAMBP were changed from to Microcephaly-capillary malformation syndrome, MIM# 614261; MONDO:0013659
Mendeliome v0.6972 STAMBP Zornitza Stark reviewed gene: STAMBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 23542699, 31638258, 29907875, 27531570, 25692795, 25266620; Phenotypes: Microcephaly-capillary malformation syndrome, MIM# 614261, MONDO:0013659; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6972 PCNT Zornitza Stark Marked gene: PCNT as ready
Mendeliome v0.6972 PCNT Zornitza Stark Phenotypes for gene: PCNT were changed from to Microcephalic osteodysplastic primordial dwarfism, type II, MIM# 210720; MONDO:0008872
Mendeliome v0.6969 PCNT Zornitza Stark reviewed gene: PCNT: Rating: GREEN; Mode of pathogenicity: None; Publications: 18174396, 12210304, 30922925, 33460028, 32557621, 32267100; Phenotypes: Microcephalic osteodysplastic primordial dwarfism, type II, MIM# 210720, MONDO:0008872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6969 NHEJ1 Zornitza Stark Marked gene: NHEJ1 as ready
Mendeliome v0.6969 NHEJ1 Zornitza Stark Phenotypes for gene: NHEJ1 were changed from to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291; Cernunnos-XLF deficiency MONDO:0012650
Mendeliome v0.6966 NHEJ1 Zornitza Stark reviewed gene: NHEJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30898087, 30666249, 28741180, 25288157, 24511403, 21721379, 21535335; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291, Cernunnos-XLF deficiency MONDO:0012650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6966 NBN Zornitza Stark Marked gene: NBN as ready
Mendeliome v0.6963 MSMO1 Zornitza Stark Marked gene: MSMO1 as ready
Mendeliome v0.6963 MSMO1 Zornitza Stark Phenotypes for gene: MSMO1 were changed from to Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834; MONDO:0014793; Disorders of the metabolism of sterols
Mendeliome v0.6960 MSMO1 Zornitza Stark reviewed gene: MSMO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21285510, 24144731, 28673550, 33161406; Phenotypes: Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834, MONDO:0014793; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6960 MCPH1 Zornitza Stark Marked gene: MCPH1 as ready
Mendeliome v0.6960 MCPH1 Zornitza Stark Phenotypes for gene: MCPH1 were changed from to Microcephaly 1, primary, autosomal recessive, MIM# 251200; MONDO:0009617
Mendeliome v0.6957 MCPH1 Zornitza Stark reviewed gene: MCPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12046007, 15199523, 16311745, 20978018, 32294449, 30351297, 29026105; Phenotypes: Microcephaly 1, primary, autosomal recessive, MIM# 251200, MONDO:0009617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6957 ATP1A3 Zornitza Stark Marked gene: ATP1A3 as ready
Mendeliome v0.6953 LARP7 Zornitza Stark Marked gene: LARP7 as ready
Mendeliome v0.6953 LARP7 Zornitza Stark Gene: larp7 has been classified as Green List (High Evidence).
Mendeliome v0.6953 LARP7 Zornitza Stark Phenotypes for gene: LARP7 were changed from to Alazami syndrome, MIM# 615071; Microcephalic primordial dwarfism, Alazami type MONDO:0014031
Mendeliome v0.6952 LARP7 Zornitza Stark Publications for gene: LARP7 were set to
Mendeliome v0.6951 LARP7 Zornitza Stark Mode of inheritance for gene: LARP7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6950 LARP7 Zornitza Stark reviewed gene: LARP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22865833, 21937992, 30006060, 33569879; Phenotypes: Alazami syndrome, MIM# 615071, Microcephalic primordial dwarfism, Alazami type MONDO:0014031; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6950 KNL1 Zornitza Stark Marked gene: KNL1 as ready
Mendeliome v0.6950 KNL1 Zornitza Stark Phenotypes for gene: KNL1 were changed from to Microcephaly 4, primary, autosomal recessive, MIM# 604321; MONDO:0011437
Mendeliome v0.6947 KNL1 Zornitza Stark reviewed gene: KNL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22983954, 26626498, 27149178, 30304678, 27784895; Phenotypes: Microcephaly 4, primary, autosomal recessive, MIM# 604321, MONDO:0011437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6946 BAAT Zornitza Stark Marked gene: BAAT as ready
Mendeliome v0.6943 KIF11 Zornitza Stark Marked gene: KIF11 as ready
Mendeliome v0.6943 KIF11 Zornitza Stark Phenotypes for gene: KIF11 were changed from to Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation, MIM# 152950; MONDO:0007918
Mendeliome v0.6940 KIF11 Zornitza Stark reviewed gene: KIF11: Rating: GREEN; Mode of pathogenicity: None; Publications: 22284827, 25115524, 25124931, 27212378, 32730767, 31993640, 25996076; Phenotypes: Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation, MIM# 152950, MONDO:0007918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6940 IER3IP1 Zornitza Stark Marked gene: IER3IP1 as ready
Mendeliome v0.6940 IER3IP1 Zornitza Stark Phenotypes for gene: IER3IP1 were changed from to Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231; Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647
Mendeliome v0.6937 IER3IP1 Zornitza Stark reviewed gene: IER3IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21835305, 22991235, 24138066, 28711742; Phenotypes: Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231, Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6937 EFTUD2 Zornitza Stark Marked gene: EFTUD2 as ready
Mendeliome v0.6934 CEP152 Zornitza Stark Marked gene: CEP152 as ready
Mendeliome v0.6934 CEP152 Zornitza Stark Phenotypes for gene: CEP152 were changed from to Microcephaly 9, primary, autosomal recessive, MIM# 614852; MONDO:0013923; Seckel syndrome 5, MIM# 613823; MONDO:0013443
Mendeliome v0.6931 CEP152 Zornitza Stark reviewed gene: CEP152: Rating: GREEN; Mode of pathogenicity: None; Publications: 20598275, 22775483, 21131973, 23199753; Phenotypes: Microcephaly 9, primary, autosomal recessive, MIM# 614852, MONDO:0013923, Seckel syndrome 5, MIM# 613823, MONDO:0013443; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6931 GNPAT Zornitza Stark Marked gene: GNPAT as ready
Mendeliome v0.6927 CD4 Zornitza Stark Marked gene: CD4 as ready
Mendeliome v0.6927 CD4 Zornitza Stark Phenotypes for gene: CD4 were changed from to Immunodeficiency 79, MIM# 619238; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts
Mendeliome v0.6924 CD4 Zornitza Stark edited their review of gene: CD4: Changed rating: GREEN; Changed publications: 31781092, 33471124; Changed phenotypes: Immunodeficiency 79, MIM# 619238, Absence of CD4+ T cells, exuberant, relapsing, treatment-refractory warts
Mendeliome v0.6924 TMEM231 Zornitza Stark Marked gene: TMEM231 as ready
Mendeliome v0.6921 TMEM216 Zornitza Stark Marked gene: TMEM216 as ready
Mendeliome v0.6918 TMEM216 Zornitza Stark changed review comment from: Ataxia is part of the phenotype.; to: p.Arg73Leu is a founder Jewish variant. Multiple families reported with JBTS and with Meckel syndrome.
Mendeliome v0.6918 TMEM138 Zornitza Stark Marked gene: TMEM138 as ready
Mendeliome v0.6915 TCTN2 Zornitza Stark changed review comment from: Multiple families reported, ataxia is part of the phenotype.; to: At least 5 families reported with JBTS phenotype, and 3 with Meckel phenotype; mouse model.
Mendeliome v0.6915 TCTN2 Zornitza Stark Marked gene: TCTN2 as ready
Mendeliome v0.6912 TCTN1 Zornitza Stark Marked gene: TCTN1 as ready
Mendeliome v0.6909 TCTN1 Zornitza Stark changed review comment from: Rare cause of JBS, ataxia specifically mentioned in at least one individual.; to: Rare cause of JBS, at least 4 families reported, mouse model.
Mendeliome v0.6908 SMCHD1 Zornitza Stark edited their review of gene: SMCHD1: Added comment: Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. Choanal atresia is a feature. More than 30 unrelated individuals reported. Caused by gain of function missense variants with the extended ATPase domain.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed publications: 28067909; Changed phenotypes: Bosma arhinia microphthalmia syndrome, MIM# 603457, Arhinia, choanal atresia, microphthalmia MONDO:0011323; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6908 SMCHD1 Zornitza Stark Phenotypes for gene: SMCHD1 were changed from Bosma arhinia microphthalmia syndrome, MIM 603457; Fascioscapulohumeral muscular dystrophy 2, digenic to Bosma arhinia microphthalmia syndrome, MIM 603457; Arhinia, choanal atresia, microphthalmia MONDO:0011323; Fascioscapulohumeral muscular dystrophy 2, digenic
Mendeliome v0.6906 TXNL4A Zornitza Stark Marked gene: TXNL4A as ready
Mendeliome v0.6906 TXNL4A Zornitza Stark Phenotypes for gene: TXNL4A were changed from to Burn-McKeown syndrome, MIM# 608572; Choanal atresia - deafness - cardiac defects - dysmorphism syndrome, MONDO:0012064
Mendeliome v0.6903 TXNL4A Zornitza Stark reviewed gene: TXNL4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25434003; Phenotypes: Burn-McKeown syndrome, MIM# 608572, Choanal atresia - deafness - cardiac defects - dysmorphism syndrome, MONDO:0012064; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6903 SPINT2 Zornitza Stark Phenotypes for gene: SPINT2 were changed from Diarrhoea 3, secretory sodium, congenital, syndromic 270420 to Diarrhoea 3, secretory sodium, congenital, syndromic 270420; MONDO:0010036
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 v0.6901 SPINT2 Zornitza Stark edited their review of gene: SPINT2: Changed publications: 19185281, 20009592, 24142340, 30445423; Changed phenotypes: Diarrhoea 3, secretory sodium, congenital, syndromic 270420, MONDO:0010036
Mendeliome v0.6901 FOXE1 Zornitza Stark Marked gene: FOXE1 as ready
Mendeliome v0.6901 FOXE1 Zornitza Stark Phenotypes for gene: FOXE1 were changed from to Bamforth-Lazarus syndrome, MIM# 241850; MONDO:0009437
Mendeliome v0.6898 FOXE1 Zornitza Stark reviewed gene: FOXE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9697705, 12165566, 16882747, 24219130, 20484477; Phenotypes: Bamforth-Lazarus syndrome, MIM# 241850, MONDO:0009437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6898 MIB1 Zornitza Stark Marked gene: MIB1 as ready
Mendeliome v0.6898 MIB1 Zornitza Stark Added comment: Comment when marking as ready: Amber for LVNC/cardiomyopathy. Green for congenital heart disease.
Mendeliome v0.6898 MIB1 Zornitza Stark Phenotypes for gene: MIB1 were changed from Left ventricular noncompaction 7 MIM#615092 to Left ventricular noncompaction 7 MIM#615092; cardiomyopathy; congenital heart disease
Mendeliome v0.6897 MIB1 Zornitza Stark reviewed gene: MIB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30322850, 23314057; Phenotypes: Left ventricular noncompaction 7, MIM# 615092, cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6897 ANO3 Zornitza Stark Marked gene: ANO3 as ready
Mendeliome v0.6894 IPO8 Zornitza Stark Marked gene: IPO8 as ready
Mendeliome v0.6893 IPO8 Zornitza Stark gene: IPO8 was added
gene: IPO8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Review for gene: IPO8 was set to AMBER
Added comment: 12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression.
Sources: Expert Review
Mendeliome v0.6891 DDB1 Zornitza Stark edited their review of gene: DDB1: Added comment: 8 individuals with de novo missense variants and varying degrees of intellectual disability, hypotonia, and some malformations, brachydactyly and syndactyly. Functional evidence of abnormal DNA repair in patient lymphoblasts.; Changed publications: 33743206
Mendeliome v0.6891 FAM20C Zornitza Stark Marked gene: FAM20C as ready
Mendeliome v0.6886 ANKS6 Zornitza Stark Marked gene: ANKS6 as ready
Mendeliome v0.6878 CLDN2 Zornitza Stark changed review comment from: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype. Likely polygenic susceptibility rather than Mendelian disorder.; to: Pancreatitis: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype. Likely polygenic susceptibility rather than Mendelian disorder.
Mendeliome v0.6878 FLII Zornitza Stark changed review comment from: Two unrelated families reported with homozygous missense variants. Emerging evidence.
Sources: Literature; to: Two unrelated families reported with homozygous missense variants. Emerging evidence: aware of two more families.
Sources: Literature
Mendeliome v0.6876 POLR3A Elena Savva commented on gene: POLR3A: c.1909+22G>A is a recurring variant that results in a leaky splice site

Bi-allelic variants associated with Leukodystrophy and with Wiedemann-Rautenstrauch syndrome; note association between mono-allelic variants and susceptibility to severe VZV infection.

Deep intronic variants commonly pathogenic

No clear gen-phen correlation
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 v0.6876 HSF2BP Zornitza Stark Marked gene: HSF2BP as ready
Mendeliome v0.6876 HSF2BP Zornitza Stark gene: HSF2BP was added
gene: HSF2BP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSF2BP were set to 32845237
Phenotypes for gene: HSF2BP were set to Premature ovarian failure, OMIM#619245
Review for gene: HSF2BP was set to RED
Added comment: Single family reported where homozygous missense variant segregated with POF in three sisters.
Sources: Expert list
Mendeliome v0.6875 COL4A6 Zornitza Stark Marked gene: COL4A6 as ready
Mendeliome v0.6871 RNF6 Zornitza Stark Marked gene: RNF6 as ready
Mendeliome v0.6870 MED12 Zornitza Stark Marked gene: MED12 as ready
Mendeliome v0.6867 BMPR2 Zornitza Stark Marked gene: BMPR2 as ready
Mendeliome v0.6867 BMPR2 Zornitza Stark Phenotypes for gene: BMPR2 were changed from to Pulmonary venoocclusive disease 1 MIM#265450; Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600; Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600
Mendeliome v0.6863 BMPR2 Elena Savva reviewed gene: BMPR2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33380512; Phenotypes: Pulmonary venoocclusive disease 1 MIM#265450, Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600, Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6863 ZNF711 Zornitza Stark Marked gene: ZNF711 as ready
Mendeliome v0.6863 ZNF711 Zornitza Stark Phenotypes for gene: ZNF711 were changed from to Mental retardation, X-linked 97; OMIM #300803
Mendeliome v0.6860 ZNF711 Zornitza Stark reviewed gene: ZNF711: Rating: GREEN; Mode of pathogenicity: None; Publications: 27993705, 19377476; Phenotypes: Mental retardation, X-linked 97, OMIM #300803; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.6860 SLC35A2 Zornitza Stark Marked gene: SLC35A2 as ready
Mendeliome v0.6856 MEF2A Zornitza Stark Marked gene: MEF2A as ready
Mendeliome v0.6856 MEF2A Zornitza Stark Phenotypes for gene: MEF2A were changed from to {Coronary artery disease, autosomal dominant, 1} 608320
Mendeliome v0.6854 MEF2A Zornitza Stark reviewed gene: MEF2A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Coronary artery disease, autosomal dominant, 1} 608320; Mode of inheritance: None
Mendeliome v0.6854 FN1 Zornitza Stark Marked gene: FN1 as ready
Mendeliome v0.6851 IL37 Zornitza Stark Marked gene: IL37 as ready
Mendeliome v0.6851 IL37 Zornitza Stark gene: IL37 was added
gene: IL37 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Mendeliome v0.6850 CHRDL1 Zornitza Stark Marked gene: CHRDL1 as ready
Mendeliome v0.6847 HDL2 Bryony Thompson Marked STR: HDL2 as ready
Mendeliome v0.6846 HDL2 Bryony Thompson STR: HDL2 was added
STR: HDL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: HDL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: HDL2 were set to 20301701
Phenotypes for STR: HDL2 were set to Huntington disease-like 2 MIM#606438
Review for STR: HDL2 was set to GREEN
STR: HDL2 was marked as clinically relevant
Added comment: NM_001271604.2:c.431CTG[X] or NM_020655.4:c.382+760CTG[X]
In an alternatively spliced exon, the repeat can be transcribed in both directions, leading to CUG (more common) or CAG (less common) repeat-containing transcripts. While a dominant RNA toxic effect may occur, the repeat expansion also reduces levels of the Junctophilin-3 protein
Normal: ≤28 repeats
Questionable significance: 29-39 repeats, mutable normal or reduced penetrance included
Full penetrance: ≥40 repeats
Sources: Expert list
Mendeliome v0.6844 DM2 Bryony Thompson Marked STR: DM2 as ready
Mendeliome v0.6843 DM2 Bryony Thompson STR: DM2 was added
STR: DM2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: DM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM2 were set to 20301639; 29325606
Phenotypes for STR: DM2 were set to Myotonic dystrophy 2 MIM#602668
Review for STR: DM2 was set to GREEN
STR: DM2 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_003418.4:c.-14-833_-14-830[X]
Toxic gain of function RNA expected mechanism of disease
Normal: ≤30 uninterrupted CCTG repeats, 11-26 CCTG repeats with any GCTC or TCTG interruptions
Unknown significance (normal vs. mutable): 27-29 CCTG repeats
Mutable normal (premutation) alleles. ~30-~54 CCTG repeats
Unknown significance (premutation vs pathogenic): ~55-74 CCTG repeats
Pathogenic: ~75-11,000 CCTG repeats
Sources: Expert list
Mendeliome v0.6842 CNBP Bryony Thompson Marked gene: CNBP as ready
Mendeliome v0.6841 DM1 Bryony Thompson Marked STR: DM1 as ready
Mendeliome v0.6840 DM1 Bryony Thompson STR: DM1 was added
STR: DM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: DM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM1 were set to 20301344; 29325606
Phenotypes for STR: DM1 were set to Myotonic dystrophy 1 MIM#160900
Review for STR: DM1 was set to GREEN
STR: DM1 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_001081560.2:c.*224_*226CTG[X]
RNA toxic gain of function is mechanism of disease
Premutation: 35-49 repeats, no clinical signs
Mild: 50-~150 repeats, age of onset 20-70 yrs, clinical signs - cataracts, mild myotonia
Classic: ~100-~1,000 repeats, age of onset 10-30 yrs, clinical signs - weakness, myotonia, cataracts, balding, cardiac arrhythmia
Congenital: >1,000 repeats, age of onset birth-10 yrs , clinical signs - infantile hypotonia, respiratory deficits, intellectual disability, classic signs in adults
Sources: Expert list
Mendeliome v0.6838 SCA17 Bryony Thompson Marked STR: SCA17 as ready
Mendeliome v0.6837 SCA17 Bryony Thompson STR: SCA17 was added
STR: SCA17 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA17 were set to 20301611; 29325606
Phenotypes for STR: SCA17 were set to Spinocerebellar ataxia 17 MIM#607136
Review for STR: SCA17 was set to GREEN
STR: SCA17 was marked as clinically relevant
Added comment: NM_003194.4:c.172_174[X]
Mechanism of disease expected to be gain of function
Normal: ≤ 40 CAG/CAA repeats
Reduced-penetrance: 41-48 CAG/CAA repeats, individual may or may not develop symptoms.
Full-penetrance: ≥49 CAG/CAA repeats
Sources: Expert list
Mendeliome v0.6836 TBP Bryony Thompson Marked gene: TBP as ready
Mendeliome v0.6835 SCA12 Bryony Thompson Marked STR: SCA12 as ready
Mendeliome v0.6834 SCA12 Bryony Thompson STR: SCA12 was added
STR: SCA12 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA12 were set to 29325606; 20301381
Phenotypes for STR: SCA12 were set to Spinocerebellar ataxia 12 MIM#604326
Review for STR: SCA12 was set to GREEN
STR: SCA12 was marked as clinically relevant
Added comment: NM_181675.3:c.27CAG[X]
Uncertain if CAG repeat encodes polyglutamine or instead effects expression of specific splice variants of the encoded phosphatase
Normal: ≤32 repeats
Reduced penetrance: ~40-66 repeats
Full penetrance: ≥66 repeats
Sources: Expert list
Mendeliome v0.6833 PPP2R2B Bryony Thompson Marked gene: PPP2R2B as ready
Mendeliome v0.6832 SCA36 Bryony Thompson Marked STR: SCA36 as ready
Mendeliome v0.6831 SCA36 Bryony Thompson STR: SCA36 was added
STR: SCA36 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA36 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA36 were set to 25101480
Phenotypes for STR: SCA36 were set to Spinocerebellar ataxia 36 MIM#614153
Review for STR: SCA36 was set to GREEN
STR: SCA36 was marked as clinically relevant
Added comment: NM_006392​.3:c.3+71GGCCTG[X]
Toxic RNA effect is suggested mechanism of disease
Normal: 3-14 repeats
Uncertain significance: 15-650 repeats
Pathogenic: ≥650 repeats
Sources: Expert list
Mendeliome v0.6829 SCA37 Bryony Thompson Marked STR: SCA37 as ready
Mendeliome v0.6828 SCA37 Bryony Thompson STR: SCA37 was added
STR: SCA37 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA37 were set to 28686858; 31145571
Phenotypes for STR: SCA37 were set to Spinocerebellar ataxia 37 MIM#615945
Review for STR: SCA37 was set to GREEN
STR: SCA37 was marked as clinically relevant
Added comment: NC_000001.10:g.57832716_57832797ins[(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90]
Located in a 5'UTR intron, flanked by (ATTTT)n on both sides
Non-pathogenic allele: (ATTTT)7–400
Pathogenic allele: [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90]
Sources: Expert list
Mendeliome v0.6827 DAB1 Bryony Thompson Marked gene: DAB1 as ready
Mendeliome v0.6826 SCA31 Bryony Thompson Marked STR: SCA31 as ready
Mendeliome v0.6825 SCA31 Bryony Thompson STR: SCA31 was added
STR: SCA31 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA31 were set to 19878914; 31755042
Phenotypes for STR: SCA31 were set to Spinocerebellar ataxia 31 MIM#117210
Review for STR: SCA31 was set to GREEN
STR: SCA31 was marked as clinically relevant
Added comment: Complex repeat insertion (TGGAA)n, (TAGAA)n, (TAAAA)n, (TAAAATAGAA)n, TGGAA is present only in affected cases. Sequencing showed that the insertion consisted of a preceding TCAC sequence, and 3 pentanucleotide repeat components (TGGAA)n, (TAGAA)n, and (TAAAA)n in all patients tested.
2.5-3.8 KB insertion is associated with disease and RNA toxicity expected to be mechanism of disease
Normal and pathogenic cut-offs are based on animal model experiments (PMID: 31755042)
Sources: Expert list
Mendeliome v0.6824 BEAN1 Bryony Thompson Marked gene: BEAN1 as ready
Mendeliome v0.6823 SCA7 Bryony Thompson Marked STR: SCA7 as ready
Mendeliome v0.6822 SCA7 Bryony Thompson STR: SCA7 was added
STR: SCA7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA7 were set to 29325606; 20301433
Phenotypes for STR: SCA7 were set to Spinocerebellar ataxia 7 MIM#164500
Review for STR: SCA7 was set to GREEN
STR: SCA7 was marked as clinically relevant
Added comment: NM_000333​.3:c.89_91AGC[X]
Gain of function mechanism of disease
Normal: ≤27 repeats
Mutable normal: 28-33 repeats, meiotically unstable, but not associated with an abnormal phenotype.
Pathogenic reduced penetrance: 34-36 repeats, when manifestations occur, they are more likely to be later onset and milder than average
Pathogenic full penetrance: 37-460 repeats
Sources: Expert list
Mendeliome v0.6821 ATXN7 Bryony Thompson Marked gene: ATXN7 as ready
Mendeliome v0.6820 SCA3 Bryony Thompson Marked STR: SCA3 as ready
Mendeliome v0.6819 SCA3 Bryony Thompson STR: SCA3 was added
STR: SCA3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA3 were set to 20301375; 29325606
Phenotypes for STR: SCA3 were set to Machado-Joseph disease MIM#109150; Spinocerebellar ataxia type 3
Review for STR: SCA3 was set to GREEN
STR: SCA3 was marked as clinically relevant
Added comment: NM_004993​.5:c.886_888CAG[X]
Toxic aggregation and mislocalization in neurons is mechanism of disease
Normal: ≤44 repeats, mostly <31 repeats
Intermediate: 45-59 repeats, some intermediate alleles are not associated with classic clinical features of SCA3
Pathogenic (full penetrance): ≥60 repeats
Sources: Expert list
Mendeliome v0.6817 SCA2 Bryony Thompson Marked STR: SCA2 as ready
Mendeliome v0.6816 SCA2 Bryony Thompson STR: SCA2 was added
STR: SCA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA2 were set to 29325606; 20301452
Phenotypes for STR: SCA2 were set to Spinocerebellar ataxia 2 MIM#183090
Review for STR: SCA2 was set to GREEN
STR: SCA2 was marked as clinically relevant
Added comment: NM_002973​.3:c.496_498CAG[X]
Toxic protein aggregation is mechanism of disease
Benign: ≤31 repeats (homozygous 31/31 repeats reported for recessive SCA2)
Uncertain: 32 repeats
ALS risk allele: 30-32 repeats
Reduced penetrance: 33-34 repeats, may not develop symptoms or only very late in life
Full penetrance: ≥35 repeats
Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size, but may enhance the meiotic stability of the repeat
Sources: Expert list
Mendeliome v0.6814 SCA10 Bryony Thompson Marked STR: SCA10 as ready
Mendeliome v0.6813 SCA10 Bryony Thompson STR: SCA10 was added
STR: SCA10 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA10 were set to 20301354
Phenotypes for STR: SCA10 were set to Spinocerebellar ataxia 10 MIM#603516
Review for STR: SCA10 was set to GREEN
STR: SCA10 was marked as clinically relevant
Added comment: NM_013236​.2:c.1430+54822ATTCT[X]
Toxic RNA gain-of-function mechanism of disease
Normal alleles: 10-32 ATTCT repeats
Alleles of questionable significance: 33-280 ATTCT repeats
Reduced-penetrance alleles: 33-850 repeats
Full-penetrance alleles: 800-4,500 ATTCT repeats
Sources: Expert list
Mendeliome v0.6811 INPP4A Zornitza Stark Marked gene: INPP4A as ready
Mendeliome v0.6810 INPP4A Zornitza Stark gene: INPP4A was added
gene: INPP4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 31978615; 31938306; 25338135; 20011524
Phenotypes for gene: INPP4A were set to Intellectual disability
Review for gene: INPP4A was set to AMBER
Added comment: Two families reported with bi-allelic variants and a neurological phenotype. Supportive mouse model and expression data.
Sources: Literature
Mendeliome v0.6808 SATB1 Zornitza Stark edited their review of gene: SATB1: Added comment: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. This phenotype was reported in 28 patients (patients 13 to 40, PMID 33513338), including 9 patients from 3 families. Most variants were de novo, though some were inherited, suggestive of incomplete penetrance and variable expressivity.; Changed phenotypes: Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228, Kohlschutter-Tonz syndrome-like, MIM# 619229
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 v0.6805 MKS1 Zornitza Stark Marked gene: MKS1 as ready
Mendeliome v0.6805 MKS1 Zornitza Stark Phenotypes for gene: MKS1 were changed from to Joubert syndrome 28, MIM# 617121; MONDO:0014928; Meckel syndrome 1, MIM# 249000; MONDO:0009571; Bardet-Biedl syndrome 13, MIM# 615990; MONDO:0014441
Mendeliome v0.6802 MKS1 Zornitza Stark reviewed gene: MKS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17377820, 24886560, 19776033, 33193692, 27570071, 27377014, 18327255, 24608809; Phenotypes: Joubert syndrome 28, MIM# 617121, MONDO:0014928, Meckel syndrome 1, MIM# 249000, MONDO:0009571, Bardet-Biedl syndrome 13, MIM# 615990, MONDO:0014441; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6802 FLII Zornitza Stark Marked gene: FLII as ready
Mendeliome v0.6801 FLII Zornitza Stark gene: FLII was added
gene: FLII was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FLII was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLII were set to 32870709
Phenotypes for gene: FLII were set to Dilated cardiomyopathy
Review for gene: FLII was set to AMBER
Added comment: Two unrelated families reported with homozygous missense variants. Emerging evidence.
Sources: Literature
Mendeliome v0.6800 RHBDF1 Zornitza Stark Marked gene: RHBDF1 as ready
Mendeliome v0.6799 RHBDF1 Zornitza Stark gene: RHBDF1 was added
gene: RHBDF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RHBDF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHBDF1 were set to 32870709
Phenotypes for gene: RHBDF1 were set to Dilated cardiomyopathy
Review for gene: RHBDF1 was set to AMBER
Added comment: Three families reported with homozygous variants in this gene and onset of DCM in infancy/childhood. Two of the families had the same truncating variant, indicative of founder effect, and one family had a homozygous missense variant.
Sources: Literature
Mendeliome v0.6798 MYLK3 Zornitza Stark Marked gene: MYLK3 as ready
Mendeliome v0.6797 MYLK3 Zornitza Stark gene: MYLK3 was added
gene: MYLK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709
Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy
Review for gene: MYLK3 was set to AMBER
Added comment: Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Mendeliome v0.6796 NRAP Zornitza Stark Marked gene: NRAP as ready
Mendeliome v0.6795 NRAP Zornitza Stark gene: NRAP was added
gene: NRAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NRAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRAP were set to 33534821; 30384889; 28611399; 32870709
Phenotypes for gene: NRAP were set to Dilated cardiomyopathy
Review for gene: NRAP was set to GREEN
Added comment: Twenty unrelated families reported with childhood onset DCM.
Sources: Literature
Mendeliome v0.6794 MPEG1 Zornitza Stark Marked gene: MPEG1 as ready
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
Mendeliome v0.6791 INPP5E Zornitza Stark Marked gene: INPP5E as ready
Mendeliome v0.6791 INPP5E Zornitza Stark Phenotypes for gene: INPP5E were changed from to Joubert syndrome 1, MIM# 213300; MONDO:0008944; Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156; MONDO:0012423
Mendeliome v0.6788 INPP5E Zornitza Stark reviewed gene: INPP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686; Phenotypes: Joubert syndrome 1, MIM# 213300, MONDO:0008944, Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156, MONDO:0012423; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6788 CSPP1 Zornitza Stark Marked gene: CSPP1 as ready
Mendeliome v0.6785 CSPP1 Zornitza Stark changed review comment from: More than 20 unrelated families reported.; to: More than 20 unrelated families reported. Classically associated with Joubert syndrome; however, note 4 individuals reported with features consistent with Jeune asphyxiating thoracic dystrophy, including short ribs, bell-shaped chest, and pulmonary hypoplasia.
Mendeliome v0.6785 CEP41 Zornitza Stark Marked gene: CEP41 as ready
Mendeliome v0.6782 SCA1 Bryony Thompson Marked STR: SCA1 as ready
Mendeliome v0.6781 SCA1 Bryony Thompson STR: SCA1 was added
STR: SCA1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA1 were set to 29325606; 20301363
Phenotypes for STR: SCA1 were set to Spinocerebellar ataxia 1 MIM#164400
STR: SCA1 was marked as clinically relevant
Added comment: NM_000332.3:c.589_591CAG[X]
Toxic protein aggregation is mechanism of disease
Normal: ≤35 CAG repeats or 36-44 CAG repeats with CAT interruptions
Mutable normal (intermediate): 36-38 CAG repeats without CAT interruptions
Full-penetrance: ≥39 CAG repeats without CAT interruptions or ≥46 uninterrupted CAG repeats with CAT interruptions and additional CAGs
Sources: Expert list
Mendeliome v0.6779 RANBP2 Bryony Thompson Marked gene: RANBP2 as ready
Mendeliome v0.6779 NCSTN Bryony Thompson Marked gene: NCSTN as ready
Mendeliome v0.6779 PSENEN Bryony Thompson Marked gene: PSENEN as ready
Mendeliome v0.6776 ALDH1L2 Zornitza Stark Marked gene: ALDH1L2 as ready
Mendeliome v0.6775 ESCO2 Zornitza Stark Marked gene: ESCO2 as ready
Mendeliome v0.6775 ESCO2 Zornitza Stark Phenotypes for gene: ESCO2 were changed from to Juberg-Hayward syndrome, MIM# 216100; Roberts-SC phocomelia syndrome, MIM#268300
Mendeliome v0.6772 ESCO2 Zornitza Stark reviewed gene: ESCO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32977150; Phenotypes: Juberg-Hayward syndrome, MIM# 216100, Roberts-SC phocomelia syndrome, MIM#268300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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
Mendeliome v0.6769 FAM57B Zornitza Stark Marked gene: FAM57B as ready
Mendeliome v0.6768 FAM57B Zornitza Stark gene: FAM57B was added
gene: FAM57B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM57B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM57B were set to 33077892
Phenotypes for gene: FAM57B were set to Cone–rod dystrophy; Maculopathy
Review for gene: FAM57B was set to GREEN
Added comment: 4 patients with cone-rod dystrophy or maculopathy from 3 families, with LOF pathogenic variants in TLCD3B (ceramide synthase gene). Ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. Variants segregated with disease. TLCD3B showed high expression in the adult retina with higher expression in the macular than in the peripheral region. Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina.
Sources: Literature
Mendeliome v0.6767 LRRC8A Bryony Thompson Marked gene: LRRC8A as ready
Mendeliome v0.6766 SIAE Bryony Thompson Marked gene: SIAE as ready
Mendeliome v0.6765 TAOK2 Bryony Thompson Marked gene: TAOK2 as ready
Mendeliome v0.6763 TAOK2 Bryony Thompson gene: TAOK2 was added
gene: TAOK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAOK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TAOK2 were set to 28385331; 29467497
Phenotypes for gene: TAOK2 were set to Generalized verrucosis; abnormal T cell activation
Review for gene: TAOK2 was set to AMBER
Added comment: PMID: 28385331 - A single consanguineous family with generalized verrucosis and abnormal T cell activation, and a homozygous missense (p.R700C), with some assays on patient fibroblasts.
PMID: 29467497 - One of the several genes in the 16p11.2 microdeletion region associated with autism. Taok2 heterozygous and knockout mice had gene dosage-dependent impairments in cognition, anxiety, social interaction, brain size, and neural connectivity. 3 de novo variants and 3 predicted loss of function variants identified in 6 unrelated autism cases. 2 of the de novo variants have supporting functional assays, but 1 of them co-occurs in an individual with a CHD8 frameshift. 1 of the predicted loss of function variants was also identified in the unaffected father and sibling.
Sources: Literature
Mendeliome v0.6762 CC2D2A Zornitza Stark Marked gene: CC2D2A as ready
Mendeliome v0.6759 POLR3GL Zornitza Stark Phenotypes for gene: POLR3GL were changed from endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy to Short stature, oligodontia, dysmorphic facies, and motor delay (SOFM), MIM#619234; endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy
Mendeliome v0.6758 INVS Zornitza Stark Marked gene: INVS as ready
Mendeliome v0.6755 ZCCHC8 Bryony Thompson Marked gene: ZCCHC8 as ready
Mendeliome v0.6754 ZCCHC8 Bryony Thompson gene: ZCCHC8 was added
gene: ZCCHC8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZCCHC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZCCHC8 were set to 31488579
Phenotypes for gene: ZCCHC8 were set to Pulmonary fibrosis
Review for gene: ZCCHC8 was set to AMBER
Added comment: A missense variant (P186L) segregates over 3 generations in a single family, and supporting in vitro assays and mouse model.
Sources: Literature
Mendeliome v0.6753 KDM5B Zornitza Stark reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, Intellectual disability and/or autism, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6753 KDM5B Zornitza Stark Marked gene: KDM5B as ready
Mendeliome v0.6753 KDM5B Zornitza Stark Phenotypes for gene: KDM5B were changed from to Mental retardation, autosomal recessive 65 MIM#618109; Intellectual disability and/or autism, autosomal dominant
Mendeliome v0.6750 TPP2 Zornitza Stark Marked gene: TPP2 as ready
Mendeliome v0.6747 DOCK7 Zornitza Stark Marked gene: DOCK7 as ready
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.
Mendeliome v0.6742 RTN2 Zornitza Stark Marked gene: RTN2 as ready
Mendeliome v0.6742 RTN2 Zornitza Stark Phenotypes for gene: RTN2 were changed from to Spastic paraplegia 12, autosomal dominant, 604805; MONDO:0011489
Mendeliome v0.6739 RTN2 Zornitza Stark reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22232211, 27165006; Phenotypes: Spastic paraplegia 12, autosomal dominant, 604805, MONDO:0011489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6739 KDM5B Elena Savva reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29276005, 30217758, 30409806; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, autosomal dominant autism spectrum disorder or intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6739 NIPA1 Zornitza Stark Marked gene: NIPA1 as ready
Mendeliome v0.6739 NIPA1 Zornitza Stark Phenotypes for gene: NIPA1 were changed from to Spastic paraplegia 6, autosomal dominant, MIM# 600363; MONDO:0010878
Mendeliome v0.6736 NIPA1 Zornitza Stark reviewed gene: NIPA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14508710, 15711826, 32500351, 25133278; Phenotypes: Spastic paraplegia 6, autosomal dominant, MIM# 600363, MONDO:0010878; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6736 DDHD1 Zornitza Stark Marked gene: DDHD1 as ready
Mendeliome v0.6736 DDHD1 Zornitza Stark Phenotypes for gene: DDHD1 were changed from to Spastic paraplegia 28, autosomal recessive, 609340; MONDO:0012256
Mendeliome v0.6733 DDHD1 Zornitza Stark reviewed gene: DDHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 28, autosomal recessive, 609340, MONDO:0012256; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6732 CPT1C Zornitza Stark reviewed gene: CPT1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 30564185; Phenotypes: Spastic paraplegia 73, autosomal dominant MIM#616282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6732 CPT1C Zornitza Stark Phenotypes for gene: CPT1C were changed from Spastic paraplegia 73, autosomal dominant MIM#616282 to Spastic paraplegia 73, autosomal dominant MIM#616282; MONDO:0014568
Mendeliome v0.6730 CAPN1 Zornitza Stark Phenotypes for gene: CAPN1 were changed from Spastic paraplegia 76, autosomal recessive, MIM#616907 to Spastic paraplegia 76, autosomal recessive, MIM#616907; MONDO:0014827
Mendeliome v0.6729 AP5Z1 Zornitza Stark Marked gene: AP5Z1 as ready
Mendeliome v0.6729 AP5Z1 Zornitza Stark Phenotypes for gene: AP5Z1 were changed from to Spastic paraplegia 48, autosomal recessive, MIM# 613647; MONDO:0013342
Mendeliome v0.6726 AP5Z1 Zornitza Stark reviewed gene: AP5Z1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26085577, 33543803, 27606357; Phenotypes: Spastic paraplegia 48, autosomal recessive, MIM# 613647, MONDO:0013342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6726 COPB1 Zornitza Stark Marked gene: COPB1 as ready
Mendeliome v0.6725 COPB1 Zornitza Stark gene: COPB1 was added
gene: COPB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to AMBER
Added comment: Two unrelated families, some supportive functional data.
Sources: Literature
Mendeliome v0.6723 SLC1A4 Zornitza Stark Marked gene: SLC1A4 as ready
Mendeliome v0.6720 TFG Zornitza Stark Marked gene: TFG as ready
Mendeliome v0.6720 TFG Zornitza Stark Phenotypes for gene: TFG were changed from to Hereditary motor and sensory neuropathy, Okinawa type, MIM# 604484; Spastic paraplegia 57, autosomal recessive, MIM# 615658
Mendeliome v0.6718 TFG Zornitza Stark reviewed gene: TFG: Rating: GREEN; Mode of pathogenicity: None; Publications: 30467354, 30157421, 28124177, 27601211, 27492651, 23479643, 25098539, 23553329, 22883144, 31449671, 31111683; Phenotypes: Hereditary motor and sensory neuropathy, Okinawa type, MIM# 604484, Spastic paraplegia 57, autosomal recessive, MIM# 615658; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6718 WDR45B Zornitza Stark Marked gene: WDR45B as ready
Mendeliome v0.6715 REEP2 Zornitza Stark Marked gene: REEP2 as ready
Mendeliome v0.6715 REEP2 Zornitza Stark Phenotypes for gene: REEP2 were changed from to Spastic paraplegia 72, dominant and recessive, MIM# 615625; MONDO:0014282
Mendeliome v0.6712 REEP2 Zornitza Stark reviewed gene: REEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33526816, 28491902, 24388663; Phenotypes: Spastic paraplegia 72, dominant and recessive, MIM# 615625, MONDO:0014282; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6712 NT5C2 Zornitza Stark Marked gene: NT5C2 as ready
Mendeliome v0.6712 NT5C2 Zornitza Stark Phenotypes for gene: NT5C2 were changed from to Spastic paraplegia 45, autosomal recessive, MIM# 613162; MONDO:0013165
Mendeliome v0.6709 NT5C2 Zornitza Stark reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 32153630, 29123918, 28884889, 28327087; Phenotypes: Spastic paraplegia 45, autosomal recessive, MIM# 613162, MONDO:0013165; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6709 HACE1 Zornitza Stark Marked gene: HACE1 as ready
Mendeliome v0.6709 HACE1 Zornitza Stark Phenotypes for gene: HACE1 were changed from to Spastic paraplegia and psychomotor retardation with or without seizures, 616756; MONDO:0014764
Mendeliome v0.6706 HACE1 Zornitza Stark reviewed gene: HACE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26424145, 26437029, 31321300; Phenotypes: Spastic paraplegia and psychomotor retardation with or without seizures, 616756, MONDO:0014764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6706 NKX6-2 Zornitza Stark Marked gene: NKX6-2 as ready
Mendeliome v0.6703 ARPC1B Zornitza Stark Marked gene: ARPC1B as ready
Mendeliome v0.6703 ARPC1B Zornitza Stark Gene: arpc1b has been classified as Green List (High Evidence).
Mendeliome v0.6703 ARPC1B Zornitza Stark Phenotypes for gene: ARPC1B were changed from to Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease 617718
Mendeliome v0.6702 ARPC1B Zornitza Stark Publications for gene: ARPC1B were set to
Mendeliome v0.6701 ARPC1B Zornitza Stark Mode of inheritance for gene: ARPC1B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6700 ARPC1B Zornitza Stark reviewed gene: ARPC1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28368018, 33679784; Phenotypes: Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease 617718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v0.6699 KDM5C Zornitza Stark changed review comment from: Progressive lower limb spasticity is a feature of this ID syndrome. More than 5 unrelated families reported.; to: Intellectual disability, progressive lower limb spasticity, epilepsy and a number of other more variable features. Affected females reported PMID 32279304.
Mendeliome v0.6699 KDM5C Zornitza Stark Marked gene: KDM5C as ready
Mendeliome v0.6699 KDM5C Zornitza Stark Phenotypes for gene: KDM5C were changed from to Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534; MONDO:0010355
Mendeliome v0.6696 KDM5C Zornitza Stark reviewed gene: KDM5C: Rating: GREEN; Mode of pathogenicity: None; Publications: 15586325, 32279304; Phenotypes: Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534, MONDO:0010355; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6696 ENTPD1 Zornitza Stark Marked gene: ENTPD1 as ready
Mendeliome v0.6696 ENTPD1 Zornitza Stark Phenotypes for gene: ENTPD1 were changed from to Spastic paraplegia 64, autosomal recessive MIM#615683
Mendeliome v0.6693 ENTPD1 Zornitza Stark reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 30652007; Phenotypes: Spastic paraplegia 64, autosomal recessive MIM#615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6693 C12orf65 Zornitza Stark Marked gene: C12orf65 as ready
Mendeliome v0.6693 C12orf65 Zornitza Stark Phenotypes for gene: C12orf65 were changed from to Spastic paraplegia 55, autosomal recessive, MIM#615035; Combined oxidative phosphorylation deficiency 7, MIM# 613559
Mendeliome v0.6690 C12orf65 Zornitza Stark reviewed gene: C12orf65: Rating: GREEN; Mode of pathogenicity: None; Publications: 23188110, 24080142, 24198383, 20598281, 32808965, 32478789, 28804760; Phenotypes: Spastic paraplegia 55, autosomal recessive, MIM#615035, Combined oxidative phosphorylation deficiency 7, MIM# 613559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6690 C19orf12 Zornitza Stark Marked gene: C19orf12 as ready
Mendeliome v0.6690 C19orf12 Zornitza Stark Phenotypes for gene: C19orf12 were changed from to Neurodegeneration with brain iron accumulation 4, MIM# 614298; Spastic paraplegia 43, autosomal recessive, MIM# 615043
Mendeliome v0.6687 C19orf12 Zornitza Stark reviewed gene: C19orf12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33688131, 21981780, 22508347, 23269600, 31804703, 30088953, 20039086; Phenotypes: Neurodegeneration with brain iron accumulation 4, MIM# 614298, Spastic paraplegia 43, autosomal recessive, MIM# 615043; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6687 CYP2U1 Zornitza Stark Marked gene: CYP2U1 as ready
Mendeliome v0.6687 CYP2U1 Zornitza Stark Phenotypes for gene: CYP2U1 were changed from to Spastic paraplegia 56, autosomal recessive, MIM#615030
Mendeliome v0.6684 CYP2U1 Zornitza Stark edited their review of gene: CYP2U1: Added comment: SPG56 is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy. Onset is typically in the first decade. More than 5 unrelated families reported.; Changed rating: GREEN; Changed publications: 23176821, 32006740, 29034544
Mendeliome v0.6684 IFRD1 Zornitza Stark Marked gene: IFRD1 as ready
Mendeliome v0.6684 IFRD1 Zornitza Stark gene: IFRD1 was added
gene: IFRD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFRD1 were set to 29362493
Phenotypes for gene: IFRD1 were set to Hereditary spastic paraplegia; peripheral neuropathy; ataxia
Review for gene: IFRD1 was set to RED
Added comment: A variant segregated with slowly progressing gait ataxia, pyramidal tract signs and peripheral neuropathy in three siblings from a single Chinese family. No functional analyses of the variant has been conducted. The variant (c.514 A>G, p.I172V) is too common (0.3%) for a dominant condition in the African population in gnomAD.
Sources: Expert Review
Mendeliome v0.6684 IFRD1 Zornitza Stark gene: IFRD1 was added
gene: IFRD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFRD1 were set to 29362493
Phenotypes for gene: IFRD1 were set to Hereditary spastic paraplegia; peripheral neuropathy; ataxia
Review for gene: IFRD1 was set to RED
Added comment: A variant segregated with slowly progressing gait ataxia, pyramidal tract signs and peripheral neuropathy in three siblings from a single Chinese family. No functional analyses of the variant has been conducted. The variant (c.514 A>G, p.I172V) is too common (0.3%) for a dominant condition in the African population in gnomAD.
Sources: Expert Review
Mendeliome v0.6683 KLC4 Zornitza Stark Marked gene: KLC4 as ready
Mendeliome v0.6683 KLC4 Zornitza Stark gene: KLC4 was added
gene: KLC4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KLC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLC4 were set to 26423925
Phenotypes for gene: KLC4 were set to Complicated hereditary spastic paraplegia
Review for gene: KLC4 was set to RED
Added comment: Single family reported.
Sources: Expert Review
Mendeliome v0.6682 AP4M1 Zornitza Stark Marked gene: AP4M1 as ready
Mendeliome v0.6682 AP4M1 Zornitza Stark Phenotypes for gene: AP4M1 were changed from to Spastic paraplegia 50, autosomal recessive, MIM# 612936
Mendeliome v0.6679 AP4M1 Zornitza Stark reviewed gene: AP4M1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19559397, 21937992, 21937992, 32979048, 31915823, 29096665, 28464862, 25496299; Phenotypes: Spastic paraplegia 50, autosomal recessive, MIM# 612936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6679 ADAMTS13 Zornitza Stark Marked gene: ADAMTS13 as ready
Mendeliome v0.6679 ADAMTS13 Zornitza Stark Phenotypes for gene: ADAMTS13 were changed from to Thrombotic thrombocytopenic purpura, hereditary, MIM# 274150
Mendeliome v0.6676 ADAMTS13 Zornitza Stark reviewed gene: ADAMTS13: Rating: GREEN; Mode of pathogenicity: None; Publications: 11586351, 30312976; Phenotypes: Thrombotic thrombocytopenic purpura, hereditary, MIM# 274150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6676 AP4S1 Zornitza Stark Marked gene: AP4S1 as ready
Mendeliome v0.6676 AP4S1 Zornitza Stark Phenotypes for gene: AP4S1 were changed from to Spastic paraplegia 52, autosomal recessive, MIM# 614067
Mendeliome v0.6673 AP4S1 Zornitza Stark reviewed gene: AP4S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 25552650, 32979048, 32216065, 31915823, 30283821, 27444738; Phenotypes: Spastic paraplegia 52, autosomal recessive, MIM# 614067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6673 AIMP1 Zornitza Stark Marked gene: AIMP1 as ready
Mendeliome v0.6669 DSG3 Zornitza Stark Phenotypes for gene: DSG3 were changed from Mucosal blistering to Blistering, acantholytic, of oral and laryngeal mucosa, MIM# 619226
Mendeliome v0.6668 DSG3 Zornitza Stark edited their review of gene: DSG3: Changed phenotypes: Blistering, acantholytic, of oral and laryngeal mucosa, MIM# 619226
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 v0.6667 CC2D1A Zornitza Stark Marked gene: CC2D1A as ready
Mendeliome v0.6667 CC2D1A Zornitza Stark Phenotypes for gene: CC2D1A were changed from to Autosomal recessive mental retardation, (MIM#608443)
Mendeliome v0.6664 CC2D1A Zornitza Stark reviewed gene: CC2D1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066123; Phenotypes: Autosomal recessive mental retardation, (MIM#608443); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6664 ZAP70 Zornitza Stark Marked gene: ZAP70 as ready
Mendeliome v0.6660 GDF5 Michelle Torres reviewed gene: GDF5: Rating: RED; Mode of pathogenicity: None; Publications: 8589725, 33333243; Phenotypes: ? Hunter-Thompson type acromesomelic dysplasia (MIM#201250) AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6660 CST3 Zornitza Stark Marked gene: CST3 as ready
Mendeliome v0.6656 NR3C1 Zornitza Stark Marked gene: NR3C1 as ready
Mendeliome v0.6652 YY1AP1 Zornitza Stark commented on gene: YY1AP1: Grange syndrome: multiple arterial stenoses, severe early onset hypertension, fibromuscular dysplasia, variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Missense variant reported PMID: 31633303 with moyamoya like phenotype in adult case; fibroblasts suggest that the p.Pro360Leu variant decreases the stability of the YY1AP1 protein but most LOF. PMID: 30556293 non coding variants reported (intronic variants leading to aberrant splicing)
Mendeliome v0.6652 NOS3 Zornitza Stark Marked gene: NOS3 as ready
Mendeliome v0.6649 CDT1 Zornitza Stark Marked gene: CDT1 as ready
Mendeliome v0.6646 CDK5RAP2 Zornitza Stark Marked gene: CDK5RAP2 as ready
Mendeliome v0.6646 CDK5RAP2 Zornitza Stark Phenotypes for gene: CDK5RAP2 were changed from to Microcephaly 3, primary, autosomal recessive, MIM# 604804; MONDO:0011488
Mendeliome v0.6643 CDK5RAP2 Zornitza Stark reviewed gene: CDK5RAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15793586, 22887808, 23995685, 23726037, 27761245, 20460369, 32677750, 32015000; Phenotypes: Microcephaly 3, primary, autosomal recessive, MIM# 604804, MONDO:0011488; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6643 UGT2B17 Zornitza Stark Marked gene: UGT2B17 as ready
Mendeliome v0.6642 PLD1 Zornitza Stark changed review comment from: Cardiac valvular defect, developmental, MIM# 212093; neonatal cardiomyopathy; to: PMID 33645542: 31 individuals from 20 families reported, presenting predominantly with congenital cardiac valve defects and some with neonatal cardiomyopathy. p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%).
Mendeliome v0.6642 PLD1 Zornitza Stark Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, MIM# 212093 to Cardiac valvular defect, developmental, MIM# 212093; neonatal cardiomyopathy
Mendeliome v0.6639 DONSON Zornitza Stark Marked gene: DONSON as ready
Mendeliome v0.6636 SQOR Zornitza Stark Marked gene: SQOR as ready
Mendeliome v0.6633 PGK1 Zornitza Stark Marked gene: PGK1 as ready
Mendeliome v0.6630 PGM1 Zornitza Stark Marked gene: PGM1 as ready
Mendeliome v0.6626 PHKA1 Zornitza Stark Marked gene: PHKA1 as ready
Mendeliome v0.6623 PHKB Zornitza Stark Marked gene: PHKB as ready
Mendeliome v0.6620 PHKG2 Zornitza Stark Marked gene: PHKG2 as ready
Mendeliome v0.6617 PYGL Zornitza Stark Marked gene: PYGL as ready
Mendeliome v0.6614 NHLRC1 Zornitza Stark Marked gene: NHLRC1 as ready
Mendeliome v0.6611 LDHA Zornitza Stark Marked gene: LDHA as ready
Mendeliome v0.6608 SIAH1 Zornitza Stark Marked gene: SIAH1 as ready
Mendeliome v0.6607 RPL18 Zornitza Stark Marked gene: RPL18 as ready
Mendeliome v0.6605 RPS15A Zornitza Stark Marked gene: RPS15A as ready
Mendeliome v0.6604 RPL35 Zornitza Stark Marked gene: RPL35 as ready
Mendeliome v0.6603 RPS7 Zornitza Stark Marked gene: RPS7 as ready
Mendeliome v0.6600 RPS26 Zornitza Stark Marked gene: RPS26 as ready
Mendeliome v0.6597 RPS24 Zornitza Stark Marked gene: RPS24 as ready
Mendeliome v0.6593 RPS19 Zornitza Stark Marked gene: RPS19 as ready
Mendeliome v0.6589 SIAH1 Arina Puzriakova gene: SIAH1 was added
gene: SIAH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIAH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIAH1 were set to 32430360
Phenotypes for gene: SIAH1 were set to Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Review for gene: SIAH1 was set to GREEN
Added comment: - PMID: 32430360 (2021) - Five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia. All had speech delay and where cognitive assessment was age appropriate individuals exhibited learning difficulties. Trio WES revealed distinct de novo variants in SIAH1. In vitro assays demonstrated that SIAH1 mutants induce loss of Wnt stimulatory activity.
Sources: Literature
Mendeliome v0.6589 SYCP2L Zornitza Stark Marked gene: SYCP2L as ready
Mendeliome v0.6588 RPL5 Zornitza Stark Marked gene: RPL5 as ready
Mendeliome v0.6585 RPL35A Zornitza Stark Marked gene: RPL35A as ready
Mendeliome v0.6582 SYCP2L Arina Puzriakova gene: SYCP2L was added
gene: SYCP2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SYCP2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCP2L were set to 32303603
Phenotypes for gene: SYCP2L were set to Premature ovarian insufficiency
Review for gene: SYCP2L was set to AMBER
Added comment: - PMID: 32303603 (2021) - Two unrelated individuals with premature ovarian insufficiency and homozygous variants (c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L.
In vitro assays revealed that mutant SYCP2L proteins induced mislocalisation and reduced expression. Sycp2l knockout mice exhibit accelerated reproductive ageing.
Sources: Literature
Mendeliome v0.6582 RPL27 Zornitza Stark Marked gene: RPL27 as ready
Mendeliome v0.6578 RPL11 Zornitza Stark Marked gene: RPL11 as ready
Mendeliome v0.6574 TTC7A Zornitza Stark Phenotypes for gene: TTC7A were changed from Gastrointestinal defects and immunodeficiency syndrome, 243150 to Gastrointestinal defects and immunodeficiency syndrome, 243150; Very Early Onset Inflammatory Bowel Disease (VEOIBD)
Mendeliome v0.6572 TTC7A Zornitza Stark reviewed gene: TTC7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24417819, 24292712, 23830146, 29174094, 31743734; Phenotypes: Very Early Onset Inflammatory Bowel Disease (VEOIBD); Mode of inheritance: None
Mendeliome v0.6572 CLCN4 Zornitza Stark Marked gene: CLCN4 as ready
Mendeliome v0.6572 CLCN4 Zornitza Stark Phenotypes for gene: CLCN4 were changed from to Raynaud-Claes syndrome, MIM#300114; intellectual disability; epilepsy; autistic features; mood disorders; cerebral white matter changes; progressive appendicular spasticity
Mendeliome v0.6569 CLCN4 Zornitza Stark reviewed gene: CLCN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27550844; Phenotypes: Raynaud-Claes syndrome, MIM#300114, intellectual disability, epilepsy, autistic features, mood disorders, cerebral white matter changes, progressive appendicular spasticity; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6567 EN1 Zornitza Stark changed review comment from: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.
Sources: Literature; to: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.

An additional fourth individual had cerebellar hypoplasia in addition to the skeletal phenotype, and a bi-allelic LoF variant.
Sources: Literature
Mendeliome v0.6567 EN1 Zornitza Stark Marked gene: EN1 as ready
Mendeliome v0.6566 EN1 Zornitza Stark gene: EN1 was added
gene: EN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EN1 were set to 33568816
Phenotypes for gene: EN1 were set to ENDOVE syndrome, limb-only type, MIM# 619217
Review for gene: EN1 was set to GREEN
Added comment: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.
Sources: Literature
Mendeliome v0.6565 EEF2 Zornitza Stark Phenotypes for gene: EEF2 were changed from Neurodevelopmental disorder; macrocephaly; hydrocephalus; Spinocerebellar ataxia 26, MIM#609306 to Neurodevelopmental disorder, macrocephaly, hydrocephalus; Spinocerebellar ataxia 26, MIM#609306
Mendeliome v0.6564 EEF2 Zornitza Stark Phenotypes for gene: EEF2 were changed from Neurodevelopmental disorder, hydrocephalus; Spinocerebellar ataxia 26, MIM#609306 to Neurodevelopmental disorder; macrocephaly; hydrocephalus; Spinocerebellar ataxia 26, MIM#609306
Mendeliome v0.6563 EEF2 Zornitza Stark Phenotypes for gene: EEF2 were changed from Spinocerebellar ataxia 26, MIM#609306 to Neurodevelopmental disorder, hydrocephalus; Spinocerebellar ataxia 26, MIM#609306
Mendeliome v0.6562 EEF2 Zornitza Stark Phenotypes for gene: EEF2 were changed from Spinocerebellar ataxia 26 to Spinocerebellar ataxia 26, MIM#609306
Mendeliome v0.6559 MKRN3 Zornitza Stark Marked gene: MKRN3 as ready
Mendeliome v0.6556 ACSL5 Zornitza Stark Marked gene: ACSL5 as ready
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
Mendeliome v0.6555 GDF5 Zornitza Stark Marked gene: GDF5 as ready
Mendeliome v0.6552 EEF2 Eleanor Williams reviewed gene: EEF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23001565, 33355653; Phenotypes: Spinocerebellar ataxia 26 MIM#609306; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6552 KIDINS220 Zornitza Stark Marked gene: KIDINS220 as ready
Mendeliome v0.6552 KIDINS220 Zornitza Stark Phenotypes for gene: KIDINS220 were changed from to Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; cerebral ventriculomegaly; limb contractures
Mendeliome v0.6549 KIDINS220 Zornitza Stark reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: None; Publications: 27005418; Phenotypes: Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6544 COL9A3 Zornitza Stark Marked gene: COL9A3 as ready
Mendeliome v0.6541 DLK1 Zornitza Stark Marked gene: DLK1 as ready
Mendeliome v0.6540 DLK1 Zornitza Stark gene: DLK1 was added
gene: DLK1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DLK1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: DLK1 were set to 28324015; 30462238
Phenotypes for gene: DLK1 were set to central precocious puberty
Review for gene: DLK1 was set to GREEN
Added comment: PMID: 30462238 "three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1". PMID: 28324015 single large family, only affected females, central precocious puberty all carrying paternally inherited LOF variant (del/dup of 5'UTR and exon 1) absent DLK1 expression in all affected. Unclear if males affected as none reported to date.
Sources: Expert Review
Mendeliome v0.6539 COL9A3 Eleanor Williams reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33078831, 15917166; Phenotypes: autosomal recessive non-syndromic hearing impairment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 EIF5A Zornitza Stark Marked gene: EIF5A as ready
Mendeliome v0.6538 EIF5A Zornitza Stark gene: EIF5A was added
gene: EIF5A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to 33547280
Phenotypes for gene: EIF5A were set to Intellectual disability; microcephaly; dysmorphism
Review for gene: EIF5A was set to GREEN
Added comment: 7 unrelated individuals reported with de novo variants in this gene and variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism.
Sources: Literature
Mendeliome v0.6537 POLRMT Zornitza Stark Marked gene: POLRMT as ready
Mendeliome v0.6536 POLRMT Zornitza Stark gene: POLRMT was added
gene: POLRMT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLRMT were set to 33602924
Phenotypes for gene: POLRMT were set to Mitochondrial disorder; intellectual disability; hypotonia
Review for gene: POLRMT was set to GREEN
Added comment: 8 individuals from 7 families reported. 5 families with bi-allelic variants and 2 with heterozygous variants. Affected individuals presented with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype.
Sources: Literature
Mendeliome v0.6535 PERP Zornitza Stark Phenotypes for gene: PERP were changed from Erythrokeratoderma, no OMIM # yet to Olmsted syndrome 2, MIM# 619208; Erythrokeratodermia variabilis et progressiva 7, MIM# 619209
Mendeliome v0.6531 PERP Zornitza Stark edited their review of gene: PERP: Added comment: Four families reported with heterozygous variants and Olmsted syndrome-2 (OLMS2), which is characterised by mutilating hyperkeratotic skin lesions, primarily on the palms and soles, but also extending onto dorsal surfaces of the hands and feet and distal extremities. The lesions are progressive, becoming thicker with verrucous fissures on the palms and soles over time. In addition, affected individuals exhibit perioral hyperkeratosis, and may have lesions around other orifices as well, such as the nostrils, perineum, and anus. Most patients also have hyperkeratotic nails and light-colored woolly hair.

Two families reported with bi-allelic variants and Erythrokeratodermia variabilis et progressiva-7 (EKVP7), which is characterised by palmoplantar keratoderma that extends to the dorsal surface of the hands and feet (transgrediens), as well as erythematous annular skin lesions. Pruritis, woolly hair, and dystrophic nails may also be present.; Changed rating: GREEN; Changed publications: 31898316, 30321533, 31361044; Changed phenotypes: Olmsted syndrome 2, MIM# 619208, Erythrokeratodermia variabilis et progressiva 7, MIM# 619209; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6531 KARS Zornitza Stark edited their review of gene: KARS: Changed phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147, Deafness, autosomal recessive 89, MIM# 613916, Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE), MIM#619196
Mendeliome v0.6531 KARS Zornitza Stark Phenotypes for gene: KARS were changed from Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916 to Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916; Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE), MIM#619196
Mendeliome v0.6530 KARS Zornitza Stark Marked gene: KARS as ready
Mendeliome v0.6530 KARS Zornitza Stark Gene: kars has been classified as Green List (High Evidence).
Mendeliome v0.6530 KARS Zornitza Stark Phenotypes for gene: KARS were changed from to Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916
Mendeliome v0.6529 KARS Zornitza Stark Publications for gene: KARS were set to
Mendeliome v0.6528 KARS Zornitza Stark Mode of inheritance for gene: KARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6527 KARS Zornitza Stark reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 26741492, 31618474, 28887846, 25330800, 29615062, 30252186, 28496994, 23768514, 14975237; Phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147, Deafness, autosomal recessive 89, MIM# 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6527 APOO Zornitza Stark Marked gene: APOO as ready
Mendeliome v0.6526 APOO Arina Puzriakova gene: APOO was added
gene: APOO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOO 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: APOO were set to 32439808
Phenotypes for gene: APOO were set to Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour
Review for gene: APOO was set to RED
Added comment: - PMID: 32439808 (2021) - Three generation family with c.350T>C variant in APOO, encoding a component of the MICOS complex which plays a role in maintaining inner mitochondrial membrane architecture.
Phenotypes include fatigue and muscle weakness (6/8), learning difficulties and cognitive impairment (4/8), and increased blood lactate (2/8). Four individuals were asymptomatic carriers, including one male (authors indicate variability in female carriers was due to skewed X-inactivation, although skewing studies were inconclusive in some cases). Variability in clinical presentation suggests reduced penetrance or possible contribution of additional factors.
Functional studies showed altered MICOS assembly and abnormalities in mitochondria ultrastructure in patient-derived fibroblasts. Knockdown studies in Drosophila and yeast demonstrated mitochondrial structural and functional deficiencies.
Sources: Literature
Mendeliome v0.6526 ECE1 Zornitza Stark Marked gene: ECE1 as ready
Mendeliome v0.6526 ECE1 Zornitza Stark Phenotypes for gene: ECE1 were changed from to Hirschsprung disease, cardiac defects, and autonomic dysfunction, OMIM # 613870
Mendeliome v0.6522 ECE1 Zornitza Stark reviewed gene: ECE1: Rating: RED; Mode of pathogenicity: None; Publications: 9915973, 9449665, 9449664; Phenotypes: Hirschsprung disease, cardiac defects, and autonomic dysfunction, OMIM # 613870; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6522 AMH Seb Lunke Marked gene: AMH as ready
Mendeliome v0.6519 PAX4 Zornitza Stark Marked gene: PAX4 as ready
Mendeliome v0.6516 PCBD1 Zornitza Stark Marked gene: PCBD1 as ready
Mendeliome v0.6513 SPTAN1 Zornitza Stark Marked gene: SPTAN1 as ready
Mendeliome v0.6513 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from to Developmental and epileptic encephalopathy 5, MIM# 613477; hereditary motor neuropathy
Mendeliome v0.6510 PSAP Zornitza Stark changed review comment from: Well established gene-disease association. Phenotype expansion with early-onset PD reported.; to: Well established gene-disease association for bi-allelic variants. Early-onset PD reported with mono-allelic variants.
Mendeliome v0.6509 PSAP Zornitza Stark Phenotypes for gene: PSAP were changed from Parkinson disease, AD to Parkinson disease, AD; Combined SAP deficiency 611721; Gaucher disease, atypical, MIM# 610539; Krabbe disease, atypical, MIM# 611722; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900
Mendeliome v0.6508 PSAP Zornitza Stark changed review comment from: Well established gene-disease association. Phenotype expansion reported with early-onset PD reported.; to: Well established gene-disease association. Phenotype expansion with early-onset PD reported.
Mendeliome v0.6508 ACTL9 Zornitza Stark Marked gene: ACTL9 as ready
Mendeliome v0.6507 NLRP3 Zornitza Stark Phenotypes for gene: NLRP3 were changed from to Familial cold inflammatory syndrome 1, MIM#120100; Muckle-Wells syndrome, MIM#191900; CINCA syndrome, MIM#607115; Deafness, autosomal dominant 34, with or without inflammation, MIM#617772; Keratoendothelitis fugax hereditaria, MIM#148200
Mendeliome v0.6505 IRF4 Bryony Thompson Marked gene: IRF4 as ready
Mendeliome v0.6505 IRF4 Bryony Thompson Phenotypes for gene: IRF4 were changed from Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724 to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724; Combined immunodeficiency
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
Mendeliome v0.6499 PSAP Seb Lunke Marked gene: PSAP as ready
Mendeliome v0.6499 PSAP Seb Lunke Phenotypes for gene: PSAP were changed from to Parkinson disease, AD
Mendeliome v0.6496 MAST2 Seb Lunke Marked gene: MAST2 as ready
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 SPTAN1 Melanie Marty changed review comment from: 13 affected individuals from 4 families reported (nonsense variants) with AD distal hereditary motor neuropathy. Variable penetrance was noted and phenotype severity differs greatly between patients; to: 13 affected individuals from 4 families reported (nonsense variants) with AD distal hereditary motor neuropathy. Variable penetrance was noted and phenotype severity differs greatly between patients. Functional studies show NMD and reduced protein levels in patient cells.
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
Mendeliome v0.6494 EPAS1 Seb Lunke Marked gene: EPAS1 as ready
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
Mendeliome v0.6487 NLRP3 Alison Yeung Marked gene: NLRP3 as ready
Mendeliome v0.6487 SPTAN1 Melanie Marty reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33578420, 31332438; Phenotypes: hereditary motor neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6487 MED27 Alison Yeung Marked gene: MED27 as ready
Mendeliome v0.6486 PSAP Ain Roesley reviewed gene: PSAP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32201884; Phenotypes: parkinson's disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Mendeliome v0.6485 ACTL9 Elena Savva gene: ACTL9 was added
gene: ACTL9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTL9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL9 were set to PMID: 33626338
Phenotypes for gene: ACTL9 were set to Fertilization failure; male infertility
Review for gene: ACTL9 was set to GREEN
Added comment: Three families with homozygous pathogenic variants (two missense, one PTC). Single affected in each family. Functional analysis from patients shows all sperm had morphological defects, protein had reduced binding to ACTL7A
All variants very rare in gnomAD.
Sources: Literature
Mendeliome v0.6485 MAST2 Elena Savva gene: MAST2 was added
gene: MAST2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST2 were set to PMID: 33465109
Phenotypes for gene: MAST2 were set to Thrombophilia; venous thrombosis
Review for gene: MAST2 was set to RED
Added comment: Single missense identified in a family with venous thrombosis and thrombophilia. Missense variant reviewed by in silicos only. Shown to affect regulation of TFP1 and SERPINE1 gene expression.

RNAi of MAST2 followed by RNAseq showed expression changes in many downstream targets
Sources: Literature
Mendeliome v0.6485 NLRP3 Elena Savva reviewed gene: NLRP3: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 25038238; Phenotypes: Familial cold inflammatory syndrome 1, MIM#120100, Muckle-Wells syndrome, MIM#191900, CINCA syndrome, MIM#607115, Deafness, autosomal dominant 34, with or without inflammation, MIM#617772, Keratoendothelitis fugax hereditaria, MIM#148200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6485 AGPS Zornitza Stark Marked gene: AGPS as ready
Mendeliome v0.6482 BANF1 Zornitza Stark Marked gene: BANF1 as ready
Mendeliome v0.6478 FOXP2 Zornitza Stark Marked gene: FOXP2 as ready
Mendeliome v0.6475 GLI3 Zornitza Stark Marked gene: GLI3 as ready
Mendeliome v0.6472 KIF22 Zornitza Stark Marked gene: KIF22 as ready
Mendeliome v0.6468 ANKZF1 Bryony Thompson Marked gene: ANKZF1 as ready
Mendeliome v0.6465 ANGPT1 Bryony Thompson gene: ANGPT1 was added
gene: ANGPT1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ANGPT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPT1 were set to 28601681; 24852101; 30689269; 10617467; 8980224
Phenotypes for gene: ANGPT1 were set to Hereditary angioedema
Review for gene: ANGPT1 was set to AMBER
Added comment: A missense variant (A119S) identified in 4 affected individuals in a single family. Supportive data in patient cells, functional assays of the variant, and animal models (both overexpression and null) for the gene.
Sources: Other
Mendeliome v0.6464 CLTCL1 Bryony Thompson Marked gene: CLTCL1 as ready
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
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
Mendeliome v0.6462 C14orf39 Zornitza Stark Phenotypes for gene: C14orf39 were changed from Azoospermia; Premature ovarian insufficiency to Spermatogenic failure 52, MIM# 619202; Premature ovarian failure 18 619203
Mendeliome v0.6461 C14orf39 Zornitza Stark reviewed gene: C14orf39: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 52, MIM# 619202, Premature ovarian failure 18 619203; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6460 G6PC Zornitza Stark Marked gene: G6PC as ready
Mendeliome v0.6456 NMNAT2 Bryony Thompson Marked gene: NMNAT2 as ready
Mendeliome v0.6456 NMNAT2 Bryony Thompson Marked gene: NMNAT2 as ready
Mendeliome v0.6455 NMNAT2 Bryony Thompson gene: NMNAT2 was added
gene: NMNAT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NMNAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NMNAT2 were set to 31132363; 25271157; 20126265
Phenotypes for gene: NMNAT2 were set to polyneuropathy; erythromelalgia
Review for gene: NMNAT2 was set to AMBER
Added comment: A single family with siblings with a homozygous variant that confers a partial loss of function. Strong supporting functional evidence that the gene plays a key role in axonal survival.
Sources: Literature
Mendeliome v0.6454 CCT5 Bryony Thompson Phenotypes for gene: CCT5 were changed from to Neuropathy, hereditary sensory, with spastic paraplegia MIM#256840
Mendeliome v0.6451 USF1 Bryony Thompson Marked gene: USF1 as ready
Mendeliome v0.6447 LIPI Bryony Thompson Marked gene: LIPI as ready
Mendeliome v0.6446 GALNT12 Bryony Thompson Marked gene: GALNT12 as ready
Mendeliome v0.6445 ABCG2 Bryony Thompson Marked gene: ABCG2 as ready
Mendeliome v0.6444 SAT1 Bryony Thompson Marked gene: SAT1 as ready
Mendeliome v0.6443 SAT1 Bryony Thompson reviewed gene: SAT1: Rating: RED; Mode of pathogenicity: None; Publications: 12215835, 20672378, 9228047; Phenotypes: Keratosis follicularis spinulosa decalvans; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6441 MIR5004 Bryony Thompson Marked gene: MIR5004 as ready
Mendeliome v0.6440 TOGARAM1 Zornitza Stark Phenotypes for gene: TOGARAM1 were changed from Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus to Joubert syndrome 37, MIM# 619185
Mendeliome v0.6439 TOGARAM1 Zornitza Stark Publications for gene: TOGARAM1 were set to 32747439
Mendeliome v0.6438 TOGARAM1 Zornitza Stark Classified gene: TOGARAM1 as Green List (high evidence)
Mendeliome v0.6438 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Green List (High Evidence).
Mendeliome v0.6437 TOGARAM1 Zornitza Stark reviewed gene: TOGARAM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32453716; Phenotypes: Joubert syndrome 37, MIM# 619185; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6437 ALDOA Zornitza Stark Marked gene: ALDOA as ready
Mendeliome v0.6434 RDH5 Zornitza Stark Marked gene: RDH5 as ready
Mendeliome v0.6431 RPGRIP1 Zornitza Stark Marked gene: RPGRIP1 as ready
Mendeliome v0.6428 IRX4 Zornitza Stark Marked gene: IRX4 as ready
Mendeliome v0.6428 IRX4 Zornitza Stark Phenotypes for gene: IRX4 were changed from to Ventricular septal defect
Mendeliome v0.6424 IRX4 Zornitza Stark reviewed gene: IRX4: Rating: RED; Mode of pathogenicity: None; Publications: 21544582; Phenotypes: Ventricular septal defect; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6424 AKAP6 Zornitza Stark Marked gene: AKAP6 as ready
Mendeliome v0.6420 ASCC3 Bryony Thompson Marked gene: ASCC3 as ready
Mendeliome v0.6419 ASCC3 Bryony Thompson gene: ASCC3 was added
gene: ASCC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASCC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASCC3 were set to 21937992; https://doi.org/10.1016/j.xhgg.2021.100024
Phenotypes for gene: ASCC3 were set to Neuromuscular syndrome; congenital myopathy
Review for gene: ASCC3 was set to GREEN
Added comment: 11 individuals from 7 unrelated families with homozygous (missense) or compound heterozygous variants (missense with a presumed LoF variant or 2 missense, no biallelic LoF) with a neurologic phenotype that ranges from severe developmental delay to muscle fatigue.
Sources: Literature
Mendeliome v0.6415 ARSG Bryony Thompson Publications for gene: ARSG were set to 29300381; 20679209; 25452429; 26975023; 32455177
Mendeliome v0.6414 ARSG Bryony Thompson Classified gene: ARSG as Green List (high evidence)
Mendeliome v0.6414 ARSG Bryony Thompson Gene: arsg has been classified as Green List (High Evidence).
Mendeliome v0.6413 ARSG Bryony Thompson reviewed gene: ARSG: Rating: GREEN; Mode of pathogenicity: None; Publications: 33300174, 29300381, 32455177, 26975023; Phenotypes: Usher syndrome, type IV MIM#618144; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6413 LMNB2 Zornitza Stark Phenotypes for gene: LMNB2 were changed from {Lipodystrophy, partial, acquired, susceptibility to} 608709; Congenital microcephaly, Intellectual disability to {Lipodystrophy, partial, acquired, susceptibility to} 608709; Microcephaly 27, primary, autosomal dominant, MIM# 619180; Congenital microcephaly, Intellectual disability
Mendeliome v0.6412 LMNB2 Zornitza Stark edited their review of gene: LMNB2: Changed phenotypes: {Lipodystrophy, partial, acquired, susceptibility to} 608709, Microcephaly 27, primary, autosomal dominant, MIM# 619180, Congenital microcephaly, Intellectual disability
Mendeliome v0.6412 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500 to Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Mendeliome v0.6411 LMNB1 Zornitza Stark edited their review of gene: LMNB1: Changed phenotypes: Microcephaly 26, primary, autosomal dominant, MIM# 619179, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis, Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Mendeliome v0.6410 CRYM Zornitza Stark Marked gene: CRYM as ready
Mendeliome v0.6407 HARS Zornitza Stark Marked gene: HARS as ready
Mendeliome v0.6407 HARS Zornitza Stark Gene: hars has been classified as Green List (High Evidence).
Mendeliome v0.6407 HARS Zornitza Stark Phenotypes for gene: HARS were changed from Charcot-Marie-Tooth disease, axonal, type 2W, MIM# 616625 to Charcot-Marie-Tooth disease, axonal, type 2W MIM#616625; Usher syndrome type 3B MIM#614504; Multisystemic ataxic syndrome
Mendeliome v0.6406 HARS Zornitza Stark Publications for gene: HARS were set to 26072516
Mendeliome v0.6405 HARS Zornitza Stark Mode of inheritance for gene: HARS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6404 HARS Elena Savva reviewed gene: HARS: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32333447, 32940403, 26072516; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2W MIM#616625, Usher syndrome type 3B MIM#614504, Multisystemic ataxic syndrome; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6401 PMVK Zornitza Stark Marked gene: PMVK as ready
Mendeliome v0.6399 MVD Zornitza Stark Marked gene: MVD as ready
Mendeliome v0.6398 MVD Zornitza Stark gene: MVD was added
gene: MVD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MVD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MVD were set to 30942823; 33491095
Phenotypes for gene: MVD were set to Porokeratosis 7, multiple types, MIM# 614714
Review for gene: MVD was set to GREEN
Added comment: Porokeratoses are a heterogeneous group of keratinization disorders. For linear porokeratosis and disseminated superficial actinic porokeratosis, a heterozygous pathogenic germline variant in a mevalonate pathway gene and a postzygotic second hit mutation present in affected skin have been shown to be the patho-genetic mechanism for the development of the lesions. At least 5 individuals reported.
Sources: Expert list
Mendeliome v0.6397 SCUBE3 Zornitza Stark Phenotypes for gene: SCUBE3 were changed from Short stature; skeletal abnormalities; craniofacial abnormalities; dental anomalies to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies, MIM# 619184; Short stature; skeletal abnormalities; craniofacial abnormalities; dental anomalies
Mendeliome v0.6396 SCUBE3 Zornitza Stark edited their review of gene: SCUBE3: Changed phenotypes: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies, MIM# 619184, Short stature, skeletal abnormalities, craniofacial abnormalities, dental anomalies
Mendeliome v0.6396 UNC45B Zornitza Stark Phenotypes for gene: UNC45B were changed from Progressive Myopathy with Eccentric Cores to Myofibrillar myopathy 11, MIM# 619178; Progressive Myopathy with Eccentric Cores
Mendeliome v0.6395 UNC45B Zornitza Stark reviewed gene: UNC45B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myofibrillar myopathy 11, MIM# 619178; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6395 SHROOM3 Zornitza Stark Marked gene: SHROOM3 as ready
Mendeliome v0.6393 FLT3 Zornitza Stark Marked gene: FLT3 as ready
Mendeliome v0.6392 MSL3 Zornitza Stark Marked gene: MSL3 as ready
Mendeliome v0.6392 MSL3 Zornitza Stark Phenotypes for gene: MSL3 were changed from to Basilicata-Akhtar syndrome, OMIM # 301032
Mendeliome v0.6389 MSL3 Zornitza Stark reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33173220; Phenotypes: Basilicata-Akhtar syndrome, OMIM # 301032; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6389 TOE1 Zornitza Stark Marked gene: TOE1 as ready
Mendeliome v0.6389 TOE1 Zornitza Stark Phenotypes for gene: TOE1 were changed from to Pontocerebellar hypoplasia, type 7, MIM# 614969
Mendeliome v0.6386 TOE1 Zornitza Stark reviewed gene: TOE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28092684; Phenotypes: Pontocerebellar hypoplasia, type 7, MIM# 614969; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6386 VRK1 Zornitza Stark Marked gene: VRK1 as ready
Mendeliome v0.6386 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from to Pontocerebellar hypoplasia type 1A, MIM# 607596; SMA
Mendeliome v0.6383 VRK1 Zornitza Stark edited their review of gene: VRK1: Changed rating: GREEN; Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, SMA
Mendeliome v0.6383 SPTBN2 Zornitza Stark Marked gene: SPTBN2 as ready
Mendeliome v0.6383 SPTBN2 Zornitza Stark Phenotypes for gene: SPTBN2 were changed from to Spinocerebellar ataxia, autosomal recessive 14, MIM# 615386; Spinocerebellar ataxia 5, MIM# 600224
Mendeliome v0.6380 SEPSECS Zornitza Stark Marked gene: SEPSECS as ready
Mendeliome v0.6380 SEPSECS Zornitza Stark Phenotypes for gene: SEPSECS were changed from to Pontocerebellar hypoplasia type 2D, 613811; cerebellar ataxia and cognitive impairment
Mendeliome v0.6377 SEPSECS Zornitza Stark reviewed gene: SEPSECS: Rating: GREEN; Mode of pathogenicity: None; Publications: 20920667, 25044680, 31748115, 29464431; Phenotypes: Pontocerebellar hypoplasia type 2D, MIM# 613811; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6377 ITPR1 Zornitza Stark changed review comment from: Gillespie syndrome is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild. Multiple families reported with bi-allelic or de novo heterozygous variants.; to: Gillespie syndrome: usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild. Multiple families reported with bi-allelic or de novo heterozygous variants.
Mendeliome v0.6377 ITPR1 Zornitza Stark Marked gene: ITPR1 as ready
Mendeliome v0.6377 ITPR1 Zornitza Stark Phenotypes for gene: ITPR1 were changed from to Gillespie syndrome, MIM# 206700; Spinocerebellar ataxia 15 MIM#606658; Spinocerebellar ataxia 29, congenital nonprogressive MIM#117360
Mendeliome v0.6374 EXOSC8 Zornitza Stark Marked gene: EXOSC8 as ready
Mendeliome v0.6374 EXOSC8 Zornitza Stark Phenotypes for gene: EXOSC8 were changed from to Pontocerebellar hypoplasia, type 1C, MIM# 616081
Mendeliome v0.6371 EXOSC8 Zornitza Stark reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24989451; Phenotypes: Pontocerebellar hypoplasia, type 1C, MIM# 616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6371 EXOSC3 Zornitza Stark Marked gene: EXOSC3 as ready
Mendeliome v0.6371 EXOSC3 Zornitza Stark Phenotypes for gene: EXOSC3 were changed from to Pontocerebellar hypoplasia, type 1B, MIM# 614678
Mendeliome v0.6368 EXOSC3 Zornitza Stark reviewed gene: EXOSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22544365, 23284067, 24524299; Phenotypes: Pontocerebellar hypoplasia, type 1B, MIM# 614678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6368 CLP1 Zornitza Stark Marked gene: CLP1 as ready
Mendeliome v0.6368 CLP1 Zornitza Stark Phenotypes for gene: CLP1 were changed from to Pontocerebellar hypoplasia type 10, MIM# 615803
Mendeliome v0.6365 CLP1 Zornitza Stark reviewed gene: CLP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24766809, 29307788; Phenotypes: Pontocerebellar hypoplasia type 10, MIM# 615803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6365 CHMP1A Zornitza Stark Marked gene: CHMP1A as ready
Mendeliome v0.6365 CHMP1A Zornitza Stark Phenotypes for gene: CHMP1A were changed from to Pontocerebellar hypoplasia, type 8, MIM# 614961
Mendeliome v0.6362 CHMP1A Zornitza Stark reviewed gene: CHMP1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23023333; Phenotypes: Pontocerebellar hypoplasia, type 8, MIM# 614961; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6362 BRF1 Zornitza Stark Marked gene: BRF1 as ready
Mendeliome v0.6359 DHODH Zornitza Stark Marked gene: DHODH as ready
Mendeliome v0.6356 ITGB4 Zornitza Stark Marked gene: ITGB4 as ready
Mendeliome v0.6353 LAMA3 Zornitza Stark Marked gene: LAMA3 as ready
Mendeliome v0.6350 LAMB3 Zornitza Stark Marked gene: LAMB3 as ready
Mendeliome v0.6347 LAMC2 Zornitza Stark Marked gene: LAMC2 as ready
Mendeliome v0.6344 KRT5 Zornitza Stark Marked gene: KRT5 as ready
Mendeliome v0.6344 KRT5 Zornitza Stark Phenotypes for gene: KRT5 were changed from to Dowling-Degos disease 1, MIM# 179850; Epidermolysis bullosa simplex-MCR, MIM# 609352; Epidermolysis bullosa simplex-MP 131960; Epidermolysis bullosa simplex, Dowling-Meara type, MIM# 131760; Epidermolysis bullosa simplex, Koebner type, MIM# 131900; Epidermolysis bullosa simplex, recessive 1, MIM# 601001; Epidermolysis bullosa simplex, Weber-Cockayne type, MIM# 131800
Mendeliome v0.6342 KRT5 Zornitza Stark reviewed gene: KRT5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dowling-Degos disease 1, MIM# 179850, Epidermolysis bullosa simplex-MCR, MIM# 609352, Epidermolysis bullosa simplex-MP 131960, Epidermolysis bullosa simplex, Dowling-Meara type, MIM# 131760, Epidermolysis bullosa simplex, Koebner type, MIM# 131900, Epidermolysis bullosa simplex, recessive 1, MIM# 601001, Epidermolysis bullosa simplex, Weber-Cockayne type, MIM# 131800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6342 CLCN6 Zornitza Stark Phenotypes for gene: CLCN6 were changed from Benign partial epilepsy; febrile seizures; NCL to Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities, MIM# 619173; Neurodegeneration; Benign partial epilepsy; febrile seizures; NCL
Mendeliome v0.6340 CLCN6 Zornitza Stark edited their review of gene: CLCN6: Changed phenotypes: Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities, MIM# 619173, Neurodegeneration, Benign partial epilepsy, febrile seizures, NCL
Mendeliome v0.6340 ITGA6 Zornitza Stark Marked gene: ITGA6 as ready
Mendeliome v0.6337 ITGA3 Zornitza Stark Marked gene: ITGA3 as ready
Mendeliome v0.6334 FERMT1 Zornitza Stark Marked gene: FERMT1 as ready
Mendeliome v0.6331 EXPH5 Zornitza Stark Marked gene: EXPH5 as ready
Mendeliome v0.6328 COL7A1 Zornitza Stark Marked gene: COL7A1 as ready
Mendeliome v0.6328 COL7A1 Zornitza Stark Phenotypes for gene: COL7A1 were changed from to EBD inversa, MIM# 226600; EBD, Bart type MIM# 132000; EBD, localisata variant; Epidermolysis bullosa dystrophica, MIM# 131750; Epidermolysis bullosa dystrophica, 226600; Epidermolysis bullosa pruriginosa 604129; Epidermolysis bullosa, pretibial, MIM# 131850; Transient bullous of the newborn 131705
Mendeliome v0.6326 COL7A1 Zornitza Stark reviewed gene: COL7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: EBD inversa, MIM# 226600, EBD, Bart type MIM# 132000, EBD, localisata variant, Epidermolysis bullosa dystrophica, MIM# 131750, Epidermolysis bullosa dystrophica, 226600, Epidermolysis bullosa pruriginosa 604129, Epidermolysis bullosa, pretibial, MIM# 131850, Transient bullous of the newborn 131705; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6326 IGSF1 Zornitza Stark Marked gene: IGSF1 as ready
Mendeliome v0.6326 IGSF1 Zornitza Stark Phenotypes for gene: IGSF1 were changed from to Hypothyroidism, central, and testicular enlargement, MIM# 300888
Mendeliome v0.6323 IGSF1 Zornitza Stark reviewed gene: IGSF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27310681, 30086211, 24108313, 26840047, 27762734, 23143598; Phenotypes: Hypothyroidism, central, and testicular enlargement, MIM# 300888; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6323 FSTL5 Zornitza Stark Marked gene: FSTL5 as ready
Mendeliome v0.6322 NCOA3 Zornitza Stark Marked gene: NCOA3 as ready
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
Mendeliome v0.6320 NCOA3 Eleanor Williams gene: NCOA3 was added
gene: NCOA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCOA3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NCOA3 were set to 33326993
Phenotypes for gene: NCOA3 were set to non-syndromic hearing loss
Review for gene: NCOA3 was set to RED
Added comment: PMID: 33326993 - Salazar da Silva et al 2020 - report a 5 generation Brazilian family with 15 individuals with non-syndromic, bilateral and progressive hearing loss. Using linkage analysis and then exome sequencing they identified a heterozygous variant in NCOA3 (NM_181659, c.2810C > G; p.Ser937Cys) that was found in the 7 analysed affected individuals. It was also found in 4 unaffected individuals but they are within the range of onset of hearing loss observed in the family. Expression of nco3 was found in the inner ear of mice and zebrafish. ncoa3-/- zebrafish showed subtle alterations in cartilage, mineral density and abnormal adult swimming behaviour, which may suggest the mechanism of pathogenicity.
Sources: Literature
Mendeliome v0.6320 CFHR3 Zornitza Stark Marked gene: CFHR3 as ready
Mendeliome v0.6317 CFHR1 Zornitza Stark Marked gene: CFHR1 as ready
Mendeliome v0.6314 CFHR3 Elena Savva reviewed gene: CFHR3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:32424742; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to} MIM#235400, {Macular degeneration, age-related, reduced risk of} MIM#603075; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6314 CFHR1 Elena Savva reviewed gene: CFHR1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:32424742; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to} MIM#235400, {Macular degeneration, age-related, reduced risk of} MIM#603075; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6314 OTUD5 Zornitza Stark Phenotypes for gene: OTUD5 were changed from X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality to Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056
Mendeliome v0.6311 OTUD5 Zornitza Stark edited their review of gene: OTUD5: Added comment: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; Changed rating: GREEN; Changed publications: 33131077, 33523931; Changed phenotypes: Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056
Mendeliome v0.6311 SCARB1 Bryony Thompson Marked gene: SCARB1 as ready
Mendeliome v0.6311 SCARB1 Bryony Thompson Gene: scarb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6311 SCARB1 Bryony Thompson Phenotypes for gene: SCARB1 were changed from to High density lipoprotein cholesterol level QTL6 MIM#610762; Scavenger receptor class B type I deficiency; Inherited hypolipidaemias
Mendeliome v0.6310 SCARB1 Bryony Thompson Publications for gene: SCARB1 were set to
Mendeliome v0.6309 SCARB1 Bryony Thompson Mode of inheritance for gene: SCARB1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6308 SCARB1 Bryony Thompson Classified gene: SCARB1 as Amber List (moderate evidence)
Mendeliome v0.6308 SCARB1 Bryony Thompson Gene: scarb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6307 SCARB1 Bryony Thompson reviewed gene: SCARB1: Rating: ; Mode of pathogenicity: None; Publications: 21226579, 30720493, 21480869, 26965621, 27604308; Phenotypes: High density lipoprotein cholesterol level QTL6 MIM#610762, Scavenger receptor class B type I deficiency, Inherited hypolipidaemias; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6307 CETP Bryony Thompson Marked gene: CETP as ready
Mendeliome v0.6301 DMGDH Bryony Thompson reviewed gene: DMGDH: Rating: ; Mode of pathogenicity: None; Publications: 11231903, 18937046, 28881522, 27604308; Phenotypes: Dimethylglycine dehydrogenase deficiency MIM#605850, Disorders and variants of other enzymes that oxidise xenobiotics; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6301 CD320 Bryony Thompson Marked gene: CD320 as ready
Mendeliome v0.6298 SHPK Bryony Thompson Marked gene: SHPK as ready
Mendeliome v0.6297 SHPK Bryony Thompson gene: SHPK was added
gene: SHPK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHPK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHPK were set to 25647543; 27604308
Phenotypes for gene: SHPK were set to Sedoheptulokinase deficiency MIM#617213
Review for gene: SHPK was set to AMBER
Added comment: 2 unrelated cases reported, with elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense variant. The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms. Due to inconsistency in phenotypes, likely SHPK deficiency is a benign disorder.
Sources: Literature
Mendeliome v0.6296 PNLIP Bryony Thompson Marked gene: PNLIP as ready
Mendeliome v0.6296 PNLIP Bryony Thompson Added comment: Comment on list classification: Appears to be a clinically benign metabolic condition
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
Mendeliome v0.6294 TDO2 Zornitza Stark Marked gene: TDO2 as ready
Mendeliome v0.6294 TDO2 Zornitza Stark gene: TDO2 was added
gene: TDO2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TDO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDO2 were set to 28285122; 27604308
Phenotypes for gene: TDO2 were set to Hypertryptophanemia MIM#600627; Disorders of histidine, tryptophan or lysine metabolism
Review for gene: TDO2 was set to RED
Added comment: Single case reported, biochemical phenotype of hypertryptophanemia and hyperserotoninemia does not appear to have significant clinical consequences
Sources: Expert list
Mendeliome v0.6293 SUGCT Zornitza Stark Marked gene: SUGCT as ready
Mendeliome v0.6293 SUGCT Zornitza Stark Phenotypes for gene: SUGCT were changed from to Glutaric aciduria III MIM#231690; Organic acidurias
Mendeliome v0.6289 SUGCT Zornitza Stark reviewed gene: SUGCT: Rating: AMBER; Mode of pathogenicity: None; Publications: 28766179, 18926513, 33483254, 32779420, 27604308; Phenotypes: Glutaric aciduria III MIM#231690, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6289 SLC36A2 Zornitza Stark Marked gene: SLC36A2 as ready
Mendeliome v0.6285 SARDH Zornitza Stark Marked gene: SARDH as ready
Mendeliome v0.6285 SARDH Zornitza Stark Gene: sardh has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6285 SARDH Zornitza Stark Phenotypes for gene: SARDH were changed from to Sarcosinemia MIM#268900; Disorders of serine, glycine or glycerate metabolism
Mendeliome v0.6284 SARDH Zornitza Stark Publications for gene: SARDH were set to
Mendeliome v0.6283 SARDH Zornitza Stark Mode of inheritance for gene: SARDH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6282 SARDH Zornitza Stark Classified gene: SARDH as Amber List (moderate evidence)
Mendeliome v0.6282 SARDH Zornitza Stark Gene: sardh has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6281 SARDH Zornitza Stark reviewed gene: SARDH: Rating: AMBER; Mode of pathogenicity: None; Publications: 22825317, 27604308; Phenotypes: Sarcosinemia MIM#268900, Disorders of serine, glycine or glycerate metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6281 OPLAH Zornitza Stark Marked gene: OPLAH as ready
Mendeliome v0.6277 KHK Zornitza Stark Marked gene: KHK as ready
Mendeliome v0.6273 HAL Zornitza Stark Marked gene: HAL as ready
Mendeliome v0.6267 DCXR Zornitza Stark Marked gene: DCXR as ready
Mendeliome v0.6265 CTH Zornitza Stark Marked gene: CTH as ready
Mendeliome v0.6261 ACSF3 Zornitza Stark Marked gene: ACSF3 as ready
Mendeliome v0.6257 PHGDH Zornitza Stark Marked gene: PHGDH as ready
Mendeliome v0.6253 PNP Zornitza Stark Marked gene: PNP as ready
Mendeliome v0.6250 PNPLA2 Zornitza Stark Marked gene: PNPLA2 as ready
Mendeliome v0.6247 ESRP2 Zornitza Stark Marked gene: ESRP2 as ready
Mendeliome v0.6243 ACBD5 Zornitza Stark Marked gene: ACBD5 as ready
Mendeliome v0.6240 SAR1B Zornitza Stark Marked gene: SAR1B as ready
Mendeliome v0.6240 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
Mendeliome v0.6240 SAR1B Zornitza Stark Phenotypes for gene: SAR1B were changed from to Chylomicron retention disease, MIM# 246700
Mendeliome v0.6239 SAR1B Zornitza Stark Publications for gene: SAR1B were set to
Mendeliome v0.6238 SAR1B Zornitza Stark Mode of inheritance for gene: SAR1B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6237 SAR1B Zornitza Stark reviewed gene: SAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 12692552; Phenotypes: Chylomicron retention disease, MIM# 246700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6237 SC5D Zornitza Stark Marked gene: SC5D as ready
Mendeliome v0.6234 SLC39A14 Zornitza Stark Marked gene: SLC39A14 as ready
Mendeliome v0.6231 SLC46A1 Zornitza Stark Marked gene: SLC46A1 as ready
Mendeliome v0.6231 SLC46A1 Zornitza Stark Phenotypes for gene: SLC46A1 were changed from to Folate malabsorption, hereditary, MIM# 229050
Mendeliome v0.6228 SLC46A1 Zornitza Stark changed review comment from: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.; to: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhoea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.
Mendeliome v0.6228 SLC46A1 Zornitza Stark reviewed gene: SLC46A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17446347, 17129779, 21333572; Phenotypes: Folate malabsorption, hereditary, MIM# 229050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6228 ST3GAL3 Zornitza Stark Marked gene: ST3GAL3 as ready
Mendeliome v0.6228 ST3GAL3 Zornitza Stark Phenotypes for gene: ST3GAL3 were changed from to Mental retardation, autosomal recessive 12 MIM# 611090
Mendeliome v0.6225 ST3GAL3 Zornitza Stark reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23252400, 21907012, 31584066; Phenotypes: Mental retardation, autosomal recessive 12 MIM# 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6225 DDX58 Zornitza Stark edited their review of gene: DDX58: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.6224 DDX58 Zornitza Stark Mode of pathogenicity for gene: DDX58 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
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 v0.6221 KL Bryony Thompson Marked gene: KL as ready
Mendeliome v0.6218 GLRX2 Bryony Thompson Marked gene: GLRX2 as ready
Mendeliome v0.6216 GSTO2 Bryony Thompson Marked gene: GSTO2 as ready
Mendeliome v0.6215 SIX1 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen. Variable expressivity, some families reported with isolated deafness, however this likely represents a spectrum rather than a separate disorder.; to: Deafness/BOS: DEFINITIVE by ClinGen. Variable expressivity, some families reported with isolated deafness, however this likely represents a spectrum rather than a separate disorder.
Mendeliome v0.6213 BMP7 Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract to Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract; Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS)
Mendeliome v0.6211 BMP7 Zornitza Stark changed review comment from: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature; to: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature

PMID 33434492: Two individuals with likely deleterious variants identified in a cohort of individuals with MRKHS.
Mendeliome v0.6211 BMP7 Zornitza Stark edited their review of gene: BMP7: Changed phenotypes: Non-syndromic metopic craniosynostosis, Congenital abnormalities of the kidneys and urinary tract, Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS)
Mendeliome v0.6211 BMP7 Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis to Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.6210 BMP7 Zornitza Stark edited their review of gene: BMP7: Changed phenotypes: Non-syndromic metopic craniosynostosis, Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.6210 WBP11 Zornitza Stark Marked gene: WBP11 as ready
Mendeliome v0.6208 CLRN2 Zornitza Stark Marked gene: CLRN2 as ready
Mendeliome v0.6208 CLRN2 Zornitza Stark Phenotypes for gene: CLRN2 were changed from Non-syndromic hearing loss to Non-syndromic hearing loss; Deafness, autosomal recessive 117, MIM# 619174
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
Mendeliome v0.6207 PRUNE1 Eleanor Williams reviewed gene: PRUNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33105479; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies , MIM#617481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6207 TTF2 Zornitza Stark Marked gene: TTF2 as ready
Mendeliome v0.6206 DUOXA1 Zornitza Stark Marked gene: DUOXA1 as ready
Mendeliome v0.6205 DUOXA1 Zornitza Stark gene: DUOXA1 was added
gene: DUOXA1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DUOXA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DUOXA1 were set to 29650690
Phenotypes for gene: DUOXA1 were set to congenital hypothyroidism, No OMIM #
Review for gene: DUOXA1 was set to AMBER
Added comment: 12 cases, but digenic model with variants in other genes
Sources: Expert Review
Mendeliome v0.6204 DUOX1 Zornitza Stark Marked gene: DUOX1 as ready
Mendeliome v0.6203 DUOX1 Zornitza Stark gene: DUOX1 was added
gene: DUOX1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DUOX1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DUOX1 were set to 29650690
Phenotypes for gene: DUOX1 were set to congenital hypothyroidism, No OMIM #
Review for gene: DUOX1 was set to AMBER
Added comment: 11 cases, but digenic model, with variants in other genes.
Sources: Expert Review
Mendeliome v0.6202 TTF1 Zornitza Stark Marked gene: TTF1 as ready
Mendeliome v0.6198 CDCA8 Zornitza Stark Marked gene: CDCA8 as ready
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
Mendeliome v0.6196 DNAJC30 Zornitza Stark Marked gene: DNAJC30 as ready
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
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 v0.6192 SLC7A6OS Zornitza Stark Marked gene: SLC7A6OS as ready
Mendeliome v0.6192 SLC7A6OS Zornitza Stark gene: SLC7A6OS was added
gene: SLC7A6OS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC7A6OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC7A6OS were set to 33085104
Phenotypes for gene: SLC7A6OS were set to Progressive myoclonus epilepsy
Review for gene: SLC7A6OS was set to RED
Added comment: Two unrelated families reported with same homozygous splice site variant, shared haplotype (founder effect). Limited functional data.
Sources: Literature
Mendeliome v0.6191 TLR8 Zornitza Stark Marked gene: TLR8 as ready
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
Mendeliome v0.6189 PIGF Zornitza Stark Marked gene: PIGF as ready
Mendeliome v0.6188 BRWD1 Zornitza Stark Marked gene: BRWD1 as ready
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
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
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
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
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
Mendeliome v0.6187 HIRA Zornitza Stark Marked gene: HIRA as ready
Mendeliome v0.6186 EYA3 Zornitza Stark Marked gene: EYA3 as ready
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
Mendeliome v0.6184 POLR3B Zornitza Stark changed review comment from: Ataxia is a presenting feature.; to: Bi-allelic variants are associated with leukodystrophy.
Mendeliome v0.6184 POLR3B Zornitza Stark Marked gene: POLR3B as ready
Mendeliome v0.6181 CFAP47 Zornitza Stark Marked gene: CFAP47 as ready
Mendeliome v0.6181 CFAP47 Zornitza Stark Added comment: Comment when marking as ready: 3-4 unrelated individuals and animal model.
Mendeliome v0.6180 C14orf39 Zornitza Stark Marked gene: C14orf39 as ready
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
Mendeliome v0.6179 ENO1 Zornitza Stark Marked gene: ENO1 as ready
Mendeliome v0.6178 HEY2 Zornitza Stark gene: HEY2 was added
gene: HEY2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEY2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: HEY2 were set to 32820247
Phenotypes for gene: HEY2 were set to congenital heart defects and thoracic aortic aneurysms
Review for gene: HEY2 was set to RED
Added comment: A very large family affected by CHD and familial thoracic aortic aneurysms. Trio genome sequencing was carried out in an index patient with critical CHD, and family members had either exome or Sanger sequencing. Identified homozygous loss-of-function variant (c.318_319delAG, p.G108*) in HEY2 in 3 individuals in family with critical CHD, whereas the 20 heterozygous carriers show a spectrum of CVDs (CHD and FTAA, but varying expressivity and incomplete penetrance). Other studies show that knockout of HEY2 in mice results in cardiovascular defects (CVDs), including septal defects, cardiomyopathy, a thin-walled aorta, and valve anomalies.
Sources: Literature
Mendeliome v0.6177 FGF9 Zornitza Stark Marked gene: FGF9 as ready
Mendeliome v0.6174 OTUD5 Zornitza Stark Marked gene: OTUD5 as ready
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
Mendeliome v0.6173 BCAT2 Bryony Thompson Marked gene: BCAT2 as ready
Mendeliome v0.6172 BCAT2 Bryony Thompson changed review comment from: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS; to: 6 cases from 5 unrelated families with homozygous or compound heterozygous variant, and supporting functional studies demonstrating decreased BCAT2 enzyme activity for some of the variants. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS
Mendeliome v0.6172 BCAT2 Bryony Thompson gene: BCAT2 was added
gene: BCAT2 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: BCAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAT2 were set to 14755340; 25653144
Phenotypes for gene: BCAT2 were set to Hypervalinemia or hyperleucine-isoleucinemia MIM#618850; disorder of branched-chain amino acid metabolism
Review for gene: BCAT2 was set to AMBER
Added comment: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS
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
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
Mendeliome v0.6171 C14orf39 Elena Savva gene: C14orf39 was added
gene: C14orf39 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C14orf39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C14orf39 were set to PMID: 33508233; 27796301
Phenotypes for gene: C14orf39 were set to Azoospermia; Premature ovarian insufficiency
Review for gene: C14orf39 was set to GREEN
Added comment: PMID: 33508233
- 1 family with two males (azoospermia) and 1 female (premature ovarian insufficiency)
- 2 unrelated Chinese males with azoospermia
All patients had either homozygous PTCs or splice

PMID: 27796301
Mouse K/O had azoospermia and ovarian failure
Sources: Literature
Mendeliome v0.6170 KCNN2 Sebastian Lunke Marked gene: KCNN2 as ready
Mendeliome v0.6167 METAP1 Zornitza Stark Marked gene: METAP1 as ready
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
Mendeliome v0.6166 MYADML2 Zornitza Stark Marked gene: MYADML2 as ready
Mendeliome v0.6165 CCDC186 Zornitza Stark Marked gene: CCDC186 as ready
Mendeliome v0.6165 CCDC186 Zornitza Stark gene: CCDC186 was added
gene: CCDC186 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146
Phenotypes for gene: CCDC186 were set to Epileptic encephalopathy
Review for gene: CCDC186 was set to RED
Added comment: One individual reported with bi-allelic truncating variant and EE.
Sources: Literature
Mendeliome v0.6164 KCNN2 Ain Roesley gene: KCNN2 was added
gene: KCNN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNN2 were set to 33242881
Phenotypes for gene: KCNN2 were set to neurodevelopmental movement disorders
Penetrance for gene: KCNN2 were set to unknown
Review for gene: KCNN2 was set to GREEN
Added comment: - 11 probands all de novo except for 1 mother-daughter pair.
- a mix of null and missense variants
- 2/11 with microcephaly, 10/11 motor delay, 7/11 language delay (excluding 2 with regression), all with varying degrees of ID, 3/11 seizures, 7/11 movement disorder, 4/11 cerebellar ataxia, 6/11 MRI anomalies

additional variants were noted in 2 patients: 1x cHet for variants in MED12L and 1x de novo TNK2 variant

patch clamp functional studies were also done
Sources: Literature
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
Mendeliome v0.6163 HYAL2 Zornitza Stark Marked gene: HYAL2 as ready
Mendeliome v0.6162 HYAL2 Zornitza Stark gene: HYAL2 was added
gene: HYAL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYAL2 were set to 28081210; 23172227; 26515055
Phenotypes for gene: HYAL2 were set to Cleft lip and palate; cor triatriatum; congenital cardiac malformations
Review for gene: HYAL2 was set to AMBER
Added comment: 2 unrelated consanguineous extended families (Amish and Arab) with an orofacial clefting phenotype with cardiac anomalies.
Sources: Literature
Mendeliome v0.6161 SLC6A20 Zornitza Stark Marked gene: SLC6A20 as ready
Mendeliome v0.6158 SUOX Zornitza Stark Marked gene: SUOX as ready
Mendeliome v0.6155 PDE2A Zornitza Stark Phenotypes for gene: PDE2A were changed from Paroxysmal dyskinesia to Paroxysmal dyskinesia; Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150
Mendeliome v0.6153 PDE2A Zornitza Stark edited their review of gene: PDE2A: Changed phenotypes: Paroxysmal dyskinesia, Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150
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
Mendeliome v0.6149 NBEA Zornitza Stark Phenotypes for gene: NBEA were changed from Intellectual disability; Seizures to Neurodevelopmental disorder with or without early-onset generalized epilepsy, MIM# 619157; Intellectual disability; Seizures
Mendeliome v0.6148 NBEA Zornitza Stark edited their review of gene: NBEA: Changed phenotypes: Neurodevelopmental disorder with or without early-onset generalized epilepsy, MIM# 619157, Intellectual disability, Seizures
Mendeliome v0.6148 DCT Zornitza Stark Marked gene: DCT as ready
Mendeliome v0.6146 SDHAF1 Zornitza Stark Marked gene: SDHAF1 as ready
Mendeliome v0.6146 SDHAF1 Zornitza Stark Phenotypes for gene: SDHAF1 were changed from to Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166
Mendeliome v0.6143 SDHAF1 Zornitza Stark reviewed gene: SDHAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19465911, 26749241, 22995659; Phenotypes: Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6142 NDUFC2 Zornitza Stark Marked gene: NDUFC2 as ready
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
Mendeliome v0.6140 UPB1 Zornitza Stark Marked gene: UPB1 as ready
Mendeliome v0.6137 UROC1 Zornitza Stark Marked gene: UROC1 as ready
Mendeliome v0.6133 DLX4 Zornitza Stark Marked gene: DLX4 as ready
Mendeliome v0.6132 DLG1 Zornitza Stark Marked gene: DLG1 as ready
Mendeliome v0.6131 PLEKHA7 Zornitza Stark Marked gene: PLEKHA7 as ready
Mendeliome v0.6127 GYS2 Zornitza Stark Marked gene: GYS2 as ready
Mendeliome v0.6124 HNRNPU Zornitza Stark Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy, early infantile, 54, MIM#617391 to Developmental and epileptic encephalopathy 54 MIM# 617391
Mendeliome v0.6123 OPA3 Zornitza Stark Marked gene: OPA3 as ready
Mendeliome v0.6123 OPA3 Zornitza Stark Phenotypes for gene: OPA3 were changed from to 3-methylglutaconic aciduria, type III (MGA3) (MIM#258501), AR; Optic atrophy 3 with cataract (MIM#165300), AD
Mendeliome v0.6119 OPA3 Zornitza Stark reviewed gene: OPA3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 25159689, 31119193, 31928268; Phenotypes: 3-methylglutaconic aciduria, type III (MGA3) (MIM#258501), AR, Optic atrophy 3 with cataract (MIM#165300), AD; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6119 FOXF1 Zornitza Stark changed review comment from: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period. Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs.; to: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period. Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs.

Over 50 families reported.
Mendeliome v0.6119 FOXF1 Zornitza Stark Marked gene: FOXF1 as ready
Mendeliome v0.6119 FOXF1 Zornitza Stark Phenotypes for gene: FOXF1 were changed from to Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380
Mendeliome v0.6116 FOXF1 Zornitza Stark reviewed gene: FOXF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19500772, 23505205; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6116 FOXF1 Kristin Rigbye reviewed gene: FOXF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23505205, 27071622, 27855150; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins (MIM#265380), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6116 STEAP3 Zornitza Stark Marked gene: STEAP3 as ready
Mendeliome v0.6112 FTH1 Zornitza Stark Marked gene: FTH1 as ready
Mendeliome v0.6112 FTH1 Zornitza Stark gene: FTH1 was added
gene: FTH1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FTH1 were set to 11389486
Phenotypes for gene: FTH1 were set to Hemochromatosis, type 5, MIM# 615517
Review for gene: FTH1 was set to RED
Added comment: One multi-generational family with 5' UTR variant.
Sources: Expert list
Mendeliome v0.6111 CYBRD1 Zornitza Stark Marked gene: CYBRD1 as ready
Mendeliome v0.6111 CYBRD1 Zornitza Stark gene: CYBRD1 was added
gene: CYBRD1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CYBRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CYBRD1 were set to 15338274
Phenotypes for gene: CYBRD1 were set to Iron overload
Review for gene: CYBRD1 was set to RED
Added comment: Paucity of publications. One of the variants reported in PMID 15338274, p.Arg226His is present in over 1,000 hets in gnomad.
Sources: Expert list
Mendeliome v0.6110 BMP6 Zornitza Stark Marked gene: BMP6 as ready
Mendeliome v0.6109 BMP6 Zornitza Stark gene: BMP6 was added
gene: BMP6 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: BMP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP6 were set to 26582087; 32464486
Phenotypes for gene: BMP6 were set to Iron overload, mild to moderate
Review for gene: BMP6 was set to GREEN
Added comment: More than 9 individuals reported with iron overload and variants in this gene.
Sources: Expert list
Mendeliome v0.6107 CREB3L3 Bryony Thompson gene: CREB3L3 was added
gene: CREB3L3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CREB3L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CREB3L3 were set to 32580631; 29954705; 27982131; 27291420; 26427795; 21666694
Phenotypes for gene: CREB3L3 were set to Hyperlipidaemia; hypertriglyceridemia
Review for gene: CREB3L3 was set to AMBER
Added comment: PMID: 26427795 - a loss of function variant (c.359delG p.K120fsX20) was identified in 2 affected adult siblings and a 13 yo normotriglyceridemic daughter of one of the siblings.
PMID: 21666694 - Lipoprotein profiles of the families of 4 individuals with CREB3L3 nonsense mutations showed a significantly elevated mean plasma TG level in 11 mutation carriers compared with 5 non-carrier first-degree relatives (9.67 ± 4.70 vs. 1.66 ± 0.55 mM, P = 0.021, Wilcoxon test). 3 of those families have the same variant - Lys245GlufsTer130, which has 126 (281,946 alleles) hets in gnomAD v2.1.
PMID: 32580631 - case-control analysis of nonmonogenic severe hypertriglyceridemia cases (N=265) vs normolipidemic controls (N=477), identified 5 cases with LoF variants (3 of whom had the Lys245GlufsTer130 frameshift) and none in controls. OR 20.2 (95% CI 1.11–366.1) p = 0.002, adjusted p = 0.03.
The frequency of Lys245GlufsTer130 is higher than expected for a dominant disorder, but other loss of function variants have been identified. The gene may be associated with variable penetrance. There are multiple supporting null mouse models with hyperlipidaemia.
Sources: Expert list
Mendeliome v0.6106 GPIHBP1 Bryony Thompson Marked gene: GPIHBP1 as ready
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
Mendeliome v0.6103 CBY1 Bryony Thompson Marked gene: CBY1 as ready
Mendeliome v0.6102 CBY1 Bryony Thompson gene: CBY1 was added
gene: CBY1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBY1 were set to 33131181; 25103236; 25220153
Phenotypes for gene: CBY1 were set to intellectual disability; cerebellar ataxia; molar tooth sign; polydactyly; Joubert syndrome
Review for gene: CBY1 was set to GREEN
Added comment: Three cases in two unrelated consanguineous families with homozygous loss of function variants. Multiple null model organisms recapitulate the human phenotype: Null mouse model had cystic kidneys, a phenotype common to ciliopathies. Reducing Cby levels in Xenopus laevis model reduced the density of multiciliated cells, the number of basal bodies per multiciliated cell, and the numbers of neural tube primary cilia; it also led to abnormal development of the neural crest, central nervous system, and pronephros. Depletion of cby1 in zebrafish results in ciliopathy‐related phenotypes.
Sources: Literature
Mendeliome v0.6101 ZMYND15 Bryony Thompson Marked gene: ZMYND15 as ready
Mendeliome v0.6100 ZMYND15 Bryony Thompson gene: ZMYND15 was added
gene: ZMYND15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYND15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZMYND15 were set to 24431330; 33169450; 20675388
Phenotypes for gene: ZMYND15 were set to Severe oligozoospermia
Review for gene: ZMYND15 was set to GREEN
Added comment: 4 unrelated consanguineous cases with homozygous loss of function variants. Zmynd15-null male mice display reduced testis weight and azoospermia
Sources: Literature
Mendeliome v0.6099 PNPLA1 Zornitza Stark Marked gene: PNPLA1 as ready
Mendeliome v0.6096 TMEM251 Bryony Thompson Marked gene: TMEM251 as ready
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
Mendeliome v0.6094 LOR Zornitza Stark Marked gene: LOR as ready
Mendeliome v0.6091 CYP4F22 Zornitza Stark Marked gene: CYP4F22 as ready
Mendeliome v0.6088 CERS3 Zornitza Stark Marked gene: CERS3 as ready
Mendeliome v0.6085 ALOX12B Zornitza Stark Marked gene: ALOX12B as ready
Mendeliome v0.6082 ALX3 Zornitza Stark Marked gene: ALX3 as ready
Mendeliome v0.6079 ALX3 Zornitza Stark changed review comment from: Intellectual disability is part of the phenotype.
Sources: Expert list; to: Well established gene-disease association.
Sources: Expert list
Mendeliome v0.6079 ALX1 Zornitza Stark Marked gene: ALX1 as ready
Mendeliome v0.6076 HIST1H1E Zornitza Stark Marked gene: HIST1H1E as ready
Mendeliome v0.6073 EED Zornitza Stark Marked gene: EED as ready
Mendeliome v0.6070 CLCN1 Zornitza Stark Marked gene: CLCN1 as ready
Mendeliome v0.6067 TUBG1 Zornitza Stark Marked gene: TUBG1 as ready
Mendeliome v0.6064 TUBB3 Zornitza Stark Marked gene: TUBB3 as ready
Mendeliome v0.6064 TUBB3 Zornitza Stark Phenotypes for gene: TUBB3 were changed from to Cortical dysplasia, complex, with other brain malformations 1, MIM# 614039; Fibrosis of extraocular muscles, congenital, 3A, MIM# 600638
Mendeliome v0.6061 TUBB3 Zornitza Stark reviewed gene: TUBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20829227, 25059107, 33318778, 20074521; Phenotypes: Cortical dysplasia, complex, with other brain malformations 1, MIM# 614039, Fibrosis of extraocular muscles, congenital, 3A, MIM# 600638; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6061 TUBB2B Zornitza Stark Marked gene: TUBB2B as ready
Mendeliome v0.6058 TUBB Zornitza Stark Marked gene: TUBB as ready
Mendeliome v0.6055 FZD4 Zornitza Stark Marked gene: FZD4 as ready
Mendeliome v0.6052 TSPAN12 Zornitza Stark Marked gene: TSPAN12 as ready
Mendeliome v0.6049 PPP2R5D Zornitza Stark Marked gene: PPP2R5D as ready
Mendeliome v0.6049 PPP2R5D Zornitza Stark Phenotypes for gene: PPP2R5D were changed from to Mental retardation, autosomal dominant 35, MIM#616355
Mendeliome v0.6045 KAT6B Zornitza Stark Marked gene: KAT6B as ready
Mendeliome v0.6045 KAT6B Zornitza Stark Phenotypes for gene: KAT6B were changed from to SBBYSS syndrome MIM#603736; Genitopatellar syndrome MIM#606170
Mendeliome v0.6041 DVL1 Zornitza Stark Marked gene: DVL1 as ready
Mendeliome v0.6039 DVL1 Zornitza Stark Mode of pathogenicity for gene: DVL1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.6037 ZFP36L1 Zornitza Stark Marked gene: ZFP36L1 as ready
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 v0.6032 ZNF526 Zornitza Stark Phenotypes for gene: ZNF526 were changed from to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Mendeliome v0.6027 MORC2 Zornitza Stark Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM# 616688; Intellectual disability to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM# 616688; Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, MIM# 619090
Mendeliome v0.6026 MORC2 Zornitza Stark edited their review of gene: MORC2: Changed phenotypes: Charcot-Marie-Tooth disease, axonal, type 2Z, MIM# 616688, Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, MIM# 619090
Mendeliome v0.6026 PPP2R5D Elena Savva reviewed gene: PPP2R5D: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32074998, 26168268; Phenotypes: Mental retardation, autosomal dominant 35, MIM#616355; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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 v0.6026 DVL1 Kristin Rigbye reviewed gene: DVL1: 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: 25817014, 25817016; Phenotypes: Robinow syndrome, autosomal dominant 2 (MIM#616331); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.6026 ZNF526 Arina Puzriakova reviewed gene: ZNF526: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 25558065, 33397746; Phenotypes: Intellectual disability, Microcephaly, Cataracts, Epilepsy, Hypertonia, Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6026 INTS6 Zornitza Stark Marked gene: INTS6 as ready
Mendeliome v0.6025 BCS1L Zornitza Stark Marked gene: BCS1L as ready
Mendeliome v0.6025 BCS1L Zornitza Stark Phenotypes for gene: BCS1L were changed from to Bjornstad syndrome MIM#262000; GRACILE syndrome, MIM#603358; Mitochondrial complex III deficiency, nuclear type MIM#1124000
Mendeliome v0.6022 MRPS22 Zornitza Stark Marked gene: MRPS22 as ready
Mendeliome v0.6022 MRPS22 Zornitza Stark Phenotypes for gene: MRPS22 were changed from to Combined oxidative phosphorylation deficiency 5 MIM#611719; Ovarian dysgenesis 7 MIM#618117
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 v0.6019 MRPS22 Elena Savva reviewed gene: MRPS22: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29566152; Phenotypes: Combined oxidative phosphorylation deficiency 5 MIM#611719, Ovarian dysgenesis 7 MIM#618117; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6019 CELF2 Zornitza Stark Marked gene: CELF2 as ready
Mendeliome v0.6018 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 33131106
Phenotypes for gene: CELF2 were set to Developmental and epileptic encephalopathy
Review for gene: CELF2 was set to GREEN
Added comment: Five unrelated individuals reported. Four with de novo variants, and one inherited from a mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal.
Sources: Literature
Mendeliome v0.6017 FGF13 Zornitza Stark Marked gene: FGF13 as ready
Mendeliome v0.6016 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay.

The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Mendeliome v0.6015 SCUBE3 Zornitza Stark Marked gene: SCUBE3 as ready
Mendeliome v0.6014 SCUBE3 Zornitza Stark changed review comment from: Eighteen affected individuals from nine unrelated families reported with a consistent phenotype characterised by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies.
Sources: Literature; to: Eighteen affected individuals from nine unrelated families reported with a consistent phenotype characterised by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. Mouse model recapitulated phenotype.
Sources: Literature
Mendeliome v0.6014 SCUBE3 Zornitza Stark gene: SCUBE3 was added
gene: SCUBE3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature; skeletal abnormalities; craniofacial abnormalities; dental anomalies
Review for gene: SCUBE3 was set to GREEN
Added comment: Eighteen affected individuals from nine unrelated families reported with a consistent phenotype characterised by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies.
Sources: Literature
Mendeliome v0.6013 UBR7 Zornitza Stark Marked gene: UBR7 as ready
Mendeliome v0.6012 UBR7 Zornitza Stark gene: UBR7 was added
gene: UBR7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Review for gene: UBR7 was set to GREEN
Added comment: Seven individuals from 6 unrelated families. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile). Physical examination revealed various dysmorphic features, including prominent forehead (3/7), hypertelorism (4/7), telecanthus (1/7), epicanthus(1/7), downslanting palpebral fissures (3/7), thick eyebrow (1/7), low-set ears (3/7), long philtrum (2/7), unilateral single transverse palmar crease (1/7), and hypertrichosis (1/7).
Sources: Literature
Mendeliome v0.6011 RNU7-1 Zornitza Stark Marked gene: RNU7-1 as ready
Mendeliome v0.6011 RNU7-1 Zornitza Stark Phenotypes for gene: RNU7-1 were changed from PMID: 33230297 to Aicardi–Goutières syndrome-like
Mendeliome v0.6009 RABL2A Zornitza Stark Marked gene: RABL2A as ready
Mendeliome v0.6005 AKT1 Zornitza Stark reviewed gene: AKT1: 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: 21793738; Phenotypes: Proteus syndrome, somatic 176920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6005 CEP250 Zornitza Stark Marked gene: CEP250 as ready
Mendeliome v0.6005 CEP250 Zornitza Stark Phenotypes for gene: CEP250 were changed from to Cone-rod dystrophy and hearing loss 2, MIM# 618358
Mendeliome v0.6002 CEP250 Zornitza Stark reviewed gene: CEP250: Rating: GREEN; Mode of pathogenicity: None; Publications: 24780881, 29718797, 30459346; Phenotypes: Cone-rod dystrophy and hearing loss 2, MIM# 618358; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6002 RABL2A Eleanor Williams gene: RABL2A was added
gene: RABL2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RABL2A was set to Unknown
Publications for gene: RABL2A were set to 33075816
Phenotypes for gene: RABL2A were set to male infertility; ciliopathy
Review for gene: RABL2A was set to RED
Added comment: PMID: 33075816 - Ding et al 2020 - with the aim of identifying variants that affect male fertility, the authors report on mice expressing two RABL2A SNPs found to be rare (MAF between 2% and 0.02% in gnomAD, with a deleterious prediction from SIFT and PolyPhen-2, and to affect protein stability. Mice homozygous for these variants (p.L119F and p.V158F) were found to be show ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus.
Sources: Literature
Mendeliome v0.6002 VCAN Zornitza Stark Marked gene: VCAN as ready
Mendeliome v0.5999 CAPN5 Zornitza Stark Marked gene: CAPN5 as ready
Mendeliome v0.5999 CAPN5 Zornitza Stark Phenotypes for gene: CAPN5 were changed from to Vitreoretinopathy, neovascular inflammatory, MIM# 193235
Mendeliome v0.5996 CAPN5 Zornitza Stark reviewed gene: CAPN5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23055945, 32274441, 31110225, 30986125; Phenotypes: Vitreoretinopathy, neovascular inflammatory, MIM# 193235; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5996 UBIAD1 Zornitza Stark Marked gene: UBIAD1 as ready
Mendeliome v0.5993 TGFBI Zornitza Stark Marked gene: TGFBI as ready
Mendeliome v0.5990 TACSTD2 Zornitza Stark Marked gene: TACSTD2 as ready
Mendeliome v0.5987 KIF27 Zornitza Stark Marked gene: KIF27 as ready
Mendeliome v0.5986 ZEB1 Zornitza Stark Marked gene: ZEB1 as ready
Mendeliome v0.5983 ZNF469 Zornitza Stark Marked gene: ZNF469 as ready
Mendeliome v0.5980 PIKFYVE Zornitza Stark Marked gene: PIKFYVE as ready
Mendeliome v0.5977 OVOL2 Zornitza Stark Marked gene: OVOL2 as ready
Mendeliome v0.5974 KRT3 Zornitza Stark Marked gene: KRT3 as ready
Mendeliome v0.5971 DCN Zornitza Stark Marked gene: DCN as ready
Mendeliome v0.5968 COL8A2 Zornitza Stark Marked gene: COL8A2 as ready
Mendeliome v0.5965 STX3 Zornitza Stark Marked gene: STX3 as ready
Mendeliome v0.5962 SPINT2 Zornitza Stark Marked gene: SPINT2 as ready
Mendeliome v0.5962 SPINT2 Zornitza Stark Phenotypes for gene: SPINT2 were changed from to Diarrhoea 3, secretory sodium, congenital, syndromic 270420
Mendeliome v0.5959 SPINT2 Zornitza Stark reviewed gene: SPINT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24142340, 30445423; Phenotypes: Diarrhoea 3, secretory sodium, congenital, syndromic 270420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5959 SLC9A3 Zornitza Stark Marked gene: SLC9A3 as ready
Mendeliome v0.5959 SLC9A3 Zornitza Stark Phenotypes for gene: SLC9A3 were changed from to Diarrhoea 8, secretory sodium, congenital 616868
Mendeliome v0.5956 SLC9A3 Zornitza Stark reviewed gene: SLC9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30633106, 31276831, 26358773; Phenotypes: Diarrhoea 8, secretory sodium, congenital 616868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5956 SLC5A1 Zornitza Stark Marked gene: SLC5A1 as ready
Mendeliome v0.5953 SLC39A4 Zornitza Stark Marked gene: SLC39A4 as ready
Mendeliome v0.5950 SLC26A3 Zornitza Stark Marked gene: SLC26A3 as ready
Mendeliome v0.5950 SLC26A3 Zornitza Stark Phenotypes for gene: SLC26A3 were changed from to Diarrhoea 1, secretory chloride, congenital, MIM# 214700
Mendeliome v0.5947 SLC26A3 Zornitza Stark reviewed gene: SLC26A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31325522, 19861545, 11524734; Phenotypes: Diarrhoea 1, secretory chloride, congenital, MIM# 214700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5947 SLC51B Zornitza Stark Marked gene: SLC51B as ready
Mendeliome v0.5947 SLC51B Zornitza Stark gene: SLC51B was added
gene: SLC51B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SLC51B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51B were set to 28898457
Phenotypes for gene: SLC51B were set to Congenital diarrhoea; Cholestasis
Review for gene: SLC51B was set to RED
Added comment: Two siblings reported with homozygous LOF variant in this gene and congenital diarrhoea/cholestasis.
Sources: Expert Review
Mendeliome v0.5946 SLC10A2 Zornitza Stark Marked gene: SLC10A2 as ready
Mendeliome v0.5946 SLC10A2 Zornitza Stark Phenotypes for gene: SLC10A2 were changed from to Bile acid malabsorption, primary, MIM# 613291
Mendeliome v0.5942 SLC10A2 Zornitza Stark reviewed gene: SLC10A2: Rating: RED; Mode of pathogenicity: None; Publications: 9109432; Phenotypes: Bile acid malabsorption, primary, MIM# 613291; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5942 PLVAP Zornitza Stark Marked gene: PLVAP as ready
Mendeliome v0.5942 PLVAP Zornitza Stark Phenotypes for gene: PLVAP were changed from to Diarrhoea 10, protein-losing enteropathy type, MIM# 618183
Mendeliome v0.5939 PLVAP Zornitza Stark reviewed gene: PLVAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29875123, 29661969, 26207260, 31215290; Phenotypes: Diarrhoea 10, protein-losing enteropathy type, MIM# 618183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5939 NEUROG3 Zornitza Stark Marked gene: NEUROG3 as ready
Mendeliome v0.5939 NEUROG3 Zornitza Stark Phenotypes for gene: NEUROG3 were changed from to Diarrhoea 4, malabsorptive, congenital, MIM# 610370
Mendeliome v0.5936 NEUROG3 Zornitza Stark reviewed gene: NEUROG3: Rating: GREEN; Mode of pathogenicity: None; Publications: 16855267, 32574610, 28724572, 21490072; Phenotypes: Diarrhoea 4, malabsorptive, congenital, MIM# 610370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5936 TMPRSS15 Zornitza Stark Marked gene: TMPRSS15 as ready
Mendeliome v0.5933 TTC37 Zornitza Stark Marked gene: TTC37 as ready
Mendeliome v0.5930 WNT2B Zornitza Stark Marked gene: WNT2B as ready
Mendeliome v0.5930 WNT2B Zornitza Stark Phenotypes for gene: WNT2B were changed from to Diarrhoea 9, MIM# 618168
Mendeliome v0.5927 WNT2B Zornitza Stark reviewed gene: WNT2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29909964; Phenotypes: Diarrhoea 9, MIM# 618168; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5927 MYO5B Zornitza Stark Marked gene: MYO5B as ready
Mendeliome v0.5924 LCT Zornitza Stark Marked gene: LCT as ready
Mendeliome v0.5922 FBRSL1 Zornitza Stark Marked gene: FBRSL1 as ready
Mendeliome v0.5922 CAMK2B Zornitza Stark Marked gene: CAMK2B as ready
Mendeliome v0.5922 CAMK2B Zornitza Stark Phenotypes for gene: CAMK2B were changed from to Mental retardation, autosomal dominant 54, MIM# 617799
Mendeliome v0.5919 CAMK2B Zornitza Stark reviewed gene: CAMK2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100089, 29560374, 32875707; Phenotypes: Mental retardation, autosomal dominant 54, MIM# 617799; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5918 RALGAPB Seb Lunke Marked gene: RALGAPB as ready
Mendeliome v0.5917 RALGAPB Elena Savva gene: RALGAPB was added
gene: RALGAPB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RALGAPB were set to PMID: 32853829
Phenotypes for gene: RALGAPB were set to Neurodevelopmental disorders, autism
Review for gene: RALGAPB was set to GREEN
Added comment: PMID: 32853829 - 2 patients with de novo missense variants, 1 patient with a de novo PTC with autism spectrum disorder from a large cohort.
Reviews previous publications and identifies 10 de novo variants (5 PTCs, 5 missense) in patients with ASD (7/10), epilepsy (2/10) and developmental delay (1/10).
Functional studies of patient cells show reduced mRNA expression (PTC).
Sources: Literature
Mendeliome v0.5917 RPL3L Seb Lunke Marked gene: RPL3L as ready
Mendeliome v0.5916 LSM11 Seb Lunke Marked gene: LSM11 as ready
Mendeliome v0.5915 DPH2 Seb Lunke Marked gene: DPH2 as ready
Mendeliome v0.5914 RNU7-1 Ee Ming Wong changed review comment from: - 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; to: - 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
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
Mendeliome v0.5914 RPL3L Elena Savva gene: RPL3L was added
gene: RPL3L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL3L were set to PMID: 32514796; 32870709
Phenotypes for gene: RPL3L were set to Neonatal dilated cardiomyopathy
Review for gene: RPL3L was set to GREEN
Added comment: PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype.

PMID: 32870709 - 1 hom patient w/ neonatal DCM
Sources: Literature
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
Mendeliome v0.5914 DPH2 Paul De Fazio changed review comment from: 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; to: One 19 month old reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency (gross motor delay, not walking, fine motor and expressive language delays, macrocephaly)

Another family (sibs) 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. Patients had ID and microcephaly (in contrast to the 19 month old above).

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
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
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
Mendeliome v0.5914 EPCAM Zornitza Stark Marked gene: EPCAM as ready
Mendeliome v0.5914 EPCAM Zornitza Stark Phenotypes for gene: EPCAM were changed from to Diarrhea 5, with tufting enteropathy, congenital, MIM# 613217
Mendeliome v0.5911 EPCAM Zornitza Stark reviewed gene: EPCAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 24142340; Phenotypes: Diarrhea 5, with tufting enteropathy, congenital, MIM# 613217; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5911 DGAT1 Zornitza Stark Marked gene: DGAT1 as ready
Mendeliome v0.5911 DGAT1 Zornitza Stark Phenotypes for gene: DGAT1 were changed from to Diarrhoea 7, protein-losing enteropathy type, MIM# 615863
Mendeliome v0.5908 DGAT1 Zornitza Stark reviewed gene: DGAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33261563, 32786057, 31778854, 28373485, 29604290; Phenotypes: Diarrhoea 7, protein-losing enteropathy type, MIM# 615863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5908 CPA6 Zornitza Stark Marked gene: CPA6 as ready
Mendeliome v0.5904 CPA6 Zornitza Stark edited their review of gene: CPA6: Added comment: Homozygous p.A270V variant reported in four siblings with Febrile seizures, familial, 11 (MIM 614418)(PMID:21922598), some functional data. Present in gnomad as hets but no homs. Also note one of the heterozygous individuals initially reported was subsequently found to have a second missense variant, PMID 23105115.

Disputed association between mono allelic variants and disease: variants reported have high frequency in gnomad, not in keeping with Mendelian disorder.; Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5904 HSD17B10 Zornitza Stark Marked gene: HSD17B10 as ready
Mendeliome v0.5902 HMGCS2 Zornitza Stark Marked gene: HMGCS2 as ready
Mendeliome v0.5899 HMGCL Zornitza Stark Marked gene: HMGCL as ready
Mendeliome v0.5896 GLUD1 Zornitza Stark Marked gene: GLUD1 as ready
Mendeliome v0.5891 AGPAT2 Zornitza Stark Marked gene: AGPAT2 as ready
Mendeliome v0.5888 LPIN1 Zornitza Stark Marked gene: LPIN1 as ready
Mendeliome v0.5885 MLYCD Zornitza Stark Marked gene: MLYCD as ready
Mendeliome v0.5885 MLYCD Zornitza Stark Phenotypes for gene: MLYCD were changed from to Malonyl-CoA decarboxylase deficiency, MIM# 248360
Mendeliome v0.5882 MLYCD Zornitza Stark reviewed gene: MLYCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 12955715; Phenotypes: Malonyl-CoA decarboxylase deficiency, MIM# 248360; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5882 SLC25A20 Zornitza Stark Marked gene: SLC25A20 as ready
Mendeliome v0.5882 SLC25A20 Zornitza Stark Phenotypes for gene: SLC25A20 were changed from to Carnitine-acylcarnitine translocase deficiency, MIM# 212138
Mendeliome v0.5879 SLC25A20 Zornitza Stark reviewed gene: SLC25A20: Rating: GREEN; Mode of pathogenicity: None; Publications: 15363639, 15365988, 24088670; Phenotypes: Carnitine-acylcarnitine translocase deficiency, MIM# 212138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5879 GABRD Zornitza Stark Marked gene: GABRD as ready
Mendeliome v0.5875 SPR Zornitza Stark Marked gene: SPR as ready
Mendeliome v0.5872 PRRT2 Zornitza Stark Marked gene: PRRT2 as ready
Mendeliome v0.5872 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from to Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751
Mendeliome v0.5869 PRRT2 Zornitza Stark reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33126500; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis 602066, Episodic kinesigenic dyskinesia 1 128200, Seizures, benign familial infantile, 2 605751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5869 KCNQ3 Zornitza Stark Marked gene: KCNQ3 as ready
Mendeliome v0.5866 PRKACB Zornitza Stark Marked gene: PRKACB as ready
Mendeliome v0.5866 PRKACB Zornitza Stark Phenotypes for gene: PRKACB were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Cardioacrofacial dysplasia 2, MIM# 619143; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Mendeliome v0.5865 PRKACB Zornitza Stark reviewed gene: PRKACB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 2, MIM# 619143; Mode of inheritance: None
Mendeliome v0.5865 PRKACA Zornitza Stark Phenotypes for gene: PRKACA were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth to Cardioacrofacial dysplasia 1, MIM# 619142; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Mendeliome v0.5864 PRKACA Zornitza Stark reviewed gene: PRKACA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 1, MIM# 619142; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5864 SCARF2 Zornitza Stark Marked gene: SCARF2 as ready
Mendeliome v0.5864 SCARF2 Zornitza Stark Gene: scarf2 has been classified as Green List (High Evidence).
Mendeliome v0.5864 SCARF2 Zornitza Stark Phenotypes for gene: SCARF2 were changed from to Van den Ende-Gupta syndrome, MIM# 600920
Mendeliome v0.5863 SCARF2 Zornitza Stark Publications for gene: SCARF2 were set to
Mendeliome v0.5862 SCARF2 Zornitza Stark Mode of inheritance for gene: SCARF2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5861 SCARF2 Zornitza Stark reviewed gene: SCARF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20887961, 23808541, 24478002, 27375131, 24478002; Phenotypes: Van den Ende-Gupta syndrome, MIM# 600920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5861 YIF1B Zornitza Stark Phenotypes for gene: YIF1B were changed from Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement to Kaya-Barakat-Masson syndrome, MIM# 619125; Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Mendeliome v0.5860 YIF1B Zornitza Stark edited their review of gene: YIF1B: Changed phenotypes: Kaya-Barakat-Masson syndrome, MIM# 619125, Central hypotonia, Failure to thrive, Microcephaly, Global developmental delay, Intellectual disability, Seizures, Spasticity, Abnormality of movement
Mendeliome v0.5860 GSTO1 Zornitza Stark Marked gene: GSTO1 as ready
Mendeliome v0.5857 PRR12 Zornitza Stark Marked gene: PRR12 as ready
Mendeliome v0.5854 PRSS56 Zornitza Stark Marked gene: PRSS56 as ready
Mendeliome v0.5851 GJA8 Zornitza Stark Marked gene: GJA8 as ready
Mendeliome v0.5851 GJA8 Zornitza Stark Phenotypes for gene: GJA8 were changed from to Cataract 1, multiple types, MIM# 116200; Microphthalmia
Mendeliome v0.5848 GJA8 Zornitza Stark reviewed gene: GJA8: Rating: GREEN; Mode of pathogenicity: None; Publications: 30498267, 29464339, 10480374, 18006672; Phenotypes: Cataract 1, multiple types, MIM# 116200, Microphthalmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5848 ATIC Zornitza Stark Marked gene: ATIC as ready
Mendeliome v0.5845 FZD5 Zornitza Stark Marked gene: FZD5 as ready
Mendeliome v0.5843 STRA6 Zornitza Stark Marked gene: STRA6 as ready
Mendeliome v0.5840 SOX2 Zornitza Stark Marked gene: SOX2 as ready
Mendeliome v0.5837 SIX6 Zornitza Stark Marked gene: SIX6 as ready
Mendeliome v0.5837 SIX6 Zornitza Stark Phenotypes for gene: SIX6 were changed from to Optic disc anomalies with retinal and/or macular dystrophy, MIM# 212550
Mendeliome v0.5834 SIX6 Zornitza Stark reviewed gene: SIX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23167593, 24702266, 33108933, 31207931, 24702266; Phenotypes: Optic disc anomalies with retinal and/or macular dystrophy, MIM# 212550; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5834 RERE Zornitza Stark Marked gene: RERE as ready
Mendeliome v0.5834 RERE Zornitza Stark Phenotypes for gene: RERE were changed from to Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, MIM# 616975
Mendeliome v0.5831 RERE Zornitza Stark reviewed gene: RERE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27087320, 23451234, 30896913, 30061196; Phenotypes: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, MIM# 616975; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5830 RAX Zornitza Stark Marked gene: RAX as ready
Mendeliome v0.5826 RARB Zornitza Stark Marked gene: RARB as ready
Mendeliome v0.5826 RARB Zornitza Stark Gene: rarb has been classified as Green List (High Evidence).
Mendeliome v0.5826 RARB Zornitza Stark Phenotypes for gene: RARB were changed from to Microphthalmia, syndromic 12, MIM# 615524
Mendeliome v0.5825 RARB Zornitza Stark Publications for gene: RARB were set to
Mendeliome v0.5824 RARB Zornitza Stark Mode of pathogenicity for gene: RARB was changed from to Other
Mendeliome v0.5823 RARB Zornitza Stark Mode of inheritance for gene: RARB was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5822 RARB Zornitza Stark reviewed gene: RARB: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30880327, 30281527, 24075189, 27120018, 25457163, 17506106; Phenotypes: Microphthalmia, syndromic 12, MIM# 615524; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5822 RARA Zornitza Stark Phenotypes for gene: RARA were changed from to Syndromic chorioretinal coloboma
Mendeliome v0.5821 RARA Zornitza Stark Publications for gene: RARA were set to
Mendeliome v0.5820 RARA Zornitza Stark Mode of inheritance for gene: RARA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5819 RARA Zornitza Stark edited their review of gene: RARA: Added comment: Single case report of de novo missense variant in association with syndromic coloboma.; Changed publications: 31343737; Changed phenotypes: Syndromic chorioretinal coloboma
Mendeliome v0.5819 PXDN Zornitza Stark Marked gene: PXDN as ready
Mendeliome v0.5816 SMOC1 Zornitza Stark Marked gene: SMOC1 as ready
Mendeliome v0.5813 MFRP Zornitza Stark Marked gene: MFRP as ready
Mendeliome v0.5810 MAB21L2 Zornitza Stark Marked gene: MAB21L2 as ready
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 v0.5807 PDSS1 Zornitza Stark Marked gene: PDSS1 as ready
Mendeliome v0.5807 PDSS1 Zornitza Stark Phenotypes for gene: PDSS1 were changed from to Coenzyme Q10 deficiency, primary, 2 MIM#614651
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 v0.5804 POLR1A Zornitza Stark Marked gene: POLR1A as ready
Mendeliome v0.5804 POLR1A Zornitza Stark Added comment: Comment when marking as ready: Limited evidence for the association between bi-allelic variants and leukodystrophy.
Mendeliome v0.5800 LOXL3 Zornitza Stark Marked gene: LOXL3 as ready
Mendeliome v0.5799 LOXL3 Zornitza Stark gene: LOXL3 was added
gene: LOXL3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 30362103; 25663169
Phenotypes for gene: LOXL3 were set to Stickler syndrome
Review for gene: LOXL3 was set to AMBER
Added comment: Two unrelated families reported with homozygous missense variants, mouse model supports gene-disease association.
Sources: Expert Review
Mendeliome v0.5798 RBP4 Zornitza Stark Marked gene: RBP4 as ready
Mendeliome v0.5795 VAX1 Zornitza Stark Marked gene: VAX1 as ready
Mendeliome v0.5791 VSX2 Zornitza Stark Marked gene: VSX2 as ready
Mendeliome v0.5788 WDR37 Zornitza Stark Marked gene: WDR37 as ready
Mendeliome v0.5788 WDR37 Zornitza Stark Phenotypes for gene: WDR37 were changed from to Neurooculocardiogenitourinary syndrome, MIM# 618652
Mendeliome v0.5785 WDR37 Zornitza Stark reviewed gene: WDR37: Rating: GREEN; Mode of pathogenicity: None; Publications: 31327508, 31327508; Phenotypes: Neurooculocardiogenitourinary syndrome, MIM# 618652; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5785 ALDH1A3 Zornitza Stark Marked gene: ALDH1A3 as ready
Mendeliome v0.5781 VEGFC Zornitza Stark Marked gene: VEGFC as ready
Mendeliome v0.5778 KDELR2 Zornitza Stark Phenotypes for gene: KDELR2 were changed from Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms to Osteogenesis imperfecta 21, MIM# 619131; Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms
Mendeliome v0.5777 KDELR2 Zornitza Stark edited their review of gene: KDELR2: Changed phenotypes: Osteogenesis imperfecta 21, MIM# 619131, Increased susceptibility to fractures, joint hypermobility, Scoliosis, Bowing of the legs, Bowing of the arms
Mendeliome v0.5775 RNASEH2B Zornitza Stark Marked gene: RNASEH2B as ready
Mendeliome v0.5775 RNASEH2B Zornitza Stark Phenotypes for gene: RNASEH2B were changed from to Aicardi-Goutieres syndrome 2, MIM# 610181
Mendeliome v0.5772 RNASEH2B Zornitza Stark reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 16845400, 33307271, 29239743; Phenotypes: Aicardi-Goutieres syndrome 2, MIM# 610181; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5772 PDGFB Zornitza Stark Marked gene: PDGFB as ready
Mendeliome v0.5769 XYLT1 Zornitza Stark reviewed gene: XYLT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30554721, 24581741, 23982343; Phenotypes: Desbuquois dysplasia 2, MIM# 615777, Baratela-Scott syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5769 TUSC3 Zornitza Stark Marked gene: TUSC3 as ready
Mendeliome v0.5769 TUSC3 Zornitza Stark Phenotypes for gene: TUSC3 were changed from to Mental retardation, autosomal recessive 7, MIM# 611093, MONDO:0012615; TUSC3-CDG (Disorders of protein N-glycosylation)
Mendeliome v0.5766 TUSC3 Zornitza Stark reviewed gene: TUSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18452889, 18455129, 21739581, 27148795, 31606977; Phenotypes: Mental retardation, autosomal recessive 7, MIM# 611093, MONDO:0012615, TUSC3-CDG (Disorders of protein N-glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5766 TMEM165 Zornitza Stark Marked gene: TMEM165 as ready
Mendeliome v0.5761 SLC35C1 Zornitza Stark Marked gene: SLC35C1 as ready
Mendeliome v0.5756 SEC23B Zornitza Stark changed review comment from: Over 20 families reported.; to: Bi-allelic variants and anaemia: Over 20 families reported.

Mono-allelic variants: three families reported with heterozygous missense variants, however note these are present in gnomad. In the case of one of the variants, >2,000 hets. LIMITED evidence for disease association.
Mendeliome v0.5756 GNE Zornitza Stark Marked gene: GNE as ready
Mendeliome v0.5753 EXT2 Zornitza Stark Marked gene: EXT2 as ready
Mendeliome v0.5752 TBL1X Zornitza Stark Marked gene: TBL1X as ready
Mendeliome v0.5751 CHSY1 Zornitza Stark Marked gene: CHSY1 as ready
Mendeliome v0.5748 DHDDS Zornitza Stark Marked gene: DHDDS as ready
Mendeliome v0.5743 FBLN1 Zornitza Stark reviewed gene: FBLN1: Rating: RED; Mode of pathogenicity: None; Publications: 24084572; Phenotypes: Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5743 FBLN1 Zornitza Stark Marked gene: FBLN1 as ready
Mendeliome v0.5743 FBLN1 Zornitza Stark Phenotypes for gene: FBLN1 were changed from to Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180
Mendeliome v0.5739 ST3GAL5 Zornitza Stark Marked gene: ST3GAL5 as ready
Mendeliome v0.5736 FBLN1 Elena Savva reviewed gene: FBLN1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 11836357; Phenotypes: Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5736 SUCLA2 Zornitza Stark Marked gene: SUCLA2 as ready
Mendeliome v0.5733 RFT1 Zornitza Stark Marked gene: RFT1 as ready
Mendeliome v0.5730 CHST6 Zornitza Stark Marked gene: CHST6 as ready
Mendeliome v0.5730 CHST6 Zornitza Stark Phenotypes for gene: CHST6 were changed from to Macular corneal dystrophy, MIM# 217800, MONDO:0009020
Mendeliome v0.5727 CHST6 Zornitza Stark reviewed gene: CHST6: Rating: GREEN; Mode of pathogenicity: None; Publications: 11818380, 16207214, 26604660; Phenotypes: Macular corneal dystrophy, MIM# 217800, MONDO:0009020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5727 MGAT2 Zornitza Stark Marked gene: MGAT2 as ready
Mendeliome v0.5724 MPI Zornitza Stark Marked gene: MPI as ready
Mendeliome v0.5721 PGM3 Zornitza Stark Marked gene: PGM3 as ready
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.
Mendeliome v0.5718 PGAP3 Zornitza Stark Marked gene: PGAP3 as ready
Mendeliome v0.5718 PGAP3 Zornitza Stark Phenotypes for gene: PGAP3 were changed from to Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318
Mendeliome v0.5715 PGAP3 Zornitza Stark reviewed gene: PGAP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24439110, 29620724, 30345601, 30217754; Phenotypes: Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5715 PGAP2 Zornitza Stark Marked gene: PGAP2 as ready
Mendeliome v0.5715 PGAP2 Zornitza Stark Phenotypes for gene: PGAP2 were changed from to Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628
Mendeliome v0.5712 PGAP2 Zornitza Stark reviewed gene: PGAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561846, 23561847, 31805394, 29119105, 27871432; Phenotypes: Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5712 PIGV Zornitza Stark Marked gene: PIGV as ready
Mendeliome v0.5712 PIGV Zornitza Stark Phenotypes for gene: PIGV were changed from to Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398
Mendeliome v0.5709 PIGV Zornitza Stark reviewed gene: PIGV: Rating: GREEN; Mode of pathogenicity: None; Publications: 20802478, 22315194, 28817240, 24129430; Phenotypes: Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5708 PIGO Zornitza Stark Marked gene: PIGO as ready
Mendeliome v0.5708 PIGO Zornitza Stark Phenotypes for gene: PIGO were changed from to Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882
Mendeliome v0.5705 PIGO Zornitza Stark reviewed gene: PIGO: Rating: GREEN; Mode of pathogenicity: None; Publications: 22683086, 31698102, 28900819, 28545593, 28337824; Phenotypes: Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5705 PIGN Zornitza Stark Marked gene: PIGN as ready
Mendeliome v0.5702 PIGA Zornitza Stark Marked gene: PIGA as ready
Mendeliome v0.5699 PIGL Zornitza Stark Marked gene: PIGL as ready
Mendeliome v0.5696 B3GALT6 Zornitza Stark Marked gene: B3GALT6 as ready
Mendeliome v0.5693 B3GALNT2 Zornitza Stark Marked gene: B3GALNT2 as ready
Mendeliome v0.5693 B3GALNT2 Zornitza Stark Phenotypes for gene: B3GALNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, MIM# 615181; MONDO:0014071
Mendeliome v0.5690 B3GALNT2 Zornitza Stark reviewed gene: B3GALNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23453667, 33290285, 29791932, 29273094, 28688748, 28303321; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, MIM# 615181, MONDO:0014071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5690 MPDU1 Zornitza Stark Marked gene: MPDU1 as ready
Mendeliome v0.5687 DPAGT1 Zornitza Stark Marked gene: DPAGT1 as ready
Mendeliome v0.5687 DPAGT1 Zornitza Stark Phenotypes for gene: DPAGT1 were changed from to Congenital disorder of glycosylation, type Ij, MIM# 608093; DPAGT1-CDG MONDO:0011964; Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM# 614750
Mendeliome v0.5684 DPAGT1 Zornitza Stark changed review comment from: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties.

Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder.; to: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties.

Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder. More than 5 unrelated families reported with this presentation.
Mendeliome v0.5684 DPAGT1 Zornitza Stark reviewed gene: DPAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872255, 22492991, 22304930, 31153949, 30653653, 30117111; Phenotypes: Congenital disorder of glycosylation, type Ij, MIM# 608093, DPAGT1-CDG MONDO:0011964, Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM# 614750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5684 DOLK Zornitza Stark Marked gene: DOLK as ready
Mendeliome v0.5681 SLC2A1 Zornitza Stark Marked gene: SLC2A1 as ready
Mendeliome v0.5678 MTX2 Zornitza Stark Phenotypes for gene: MTX2 were changed from Mandibuloacral dysplasia; lipodystrophy; arterial calcification to Mandibuloacral dysplasia progeroid syndrome, MIM# 619127; Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Mendeliome v0.5677 MTX2 Zornitza Stark edited their review of gene: MTX2: Changed phenotypes: Mandibuloacral dysplasia progeroid syndrome, MIM# 619127, Mandibuloacral dysplasia, lipodystrophy, arterial calcification
Mendeliome v0.5677 ERCC1 Zornitza Stark Marked gene: ERCC1 as ready
Mendeliome v0.5674 POR Zornitza Stark Marked gene: POR as ready
Mendeliome v0.5671 MYH6 Zornitza Stark Marked gene: MYH6 as ready
Mendeliome v0.5671 MYH6 Zornitza Stark Phenotypes for gene: MYH6 were changed from to Atrial septal defect 3 MIM#614089; Congenital heart disease; Cardiomyopathy, dilated, 1EE MIM#613252; Cardiomyopathy, hypertrophic, 14 MIM#613251; {Sick sinus syndrome 3} MIM#614090
Mendeliome v0.5668 MYH6 Zornitza Stark reviewed gene: MYH6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32656206, 31638415, 29969989, 29536580, 29332214, 30681346; Phenotypes: Atrial septal defect 3 MIM#614089, Congenital heart disease, Cardiomyopathy, dilated, 1EE MIM#613252, Cardiomyopathy, hypertrophic, 14 MIM#613251, {Sick sinus syndrome 3} MIM#614090; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5668 EZH2 Zornitza Stark Marked gene: EZH2 as ready
Mendeliome v0.5665 MYH6 Elena Savva reviewed gene: MYH6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 3 MIM#614089, Cardiomyopathy, dilated, 1EE MIM#613252, Cardiomyopathy, hypertrophic, 14 MIM#613251, {Sick sinus syndrome 3} MIM#614090; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5665 COG6 Zornitza Stark Marked gene: COG6 as ready
Mendeliome v0.5662 COG5 Zornitza Stark Marked gene: COG5 as ready
Mendeliome v0.5659 FIGLA Zornitza Stark Marked gene: FIGLA as ready
Mendeliome v0.5659 FIGLA Zornitza Stark Phenotypes for gene: FIGLA were changed from to Premature ovarian failure 6, MIM# 612310
Mendeliome v0.5656 FIGLA Zornitza Stark reviewed gene: FIGLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 18499083, 25314148, 29914564; Phenotypes: Premature ovarian failure 6, MIM# 612310; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5656 ESR1 Zornitza Stark Marked gene: ESR1 as ready
Mendeliome v0.5653 SHMT2 Zornitza Stark Phenotypes for gene: SHMT2 were changed from Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB), MIM#619121; Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Mendeliome v0.5652 SHMT2 Zornitza Stark edited their review of gene: SHMT2: Changed phenotypes: Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB), MIM#619121, Congenital microcephaly, Infantile axial hypotonia, Spastic paraparesis, Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Abnormal cortical gyration, Hypertrophic cardiomyopathy, Abnormality of the face, Proximal placement of thumb, 2-3 toe syndactyly
Mendeliome v0.5652 BMP15 Zornitza Stark commented on gene: BMP15: Only affects females, variants inherited from asymptomatic fathers. Over 50 individuals reported.
Mendeliome v0.5652 BMP15 Zornitza Stark Marked gene: BMP15 as ready
Mendeliome v0.5652 BMP15 Zornitza Stark Phenotypes for gene: BMP15 were changed from to Ovarian dysgenesis 2, MIM# 300510; Premature ovarian failure 4, MIM# 300510
Mendeliome v0.5649 BMP15 Zornitza Stark reviewed gene: BMP15: Rating: GREEN; Mode of pathogenicity: None; Publications: 15136966, 16508750, 16464940; Phenotypes: Ovarian dysgenesis 2, MIM# 300510, Premature ovarian failure 4, MIM# 300510; Mode of inheritance: Other
Mendeliome v0.5649 PANX1 Zornitza Stark Marked gene: PANX1 as ready
Mendeliome v0.5647 NANOS3 Bryony Thompson Marked gene: NANOS3 as ready
Mendeliome v0.5646 NANOS3 Bryony Thompson gene: NANOS3 was added
gene: NANOS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NANOS3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NANOS3 were set to 25054146; 24091668
Phenotypes for gene: NANOS3 were set to Primary ovarian insufficiency
Review for gene: NANOS3 was set to AMBER
Added comment: A homozygous missense (p.Glu120Lys) was identified in two Brazillian sisters with primary amenorrhea, and supporting in vitro functional assays. A heterozygous missense (p.Arg153Trp) was identified in a Chinese woman with POI, with supporting in vitro functional assays. Also, supporting null mouse model.
Sources: Literature
Mendeliome v0.5645 MSH5 Bryony Thompson Marked gene: MSH5 as ready
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
Mendeliome v0.5643 PATL2 Zornitza Stark Marked gene: PATL2 as ready
Mendeliome v0.5641 FANCM Bryony Thompson Phenotypes for gene: FANCM were changed from Spermatogenic failure 28, MIM# 618086 to Spermatogenic failure 28, MIM# 618086; Premature ovarian failure 15 MIM#618096
Mendeliome v0.5638 FANCM Bryony Thompson reviewed gene: FANCM: Rating: GREEN; Mode of pathogenicity: None; Publications: 29231814, 28837162, 33036707, 25010009; Phenotypes: Premature ovarian failure 15 MIM#618096; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5638 EIF4ENIF1 Bryony Thompson Marked gene: EIF4ENIF1 as ready
Mendeliome v0.5638 PGRMC1 Zornitza Stark Marked gene: PGRMC1 as ready
Mendeliome v0.5638 PGRMC1 Zornitza Stark gene: PGRMC1 was added
gene: PGRMC1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PGRMC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PGRMC1 were set to 25246111; 18782852
Phenotypes for gene: PGRMC1 were set to Premature ovarian failure
Review for gene: PGRMC1 was set to RED
Added comment: One family with translocation reported and two affected individuals. Another individual identified as part of a cohort with a missense variant (H165R), but the variant is present in >200 hets in gnomad. Subsequent cohort study did not find an association.
Sources: Expert list
Mendeliome v0.5636 EIF4ENIF1 Bryony Thompson gene: EIF4ENIF1 was added
gene: EIF4ENIF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF4ENIF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF4ENIF1 were set to 31810472; 23902945; 33095795
Phenotypes for gene: EIF4ENIF1 were set to Primary ovarian insufficiency
Review for gene: EIF4ENIF1 was set to AMBER
Added comment: 3 families: A missense (p.Q842P) segregated between a mother and daughter with diminished ovarian reserve (DOR) and premature ovarian insufficiency (POI). A nonsense variant (p.Ser429Ter) segregated in 7 affected women over 3 consecutive generations with early menopause at approximately age 30 years. A missense (p.Lys669Arg) was identified in a Brazilian case with POI.
Sources: Literature
Mendeliome v0.5635 POF1B Zornitza Stark Marked gene: POF1B as ready
Mendeliome v0.5635 POF1B Zornitza Stark Phenotypes for gene: POF1B were changed from to Premature ovarian failure 2B, MIM# 300604
Mendeliome v0.5631 DIAPH2 Bryony Thompson Marked gene: DIAPH2 as ready
Mendeliome v0.5631 POF1B Zornitza Stark reviewed gene: POF1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 16773570, 25676666; Phenotypes: Premature ovarian failure 2B, MIM# 300604; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5630 DIAPH2 Bryony Thompson reviewed gene: DIAPH2: Rating: RED; Mode of pathogenicity: None; Publications: 9497258, 30689869, 26175800, 11129329; Phenotypes: ?Premature ovarian failure 2A MIM#300511; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5630 CCDC141 Bryony Thompson Marked gene: CCDC141 as ready
Mendeliome v0.5630 POU5F1 Zornitza Stark gene: POU5F1 was added
gene: POU5F1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: POU5F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU5F1 were set to 21273125
Phenotypes for gene: POU5F1 were set to Premature ovarian failure
Review for gene: POU5F1 was set to RED
Added comment: Single individual reported in 2011 and a missense variant.
Sources: Expert list
Mendeliome v0.5628 CCDC141 Bryony Thompson gene: CCDC141 was added
gene: CCDC141 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC141 was set to Unknown
Publications for gene: CCDC141 were set to 27014940; 28324054; 25192046
Phenotypes for gene: CCDC141 were set to Anosmic hypogonadotropic hypogonadism
Review for gene: CCDC141 was set to AMBER
Added comment: A consanguineous family had a homozygous nonsense variant, but also had a homozygous missense in FEZF1. 3 other families reported with heterozygous variants, but other variants in other genes present. In an olfactory mouse model, Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration.
Sources: Literature
Mendeliome v0.5627 SGO2 Zornitza Stark Marked gene: SGO2 as ready
Mendeliome v0.5627 SGO2 Zornitza Stark gene: SGO2 was added
gene: SGO2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGO2 were set to 27629923
Phenotypes for gene: SGO2 were set to Perrault syndrome
Review for gene: SGO2 was set to RED
Added comment: Single affected individual reported, though deafness was thought to be explained by a CLDN14 variant. Protein is known to be involved in meiosis.
Sources: Expert list
Mendeliome v0.5626 SOHLH2 Zornitza Stark Marked gene: SOHLH2 as ready
Mendeliome v0.5626 SOHLH2 Zornitza Stark gene: SOHLH2 was added
gene: SOHLH2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SOHLH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOHLH2 were set to 24524832; 19014927
Phenotypes for gene: SOHLH2 were set to Premature ovarian failure
Review for gene: SOHLH2 was set to RED
Added comment: Heterozygous variants in this gene found to be enriched in a cohort of women with POF, substantial data including mouse models implicating this gene in infertility but paucity of well characterised cases.
Sources: Expert list
Mendeliome v0.5625 SYCE1 Zornitza Stark Marked gene: SYCE1 as ready
Mendeliome v0.5624 SYCE1 Zornitza Stark gene: SYCE1 was added
gene: SYCE1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SYCE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCE1 were set to 25062452; 32917591; 32741963; 32402064; 31925770; 31916078
Phenotypes for gene: SYCE1 were set to Premature ovarian failure 12, MIM# 616947; Spermatogenic failure 15 ,MIM#616950
Review for gene: SYCE1 was set to GREEN
Added comment: More than 5 families reported with POF/SF and bi-allelic variants in this gene. Mechanism is thought to be disruption of meiosis, mouse model data also supports gene-disease association.
Sources: Expert list
Mendeliome v0.5623 DACH2 Zornitza Stark Marked gene: DACH2 as ready
Mendeliome v0.5623 DACH2 Zornitza Stark gene: DACH2 was added
gene: DACH2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DACH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DACH2 were set to 15459172
Phenotypes for gene: DACH2 were set to Primary ovarian insufficiency
Review for gene: DACH2 was set to RED
Added comment: In a small candidate gene study, missense were more common in POI cases than controls (p= 0.0125). 5 missense reported in 7 POI cases, although 2 of the missense are too common in gnomAD for a dominant disorder. No other reports with evidence for an association with POI.
Sources: Expert list
Mendeliome v0.5622 TUBB8 Zornitza Stark Marked gene: TUBB8 as ready
Mendeliome v0.5619 WEE2 Zornitza Stark Marked gene: WEE2 as ready
Mendeliome v0.5616 ZP1 Zornitza Stark Marked gene: ZP1 as ready
Mendeliome v0.5615 ZP1 Zornitza Stark gene: ZP1 was added
gene: ZP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZP1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ZP1 were set to 24670168; 30810869; 32573113; 33272616
Phenotypes for gene: ZP1 were set to Oocyte maturation defect 1, MIM# 615774
Review for gene: ZP1 was set to GREEN
Added comment: Multiple unrelated individuals reported, presents as primary infertility.
Sources: Expert list
Mendeliome v0.5613 ZP3 Zornitza Stark Marked gene: ZP3 as ready
Mendeliome v0.5612 ZP3 Zornitza Stark gene: ZP3 was added
gene: ZP3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZP3 were set to 28886344; 30810869; 33272616; 32573113
Phenotypes for gene: ZP3 were set to Oocyte maturation defect 3, MIM# 617712
Review for gene: ZP3 was set to GREEN
Added comment: Oocyte maturation defect with normal ovarian reserves and menstrual cycles, presents as infertility.
Sources: Expert list
Mendeliome v0.5611 ECEL1P2 Zornitza Stark Marked gene: ECEL1P2 as ready
Mendeliome v0.5610 CCDC32 Zornitza Stark Phenotypes for gene: CCDC32 were changed from craniofacial, cardiac and neurodevelopmental anomalies to Cardiofacioneurodevelopmental syndrome (CFNDS), MIM#619123; Craniofacial, cardiac, laterality and neurodevelopmental anomalies
Mendeliome v0.5609 CCDC32 Zornitza Stark edited their review of gene: CCDC32: Changed rating: GREEN; Changed phenotypes: Cardiofacioneurodevelopmental syndrome (CFNDS), MIM#619123, Craniofacial, cardiac, laterality and neurodevelopmental anomalies; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5609 CDC40 Zornitza Stark Marked gene: CDC40 as ready
Mendeliome v0.5609 CDC40 Zornitza Stark gene: CDC40 was added
gene: CDC40 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC40 were set to 33220177
Phenotypes for gene: CDC40 were set to Pontocerebellar hypoplasia; microcephaly; seizures
Review for gene: CDC40 was set to RED
Added comment: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association. Gene referred to as PRP17 in paper.
Sources: Literature
Mendeliome v0.5608 PPIL1 Zornitza Stark Marked gene: PPIL1 as ready
Mendeliome v0.5607 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Mendeliome v0.5605 FRA12A Bryony Thompson STR: FRA12A was added
STR: FRA12A was added to Mendeliome. Sources: Other
5'UTR tags were added to STR: FRA12A.
Mode of inheritance for STR: FRA12A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FRA12A were set to 17236128
Phenotypes for STR: FRA12A were set to Mental retardation, FRA12A type MIM#136630
Review for STR: FRA12A was set to AMBER
Added comment: NM_173602.2:c.-137CGG[X]
All individuals expressing FRA12A had CGG-repeat expansion. The length of the expanded allele in 3 unaffected FRA12A carriers was 650–850 bp. In the two affected patients from 2 families with FRA12A, the length of the expanded allele was ∼1,050-1,150 bp.
70 controls used to determine the "normal" repeat range.
Sources: Other
Mendeliome v0.5601 PTPRQ Zornitza Stark changed review comment from: Additional heterozygous variants reported in PMID: 33229591; to: Additional heterozygous variants reported in PMID: 33229591, Green for both MOIs.
Mendeliome v0.5601 PTPRQ Zornitza Stark edited their review of gene: PTPRQ: Added comment: Additional heterozygous variants reported in PMID: 33229591; Changed publications: 20346435, 20472657, 25919374, 14534255, 22357859, 29849575, 29309402, 31655630, 33229591
Mendeliome v0.5601 CANVAS_ACAGG Bryony Thompson Marked STR: CANVAS_ACAGG as ready
Mendeliome v0.5600 CANVAS_ACAGG Bryony Thompson STR: CANVAS_ACAGG was added
STR: CANVAS_ACAGG was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: CANVAS_ACAGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: CANVAS_ACAGG were set to 33103729
Phenotypes for STR: CANVAS_ACAGG were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome; fasciculations; elevated serum creatine kinase levels; denervation
Review for STR: CANVAS_ACAGG was set to AMBER
Added comment: A novel RFC1 repeat expansion motif, (ACAGG)exp, identified in three affected individuals from 2 families in an Asian-Pacific cohort for CANVAS. Southern blot was used to identify the repeat was ~1000kb in one of the cases, equivalent to ~1000 repeats.
Sources: Literature
Mendeliome v0.5599 CANVAS Bryony Thompson Marked STR: CANVAS as ready
Mendeliome v0.5598 CANVAS Bryony Thompson STR: CANVAS was added
STR: CANVAS was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: CANVAS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: CANVAS were set to 30926972; 32851396
Phenotypes for STR: CANVAS were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575
Review for STR: CANVAS was set to GREEN
STR: CANVAS was marked as clinically relevant
Added comment: Simple tandem repeat (AAAAG)11 replaced with (AAGGG)n in intron 2 of RFC1. Loss of function is not the mechanism of disease. Maori population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp. (AAAGG)n repeat alone is not pathogenic.
Sources: Expert list
Mendeliome v0.5595 RNASEH2C Zornitza Stark Marked gene: RNASEH2C as ready
Mendeliome v0.5595 RNASEH2C Zornitza Stark Phenotypes for gene: RNASEH2C were changed from to Aicardi-Goutieres syndrome 3 (MIM# 610329), AR
Mendeliome v0.5592 CFAP52 Zornitza Stark Marked gene: CFAP52 as ready
Mendeliome v0.5591 CFAP45 Zornitza Stark Marked gene: CFAP45 as ready
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 v0.5589 RAP1A Zornitza Stark Marked gene: RAP1A as ready
Mendeliome v0.5583 RAP1B Zornitza Stark Marked gene: RAP1B as ready
Mendeliome v0.5579 EMC10 Zornitza Stark Marked gene: EMC10 as ready
Mendeliome v0.5579 EMC10 Zornitza Stark gene: EMC10 was added
gene: EMC10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858
Phenotypes for gene: EMC10 were set to Intellectual disability
Review for gene: EMC10 was set to RED
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD.
WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.
Sources: Literature
Mendeliome v0.5578 FBXO28 Zornitza Stark Marked gene: FBXO28 as ready
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
Mendeliome v0.5575 CFAP45 Zornitza Stark gene: CFAP45 was added
gene: CFAP45 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP45 were set to 33139725
Phenotypes for gene: CFAP45 were set to Situs inversus; asthenospermia
Review for gene: CFAP45 was set to GREEN
Added comment: Three unrelated individuals reported with bi-alleic LOF variants, mouse model recapitulated phenotype.
Sources: Literature
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 v0.5571 GDF6 Zornitza Stark Marked gene: GDF6 as ready
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."
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."
Mendeliome v0.5567 VPS4A Elena Savva Marked gene: VPS4A as ready
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 v0.5565 DAAM2 Zornitza Stark Marked gene: DAAM2 as ready
Mendeliome v0.5563 HS2ST1 Zornitza Stark Marked gene: HS2ST1 as ready
Mendeliome v0.5563 BICRA Elena Savva Marked gene: BICRA as ready
Mendeliome v0.5563 BICRA Elena Savva Added comment: Comment when marking as ready: 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.
Mendeliome v0.5561 KDM4B Zornitza Stark Marked gene: KDM4B as ready
Mendeliome v0.5559 UNC45B Zornitza Stark Marked gene: UNC45B as ready
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
Mendeliome v0.5558 AGO2 Zornitza Stark Marked gene: AGO2 as ready
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
Mendeliome v0.5556 DAAM2 Ain Roesley gene: DAAM2 was added
gene: DAAM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DAAM2 were set to steroid-resistant nephrotic syndrome (SRNS)
Penetrance for gene: DAAM2 were set to unknown
Review for gene: DAAM2 was set to GREEN
Added comment: - steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis on histologic analysis of kidney biopsies and foot process effacement shown by electron microscopy (authors have suggested the term nephrotic syndrome type 22 (NPHS22))
- 4 unrelated families, 3 of which were consanguineous
- 4 unique missense and 1 stop
- in vitro studies done for the missense variants
Sources: Literature
Mendeliome v0.5556 RRP7A Zornitza Stark Marked gene: RRP7A as ready
Mendeliome v0.5555 RRP7A Zornitza Stark gene: RRP7A was added
gene: RRP7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRP7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRP7A were set to 33199730
Phenotypes for gene: RRP7A were set to Microcephaly
Review for gene: RRP7A was set to AMBER
Added comment: 10 affected individuals from a single large consanguineous family where bi-allelic variant segregated with severe microcephaly (-6-8SD), variable ID. Supportive functional data from mouse and zebrafish.
Sources: Literature
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
Mendeliome v0.5554 MINPP1 Zornitza Stark Marked gene: MINPP1 as ready
Mendeliome v0.5553 KDM4B Kristin Rigbye gene: KDM4B was added
gene: KDM4B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to PMID: 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria.

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
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
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
Mendeliome v0.5552 RFC1 Teresa Zhao reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33103729; Phenotypes: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5552 DNAJB11 Zornitza Stark Phenotypes for gene: DNAJB11 were changed from Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061 to Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061; Ivermark II syndrome.
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 v0.5549 MYLPF Zornitza Stark Phenotypes for gene: MYLPF were changed from Distal arthrogryoposis to Distal arthrogryposis type 1C (DA1C), MIM#619110
Mendeliome v0.5548 MYLPF Zornitza Stark edited their review of gene: MYLPF: Changed rating: AMBER; Changed phenotypes: Distal arthrogryposis type 1C (DA1C), MIM#619110; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5548 HHAT Zornitza Stark Marked gene: HHAT as ready
Mendeliome v0.5547 HHAT Zornitza Stark gene: HHAT was added
gene: HHAT was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HHAT were set to 24784881; 30912300
Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome 600092
Review for gene: HHAT was set to AMBER
Added comment: Two unrelated families reported. Clinical features include progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia.
Sources: Expert list
Mendeliome v0.5541 H3F3B Zornitza Stark edited their review of gene: H3F3B: Added comment: 13 unrelated individuals reported with missense variants in H3F3B. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression, seizures; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5537 H3F3A Zornitza Stark edited their review of gene: H3F3A: Added comment: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5537 ALDH7A1 Zornitza Stark Marked gene: ALDH7A1 as ready
Mendeliome v0.5534 PRPS1 Zornitza Stark Marked gene: PRPS1 as ready
Mendeliome v0.5534 PRPS1 Zornitza Stark Phenotypes for gene: PRPS1 were changed from to Arts syndrome MIM#301835; Charcot-Marie-Tooth disease, X-linked recessive, 5 MIM#311070; Deafness, X-linked 1 MIM#304500; Gout, PRPS-related MIM#300661; Phosphoribosylpyrophosphate synthetase superactivity MIM#300661
Mendeliome v0.5530 HIVEP2 Zornitza Stark Marked gene: HIVEP2 as ready
Mendeliome v0.5530 HIVEP2 Zornitza Stark Phenotypes for gene: HIVEP2 were changed from to Mental retardation, autosomal dominant 43 MIM#616977
Mendeliome v0.5527 HIVEP2 Zornitza Stark reviewed gene: HIVEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26153216, 27003583, 16836985, 31602191; Phenotypes: Mental retardation, autosomal dominant 43, MIM# 616977; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5527 HIVEP2 Elena Savva reviewed gene: HIVEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31207095; Phenotypes: Mental retardation, autosomal dominant 43 MIM#616977; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5527 PRPS1 Elena Savva reviewed gene: PRPS1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32781272, 17701896, 7593598; Phenotypes: Arts syndrome MIM#301835, Charcot-Marie-Tooth disease, X-linked recessive, 5 MIM#311070, Deafness, X-linked 1 MIM#304500, Gout, PRPS-related MIM#300661, Phosphoribosylpyrophosphate synthetase superactivity MIM#300661; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5527 YIPF5 Zornitza Stark Marked gene: YIPF5 as ready
Mendeliome v0.5526 YIPF5 Zornitza Stark gene: YIPF5 was added
gene: YIPF5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Neonatal diabetes; microcephaly; seizures
Review for gene: YIPF5 was set to GREEN
Added comment: Six individuals from 5 unrelated consanguineous families reported with bi-allelic variants in this gene and neonatal/early-onset diabetes, severe microcephaly, and epilepsy. Functional data supports gene-disease association.
Sources: Literature
Mendeliome v0.5523 TFE3 Zornitza Stark edited their review of gene: TFE3: Added comment: PMID: 32409512 (2020) - 14 variants reported as de novo events in 17 unrelated cases (including 5 previously published) of severe intellectual disability with pigmentary mosaicism and storage disorder-like features; Changed publications: 30595499, 31833172, 32409512; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5523 SLC38A8 Zornitza Stark Marked gene: SLC38A8 as ready
Mendeliome v0.5520 CAPN15 Zornitza Stark Marked gene: CAPN15 as ready
Mendeliome v0.5519 TONSL Zornitza Stark Marked gene: TONSL as ready
Mendeliome v0.5516 FKBP8 Zornitza Stark Marked gene: FKBP8 as ready
Mendeliome v0.5514 NPPA Zornitza Stark Marked gene: NPPA as ready
Mendeliome v0.5511 FOXA2 Zornitza Stark Marked gene: FOXA2 as ready
Mendeliome v0.5507 USP7 Zornitza Stark edited their review of gene: USP7: Added comment: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay, behavioral abnormalities, such as autism, and mild dysmorphic facies. Additional features are variable, but may include hypotonia, feeding problems, delayed walking with unsteady gait, hypogonadism in males, and ocular anomalies, such as strabismus. Some patients develop seizures and some have mild white matter abnormalities on brain imaging.; Changed publications: 26365382, 30679821; Changed phenotypes: Hao-Fountain syndrome, MIM# 616863, Intellectual disability, Autism
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
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
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
Mendeliome v0.5507 MYF5 Zornitza Stark Marked gene: MYF5 as ready
Mendeliome v0.5504 TARS2 Zornitza Stark Publications for gene: TARS2 were set to 24827421; 26811336
Mendeliome v0.5503 TARS2 Zornitza Stark edited their review of gene: TARS2: Added comment: Second family reported, single affected individual, compound heterozygous missense variants, computational data only in support of pathogenicity.; Changed publications: 24827421, 26811336, 33153448
Mendeliome v0.5503 COX16 Bryony Thompson Marked gene: COX16 as ready
Mendeliome v0.5502 COX16 Bryony Thompson gene: COX16 was added
gene: COX16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COX16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX16 were set to 33169484
Phenotypes for gene: COX16 were set to Hypertrophic cardiomyopathy; encephalopathy; severe fatal lactic acidosis
Review for gene: COX16 was set to AMBER
Added comment: 2 unrelated patients with the same homozygous (non-consanguineous) nonsense variant c.244C>T (p.Arg82*), and isolated complex IV deficiency present in both patient fibroblasts/skeletal muscle biopsy. COX16 is involved in the biogenesis of complex IV, the terminal complex of the mitochondrial respiratory chain (RC)
Sources: Literature
Mendeliome v0.5500 KCNJ18 Zornitza Stark Marked gene: KCNJ18 as ready
Mendeliome v0.5500 KCNJ18 Zornitza Stark gene: KCNJ18 was added
gene: KCNJ18 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KCNJ18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ18 were set to 20074522; 27008341
Phenotypes for gene: KCNJ18 were set to {Thyrotoxic periodic paralysis, susceptibility to, 2}, MIM# 613239
Review for gene: KCNJ18 was set to RED
Added comment: Six variants reported in original publication, however note lack of segregation data and limited functional data. Subsequently, concerns raised about high nucleotide sequence homology between multiple potassium channel genes, with variant misattribution.
Sources: Expert Review
Mendeliome v0.5499 DPM3 Zornitza Stark Marked gene: DPM3 as ready
Mendeliome v0.5499 DPM3 Zornitza Stark Phenotypes for gene: DPM3 were changed from to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 , MIM#612937; Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15 618992
Mendeliome v0.5496 DPM3 Zornitza Stark reviewed gene: DPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31266720, 28803818, 19576565, 31266720, 31469168; Phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 , MIM#612937, Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15 618992; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5496 B3GAT3 Zornitza Stark Marked gene: B3GAT3 as ready
Mendeliome v0.5496 B3GAT3 Zornitza Stark Phenotypes for gene: B3GAT3 were changed from to Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects, MIM# 245600
Mendeliome v0.5493 B3GAT3 Zornitza Stark reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26754439, 31988067, 26086840, 25893793, 21763480, 24668659; Phenotypes: Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects, MIM# 245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5493 SLC10A7 Zornitza Stark Marked gene: SLC10A7 as ready
Mendeliome v0.5490 PIGP Zornitza Stark Phenotypes for gene: PIGP were changed from Epileptic encephalopathy, early infantile, 55, MIM# 617599 to Developmental and epileptic encephalopathy 55, MIM# 617599
Mendeliome v0.5489 PIGK Zornitza Stark Phenotypes for gene: PIGK were changed from Intellectual disability; seizures; cerebellar atrophy to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, MIM# 618879
Mendeliome v0.5488 PIGK Zornitza Stark edited their review of gene: PIGK: Changed phenotypes: Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, MIM# 618879
Mendeliome v0.5487 PIGH Zornitza Stark edited their review of gene: PIGH: Added comment: Further three families reported.

Common clinical features include developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies.; Changed publications: 29573052, 29603516, 33156547
Mendeliome v0.5487 PIGB Zornitza Stark Phenotypes for gene: PIGB were changed from Epileptic encephalopathy, early infantile, 80; OMIM #618580 to Developmental and epileptic encephalopathy 80, MIM# 618580
Mendeliome v0.5486 GPAA1 Zornitza Stark Marked gene: GPAA1 as ready
Mendeliome v0.5483 GPAA1 Zornitza Stark edited their review of gene: GPAA1: Added comment: At least 5 unrelated families reported with bi-allelic variants in this gene and delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.; Changed publications: 29100095
Mendeliome v0.5483 ATP7A Zornitza Stark Marked gene: ATP7A as ready
Mendeliome v0.5483 ATP7A Zornitza Stark Phenotypes for gene: ATP7A were changed from to Occipital horn syndrome, 304150; X-linked recessive Menkes disease, 309400 Spinal muscular atrophy, distal, X-linked 3, 300489
Mendeliome v0.5480 PEX1 Zornitza Stark Marked gene: PEX1 as ready
Mendeliome v0.5475 HDAC4 Bryony Thompson Phenotypes for gene: HDAC4 were changed from Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability to Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability; Intellectual disability syndrome
Mendeliome v0.5474 ATP7A Elena Savva reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 21221114; Phenotypes: Occipital horn syndrome, 304150, X-linked recessive Menkes disease, 309400 Spinal muscular atrophy, distal, X-linked 3, 300489; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5474 TMEM218 Bryony Thompson Marked gene: TMEM218 as ready
Mendeliome v0.5473 TMEM218 Bryony Thompson gene: TMEM218 was added
gene: TMEM218 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to https://doi.org/10.1016/j.xhgg.2020.100016; 25161209
Phenotypes for gene: TMEM218 were set to Joubert syndrome; retinal dystrophy; polycystic kidneys; occipital encephalocele
Review for gene: TMEM218 was set to GREEN
Added comment: 11 cases in 6 families with homozygous or compound heterozygous missense and nonsense (1) variants, with a Joubert/Meckel syndrome phenotype. Clinical features included the molar tooth sign (N=2), occipital encephalocele (N=5, all fetuses), retinal dystrophy (N=4, all living individuals), polycystic kidneys (N=2), and polydactyly (N=2), without liver involvement. A null mouse model had nephronophthisis and retinal degeneration. No OMIM entry.
Sources: Literature
Mendeliome v0.5472 AGBL1 Zornitza Stark Marked gene: AGBL1 as ready
Mendeliome v0.5472 AGBL1 Zornitza Stark gene: AGBL1 was added
gene: AGBL1 was added to Mendeliome. Sources: Expert Review
disputed tags were added to gene: AGBL1.
Mode of inheritance for gene: AGBL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGBL1 were set to 24094747; 31555324
Phenotypes for gene: AGBL1 were set to Corneal dystrophy, Fuchs endothelial, 8, MIM# 615523
Review for gene: AGBL1 was set to RED
Added comment: Gene disease association first reported in 2013 in PMID 24094747, in a large multigenerational family. However, note the variant reported, p.Arg1028Ter is present in over 400 hets in gnomad. Another variant reported in same paper, p.Cys990Ser in three unrelated individuals, is present in over 300 hets in gnomad and 1 hom.

Two further variants reported in PMID 31555324, one is missense, p.Arg748His, present in 60 hets, and the other, p.Arg1028Ter, is present is the variant identified in the previous publication, present in over 400 hets.

These variant frequencies are out of keeping for a rare disorder.
Sources: Expert Review
Mendeliome v0.5471 TLE6 Zornitza Stark Marked gene: TLE6 as ready
Mendeliome v0.5470 TLE6 Zornitza Stark gene: TLE6 was added
gene: TLE6 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: TLE6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TLE6 were set to 26537248; 31897846
Phenotypes for gene: TLE6 were set to Preimplantation embryonic lethality, MIM# 616814
Review for gene: TLE6 was set to GREEN
Added comment: At least 5 individuals reported with bi-allelic variants and early embryonic lethality.
Sources: Expert Review
Mendeliome v0.5469 OGT Zornitza Stark Marked gene: OGT as ready
Mendeliome v0.5469 OGT Zornitza Stark Phenotypes for gene: OGT were changed from to Mental retardation, X-linked 106, MIM# 300997
Mendeliome v0.5466 OGT Zornitza Stark reviewed gene: OGT: Rating: GREEN; Mode of pathogenicity: None; Publications: 28302723, 28584052, 31296563, 31627256, 29769320, 29606577; Phenotypes: Mental retardation, X-linked 106, MIM# 300997; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5466 EXTL3 Zornitza Stark Marked gene: EXTL3 as ready
Mendeliome v0.5463 SSR3 Zornitza Stark Marked gene: SSR3 as ready
Mendeliome v0.5462 SSR3 Zornitza Stark gene: SSR3 was added
gene: SSR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SSR3 were set to 30945312
Phenotypes for gene: SSR3 were set to Congenital disorder of glycosylation
Review for gene: SSR3 was set to AMBER
Added comment: Single individual reported with an unsolved type I CDG, intellectual disability, homozygous LOF variant in SSR3, supportive functional evidence.
Sources: Literature
Mendeliome v0.5461 LCP2 Zornitza Stark Marked gene: LCP2 as ready
Mendeliome v0.5461 LCP2 Zornitza Stark gene: LCP2 was added
gene: LCP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LCP2 were set to 33231617
Phenotypes for gene: LCP2 were set to Severe combined immunodeficiency
Review for gene: LCP2 was set to RED
Added comment: Infant with bi-allelic variants in this gene and early-onset life-threatening infections, combined T and B cell immunodeficiency, severe neutrophil defects, and impaired platelet aggregation.
Sources: Literature
Mendeliome v0.5458 DPM2 Zornitza Stark edited their review of gene: DPM2: Added comment: Further unrelated individual reported, main clinical features were truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting.; Changed rating: GREEN; Changed publications: 23109149, 33129689
Mendeliome v0.5458 ATP6V0A2 Zornitza Stark Marked gene: ATP6V0A2 as ready
Mendeliome v0.5455 ALG9 Zornitza Stark Marked gene: ALG9 as ready
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 v0.5449 ALG8 Zornitza Stark edited their review of gene: ALG8: Added comment: Monoallelic variants are associated with polycystic liver disease.; Changed publications: 26066342, 28375157, 15235028; Changed phenotypes: Congenital disorder of glycosylation, type Ih, MIM# 608104, Polycystic liver disease 3 with or without kidney cysts, MIM# 617874; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5449 ALG8 Zornitza Stark Marked gene: ALG8 as ready
Mendeliome v0.5446 ALG3 Zornitza Stark Marked gene: ALG3 as ready
Mendeliome v0.5441 SLC3A2 Naomi Baker changed review comment from: No evidence of mendelian gene-disease association reported in the literature.; to: Weak evidence of mendelian gene-disease association reported in the literature.

Three monoallelic missense variants reported in patients with Autism spectrum disorder (ASD) from one publication (PMID: 31701662).
Mendeliome v0.5441 SLC3A2 Zornitza Stark Marked gene: SLC3A2 as ready
Mendeliome v0.5440 HOXA4 Zornitza Stark Marked gene: HOXA4 as ready
Mendeliome v0.5435 ASTE1 Zornitza Stark Marked gene: ASTE1 as ready
Mendeliome v0.5435 ASTE1 Zornitza Stark Phenotypes for gene: ASTE1 were changed from to palmar and plantar fibromatosis
Mendeliome v0.5431 ASTE1 Naomi Baker reviewed gene: ASTE1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29104234; Phenotypes: palmar and plantar fibromatosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5431 SMARCA1 Zornitza Stark Marked gene: SMARCA1 as ready
Mendeliome v0.5431 SMARCA1 Zornitza Stark Gene: smarca1 has been classified as Red List (Low Evidence).
Mendeliome v0.5431 SMARCA1 Zornitza Stark Phenotypes for gene: SMARCA1 were changed from to Intellectual disability
Mendeliome v0.5430 SMARCA1 Zornitza Stark Publications for gene: SMARCA1 were set to
Mendeliome v0.5429 SMARCA1 Zornitza Stark Mode of inheritance for gene: SMARCA1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5428 SMARCA1 Zornitza Stark Classified gene: SMARCA1 as Red List (low evidence)
Mendeliome v0.5428 SMARCA1 Zornitza Stark Gene: smarca1 has been classified as Red List (Low Evidence).
Mendeliome v0.5427 CDKAL1 Zornitza Stark Marked gene: CDKAL1 as ready
Mendeliome v0.5426 TCHH Zornitza Stark Marked gene: TCHH as ready
Mendeliome v0.5422 SMARCA1 Naomi Baker reviewed gene: SMARCA1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 26740508, 26539891, 29249292.; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5422 CRTAP Zornitza Stark Marked gene: CRTAP as ready
Mendeliome v0.5419 USP9X Zornitza Stark Marked gene: USP9X as ready
Mendeliome v0.5419 USP9X Zornitza Stark Phenotypes for gene: USP9X were changed from to Mental retardation, X-linked 99, XLR (MIM#300919) and XLD (MIM#300968)
Mendeliome v0.5416 ALG6 Zornitza Stark Marked gene: ALG6 as ready
Mendeliome v0.5412 RORB Zornitza Stark Marked gene: RORB as ready
Mendeliome v0.5409 MYL9 Zornitza Stark Marked gene: MYL9 as ready
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 v0.5405 PHYKPL Zornitza Stark Marked gene: PHYKPL as ready
Mendeliome v0.5400 MTCL1 Bryony Thompson edited their review of gene: MTCL1: Added comment: A new report of another case with a homozygous loss of function variant and a similar phenotype to the previously reported early onset homozygous Polish case (2 independent cases), and the supporting null mouse model.; Changed rating: GREEN; Changed publications: 30548255, 28283581, 32961396; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5400 POLE Zornitza Stark Marked gene: POLE as ready
Mendeliome v0.5396 OFD1 Zornitza Stark Marked gene: OFD1 as ready
Mendeliome v0.5393 NARS Zornitza Stark Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092; Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Mendeliome v0.5392 NARS Zornitza Stark Tag new gene name tag was added to gene: NARS.
Mendeliome v0.5392 NARS Zornitza Stark edited their review of gene: NARS: Changed phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092, Abnormal muscle tone, Microcephaly, Global developmental delay, Intellectual disability, Seizures, Ataxia, Abnormality of the face, Demyelinating peripheral neuropathy
Mendeliome v0.5389 DZIP1 Zornitza Stark changed review comment from: One large 4-generation family reported, where missense variant segregated with disease. Two additional individuals identified from a cohort. All variants present at low frequency in population databases. Mouse model recapitulated phenotype.
Sources: Literature; to: Association with MVP: One large 4-generation family reported, where missense variant segregated with disease. Two additional individuals identified from a cohort. All variants present at low frequency in population databases. Mouse model recapitulated phenotype.
Sources: Literature
Mendeliome v0.5389 DZIP1 Zornitza Stark edited their review of gene: DZIP1: Added comment: Two individuals reported in PMID 32051257 with bi-allelic variants and spermatogenic failure.; Changed publications: 31118289, 32051257; Changed phenotypes: Mitral valve prolapse, MIM#610840, Spermatogenic failure 47, MIM# 619102; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5389 DZIP1 Zornitza Stark Marked gene: DZIP1 as ready
Mendeliome v0.5387 DZIP1 Zornitza Stark gene: DZIP1 was added
gene: DZIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DZIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DZIP1 were set to 31118289
Phenotypes for gene: DZIP1 were set to Mitral valve prolapse
Review for gene: DZIP1 was set to AMBER
Added comment: One large 4-generation family reported, where missense variant segregated with disease. Two additional individuals identified from a cohort. All variants present at low frequency in population databases. Mouse model recapitulated phenotype.
Sources: Literature
Mendeliome v0.5386 ADH5 Zornitza Stark Marked gene: ADH5 as ready
Mendeliome v0.5385 ADH5 Zornitza Stark gene: ADH5 was added
gene: ADH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADH5 were set to 33147438
Phenotypes for gene: ADH5 were set to Aplastic anaemia; myelodysplasia; short stature
Review for gene: ADH5 was set to GREEN
Added comment: 7 individuals reported with bi-allelic variants in this gene and a Fanconi syndrome-like phenotype. All had aplastic anaemia, 4 developed a myelodysplastic syndrome, and one developed AML. Short stature and abnormal skin pigmentation were additional features.

Note, all also had the ALDH2*2 allele, which is common in East Asian populations, and may be contributory.

Extensive experimental data.
Sources: Literature
Mendeliome v0.5384 NPHS2 Zornitza Stark Marked gene: NPHS2 as ready
Mendeliome v0.5384 NPHS2 Zornitza Stark Phenotypes for gene: NPHS2 were changed from to Nephrotic syndrome, type 2 (MIM#600995), AR
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 v0.5381 LRIF1 Bryony Thompson changed review comment from: A single consanguineous case with a homozygous truncating variant. DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature; to: A single consanguineous case with a homozygous truncating variant, and D4Z4 repeat of 13 units on a 4qA haplotype (permissive haplotype). DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature
Mendeliome v0.5380 LRIF1 Bryony Thompson gene: LRIF1 was added
gene: LRIF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRIF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRIF1 were set to 32467133
Phenotypes for gene: LRIF1 were set to Facioscapulohumeral muscular dystrophy
Review for gene: LRIF1 was set to AMBER
Added comment: A single consanguineous case with a homozygous truncating variant. DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature
Mendeliome v0.5379 DNAH8 Zornitza Stark Phenotypes for gene: DNAH8 were changed from Asthenozoospermia; primary ciliary dyskinesia to Spermatogenic failure 46, MIM#619095; Asthenozoospermia; primary ciliary dyskinesia
Mendeliome v0.5378 DNAH8 Zornitza Stark edited their review of gene: DNAH8: Changed phenotypes: Spermatogenic failure 46, MIM#619095, Asthenozoospermia, primary ciliary dyskinesia
Mendeliome v0.5378 MYRF Zornitza Stark Phenotypes for gene: MYRF were changed from Nanophthalmos; High hyperopia to Nanophthalmos and high hyperopia; Cardiac-urogenital syndrome, MIM# 618280; Encephalitis/encephalopathy, mild, with reversible myelin vacuolization, MIM# 618113
Mendeliome v0.5376 MYRF Zornitza Stark edited their review of gene: MYRF: Added comment: Association with Encephalitis/encephalopathy, mild, with reversible myelin vacuolization 618113: limited evidence, two multiplex families with same missense variant (likely founder effect) reported (p.Gln403Arg); Changed publications: 31048900, 31172260, 31266062, 31700225, 29446546, 29446546, 30532227, 31069960, 29265453; Changed phenotypes: Nanophthalmos and high hyperopia, Cardiac-urogenital syndrome, MIM# 618280, Encephalitis/encephalopathy, mild, with reversible myelin vacuolization, MIM# 618113
Mendeliome v0.5376 MYRF Zornitza Stark changed review comment from: Cardiac-urogenital syndrome is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism. More than 10 unrelated individuals reported.; to: Cardiac-urogenital syndrome MIM# 618280 is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism. More than 10 unrelated individuals reported.
Mendeliome v0.5376 MYRF Zornitza Stark edited their review of gene: MYRF: Added comment: Cardiac-urogenital syndrome is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism. More than 10 unrelated individuals reported.; Changed publications: 31048900, 31172260, 31266062, 31700225, 29446546, 29446546, 30532227, 31069960; Changed phenotypes: Nanophthalmos and high hyperopia, Cardiac-urogenital syndrome, MIM# 618280
Mendeliome v0.5376 MYRF Zornitza Stark changed review comment from: Multiple affected individuals reported.
Sources: Expert list; to: Multiple affected individuals reported with nanophthalmos and high hyperopia and C-terminal frameshift variants, with or without dextrocardia or congenital diaphragmatic hernia.
Sources: Expert list
Mendeliome v0.5376 RLIM Zornitza Stark Marked gene: RLIM as ready
Mendeliome v0.5373 DNAH2 Zornitza Stark Marked gene: DNAH2 as ready
Mendeliome v0.5370 UBA1 Zornitza Stark Phenotypes for gene: UBA1 were changed from Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830; Autoinflammatory disease, adult onset: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) to Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830; Autoinflammatory disease, adult onset: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) #301054
Mendeliome v0.5369 UBA1 Zornitza Stark edited their review of gene: UBA1: Changed phenotypes: Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830, Autoinflammatory disease, adult onset: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) #301054
Mendeliome v0.5369 FGFR1 Zornitza Stark Marked gene: FGFR1 as ready
Mendeliome v0.5369 FGFR1 Zornitza Stark Phenotypes for gene: FGFR1 were changed from to 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
Mendeliome v0.5365 B4GALT7 Zornitza Stark Marked gene: B4GALT7 as ready
Mendeliome v0.5361 KCNQ2 Zornitza Stark Marked gene: KCNQ2 as ready
Mendeliome v0.5361 KCNQ2 Zornitza Stark Phenotypes for gene: KCNQ2 were changed from to Epileptic encephalopathy, early infantile, 7, 613720; Seizures, benign neonatal, 1, 121200; Myokymia, 121200
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 v0.5357 ADAR Zornitza Stark Marked gene: ADAR as ready
Mendeliome v0.5357 ADAR Zornitza Stark Gene: adar has been classified as Green List (High Evidence).
Mendeliome v0.5357 ADAR Zornitza Stark Phenotypes for gene: ADAR were changed from to Aicardi-Goutieres syndrome 6, MIM# 615010; Dyschromatosis symmetrica hereditaria, MIM# 127400
Mendeliome v0.5356 ADAR Zornitza Stark Mode of inheritance for gene: ADAR was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5355 ADAR Zornitza Stark reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 6, MIM# 615010, Dyschromatosis symmetrica hereditaria, MIM# 127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5353 FOXJ1 Zornitza Stark Phenotypes for gene: FOXJ1 were changed from hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry to Ciliary dyskinesia, primary, 43, MIM#618699; hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry
Mendeliome v0.5352 FOXJ1 Zornitza Stark edited their review of gene: FOXJ1: Changed phenotypes: Ciliary dyskinesia, primary, 43, MIM#618699, hydrocephalus, chronic destructive airway disease, randomization of left/right body asymmetry
Mendeliome v0.5352 MAPK1 Zornitza Stark Phenotypes for gene: MAPK1 were changed from Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin to Noonan syndrome 13, MIM#619087; Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Mendeliome v0.5351 MAPK1 Zornitza Stark edited their review of gene: MAPK1: Changed phenotypes: Noonan syndrome 13, MIM# 619087, Global developmental delay, Intellectual disability, Behavioral abnormality, Growth delay, Abnormality of the face, Abnormality of the neck, Abnormality of the cardiovascular system, Abnormality of the skin
Mendeliome v0.5351 SCD5 Zornitza Stark Marked gene: SCD5 as ready
Mendeliome v0.5351 SCD5 Zornitza Stark gene: SCD5 was added
gene: SCD5 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SCD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCD5 were set to 31972369
Phenotypes for gene: SCD5 were set to Deafness, autosomal dominant 79, MIM#619086
Review for gene: SCD5 was set to RED
Added comment: Single 5-generation family reported with a missense variant segregating in 19 affected individuals. Variant is found at a low frequency in ExAC.
Sources: Expert list
Mendeliome v0.5350 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Deafness, autosomal dominant 78, MIM#619081; Congenital, severe to profound hearing loss to Delpire-McNeill syndrome, MIM# 619083; Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Deafness, autosomal dominant 78, MIM#619081; Congenital, severe to profound hearing loss
Mendeliome v0.5349 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Congenital, severe to profound hearing loss to Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Deafness, autosomal dominant 78, MIM#619081; Congenital, severe to profound hearing loss
Mendeliome v0.5348 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome: deafness, intellectual disability, dysmorphic features, absent salivation; Congenital, severe to profound hearing loss to Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Congenital, severe to profound hearing loss
Mendeliome v0.5347 OCLN Zornitza Stark Marked gene: OCLN as ready
Mendeliome v0.5344 JAM3 Zornitza Stark Marked gene: JAM3 as ready
Mendeliome v0.5344 JAM3 Zornitza Stark Phenotypes for gene: JAM3 were changed from to Hemorrhagic destruction of the brain, subependymal calcification, and cataracts, MIM# 613730
Mendeliome v0.5341 JAM3 Zornitza Stark reviewed gene: JAM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23255084, 21109224; Phenotypes: Hemorrhagic destruction of the brain, subependymal calcification, and cataracts, MIM# 613730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5341 NCKAP1 Zornitza Stark Marked gene: NCKAP1 as ready
Mendeliome v0.5338 ACAD9 Zornitza Stark Marked gene: ACAD9 as ready
Mendeliome v0.5338 ACAD9 Zornitza Stark Phenotypes for gene: ACAD9 were changed from to Mitochondrial complex I deficiency, nuclear type 20 MIM#611126
Mendeliome v0.5335 ACAD9 Zornitza Stark reviewed gene: ACAD9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30025539; Phenotypes: Mitochondrial complex I deficiency, nuclear type 20 MIM#611126; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5334 ALDOB Zornitza Stark Marked gene: ALDOB as ready
Mendeliome v0.5334 ALDOB Zornitza Stark Phenotypes for gene: ALDOB were changed from to Fructose intolerance, hereditary, 229600
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 v0.5330 MYO1A Zornitza Stark Marked gene: MYO1A as ready
Mendeliome v0.5329 ARL2 Zornitza Stark Marked gene: ARL2 as ready
Mendeliome v0.5329 ARL2 Zornitza Stark Gene: arl2 has been classified as Red List (Low Evidence).
Mendeliome v0.5329 ARL2 Zornitza Stark gene: ARL2 was added
gene: ARL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARL2 were set to 30945270
Phenotypes for gene: ARL2 were set to Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma-1 (MRCS1), MIM#619082
Review for gene: ARL2 was set to RED
Added comment: Single family reported, missense variant segregating with structural eye abnormalities in 4 individuals (father and three daughters).
Sources: Expert list
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.
Mendeliome v0.5326 UNC80 Zornitza Stark Marked gene: UNC80 as ready
Mendeliome v0.5326 UNC80 Zornitza Stark Phenotypes for gene: UNC80 were changed from to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801; MONDO:0014777
Mendeliome v0.5323 UNC80 Zornitza Stark reviewed gene: UNC80: Rating: GREEN; Mode of pathogenicity: None; Publications: 26708751, 26708753, 26545877, 32620897, 30167850, 30167850; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801, MONDO:0014777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5321 AP2S1 Zornitza Stark Marked gene: AP2S1 as ready
Mendeliome v0.5320 CARD8 Zornitza Stark Marked gene: CARD8 as ready
Mendeliome v0.5320 CARD8 Zornitza Stark Gene: card8 has been classified as Red List (Low Evidence).
Mendeliome v0.5320 CARD8 Zornitza Stark gene: CARD8 was added
gene: CARD8 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CARD8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CARD8 were set to 29408806
Phenotypes for gene: CARD8 were set to Inflammatory bowel disease-30, MIM#619079
Review for gene: CARD8 was set to RED
Added comment: Two individuals from one family reported segregating a missense variant, dominant negative effect postulated.
Sources: Expert list
Mendeliome v0.5319 UBA1 Zornitza Stark Phenotypes for gene: UBA1 were changed from Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830 to Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830; Autoinflammatory disease, adult onset: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)
Mendeliome v0.5317 UBA1 Zornitza Stark edited their review of gene: UBA1: Added comment: Association with VEXAS: 25 men reported with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation, and an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopaenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis.; Changed publications: 18179898, 32181232, 31932168, 29034082, 27699224, 26028276, 23518311, 33108101; Changed phenotypes: Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830, Autoinflammatory disease, adult onset: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)
Mendeliome v0.5317 ZFHX4 Bryony Thompson Marked gene: ZFHX4 as ready
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
Mendeliome v0.5315 ZFHX4 Bryony Thompson gene: ZFHX4 was added
gene: ZFHX4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZFHX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFHX4 were set to 33057194
Phenotypes for gene: ZFHX4 were set to Developmental disorders
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. 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
Mendeliome v0.5314 UPF1 Bryony Thompson Marked gene: UPF1 as ready
Mendeliome v0.5313 UPF1 Bryony Thompson gene: UPF1 was added
gene: UPF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UPF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UPF1 were set to 33057194
Phenotypes for gene: UPF1 were set to Developmental disorders
Review for gene: UPF1 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. 16 de novo variants (1 frameshift, 11 missense, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5311 U2AF2 Bryony Thompson gene: U2AF2 was added
gene: U2AF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 33057194
Phenotypes for gene: U2AF2 were set to Developmental disorders
Review for gene: U2AF2 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. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5309 TCF7L2 Bryony Thompson Marked gene: TCF7L2 as ready
Mendeliome v0.5305 SRRM2 Bryony Thompson Marked gene: SRRM2 as ready
Mendeliome v0.5304 SRRM2 Bryony Thompson gene: SRRM2 was added
gene: SRRM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRRM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRRM2 were set to 33057194
Phenotypes for gene: SRRM2 were set to Developmental disorders
Review for gene: SRRM2 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. 28 de novo variants (11 frameshift, 7 missense, 1 splice acceptor, 5 stopgain, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5303 SPEN Bryony Thompson Marked gene: SPEN as ready
Mendeliome v0.5302 SPEN Bryony Thompson gene: SPEN was added
gene: SPEN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPEN were set to 33057194
Phenotypes for gene: SPEN were set to Developmental disorders
Review for gene: SPEN 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. 25 de novo variants (6 frameshift, 1 in-frame, 7 missense, 8 stopgain, 3 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5301 SATB1 Bryony Thompson Marked gene: SATB1 as ready
Mendeliome v0.5300 SATB1 Bryony Thompson gene: SATB1 was added
gene: SATB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SATB1 were set to 33057194
Phenotypes for gene: SATB1 were set to Developmental disorders
Review for gene: SATB1 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. 12 de novo (2 frameshift, 7 missense, 1 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5299 RAB14 Bryony Thompson Marked gene: RAB14 as ready
Mendeliome v0.5298 RAB14 Bryony Thompson gene: RAB14 was added
gene: RAB14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB14 were set to 33057194
Phenotypes for gene: RAB14 were set to Developmental disorders
Review for gene: RAB14 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. 8 de novo variants (1 in-frame, 7 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5297 PSMC5 Bryony Thompson Marked gene: PSMC5 as ready
Mendeliome v0.5296 PSMC5 Bryony Thompson gene: PSMC5 was added
gene: PSMC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 33057194
Phenotypes for gene: PSMC5 were set to Developmental disorders
Review for gene: PSMC5 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. 10 de novo variants (1 in-frame, 9 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5295 PRPF8 Bryony Thompson Marked gene: PRPF8 as ready
Mendeliome v0.5295 PRPF8 Bryony Thompson Added comment: Comment on phenotypes: Established Retinitis pigmentosa gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 29 de novo variants (2 frameshift, 19 missense, 1 stopgain, 7 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5292 MSL2 Bryony Thompson Marked gene: MSL2 as ready
Mendeliome v0.5291 PRKAR1B Bryony Thompson Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
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
Mendeliome v0.5288 MMGT1 Bryony Thompson gene: MMGT1 was added
gene: MMGT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MMGT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMGT1 were set to 33057194
Phenotypes for gene: MMGT1 were set to Developmental disorders
Review for gene: MMGT1 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. 3 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5286 MIB1 Bryony Thompson Added comment: Comment on phenotypes: Established congenital cardiac disease gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5286 MIB1 Bryony Thompson Phenotypes for gene: MIB1 were changed from to Left ventricular noncompaction 7 MIM#615092
Mendeliome v0.5284 MFN2 Bryony Thompson Added comment: Comment on phenotypes: Established cause of hereditary neuropathy.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 9 de novo variants (8 missense, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5284 MFN2 Bryony Thompson Phenotypes for gene: MFN2 were changed from to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM #609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM #617087; Hereditary motor and sensory neuropathy VIA, OMIM #601152
Mendeliome v0.5282 KCNK3 Bryony Thompson Added comment: Comment on phenotypes: Established pulmonary hypertension gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (7 missense, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5282 KCNK3 Bryony Thompson Phenotypes for gene: KCNK3 were changed from to Pulmonary hypertension, primary, 4 MIM#615344
Mendeliome v0.5280 HNRNPD Bryony Thompson Marked gene: HNRNPD as ready
Mendeliome v0.5279 HNRNPD Bryony Thompson gene: HNRNPD was added
gene: HNRNPD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPD were set to 33057194
Phenotypes for gene: HNRNPD were set to Developmental disorders
Review for gene: HNRNPD 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. 8 de novo variants (5 frameshift, 1 missense, 1 splice acceptor, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5278 PRKG2 Zornitza Stark Marked gene: PRKG2 as ready
Mendeliome v0.5277 PLXND1 Zornitza Stark Marked gene: PLXND1 as ready
Mendeliome v0.5276 PLXND1 Zornitza Stark gene: PLXND1 was added
gene: PLXND1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLXND1 were set to 26068067
Phenotypes for gene: PLXND1 were set to Möbius syndrome
Review for gene: PLXND1 was set to GREEN
Added comment: De novo variants in 3 unrelated individuals with Moebius syndrome with some functional evidence.
Sources: Literature
Mendeliome v0.5275 ECEL1 Zornitza Stark Marked gene: ECEL1 as ready
Mendeliome v0.5275 ECEL1 Zornitza Stark Phenotypes for gene: ECEL1 were changed from to Arthrogryposis, distal, type 5D, MIM# 615065
Mendeliome v0.5274 MYMK Zornitza Stark changed review comment from: Sources: Expert list; to: Carey-Fineman-Ziter syndrome (CFZS) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. Intellect has been normal in molecularly confirmed cases. Defect in myoblast fusion. 6 unrelated families reported with CFZ phenotype and bi-allelic MYMK variants. p.Pro91Thr is a common founder variant, which is hypomorphic.
Mendeliome v0.5274 MYMK Zornitza Stark edited their review of gene: MYMK: Changed phenotypes: Carey-Fineman-Ziter syndrome, OMIM #254940
Mendeliome v0.5272 ECEL1 Zornitza Stark reviewed gene: ECEL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261301, 23236030, 25099528, 24782201; Phenotypes: Arthrogryposis, distal, type 5D, MIM# 615065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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
Mendeliome v0.5272 PRKACA Zornitza Stark Phenotypes for gene: PRKACA were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth
Mendeliome v0.5271 FOXP4 Zornitza Stark Marked gene: FOXP4 as ready
Mendeliome v0.5270 FOXP4 Zornitza Stark gene: FOXP4 was added
gene: FOXP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to GREEN
Added comment: Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays.
Sources: Literature
Mendeliome v0.5269 ASAH1 Zornitza Stark Marked gene: ASAH1 as ready
Mendeliome v0.5269 ASAH1 Zornitza Stark Phenotypes for gene: ASAH1 were changed from to Spinal muscular atrophy with progressive myoclonic epilepsy, MIM# 159950; Farber lipogranulomatosis, MIM# 228000
Mendeliome v0.5267 ASAH1 Zornitza Stark reviewed gene: ASAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy with progressive myoclonic epilepsy, MIM# 159950, Farber lipogranulomatosis, MIM# 228000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5267 DHX32 Zornitza Stark Marked gene: DHX32 as ready
Mendeliome v0.5266 TNF Zornitza Stark Marked gene: TNF as ready
Mendeliome v0.5264 ALK Zornitza Stark Marked gene: ALK as ready
Mendeliome v0.5261 RHOB Zornitza Stark Marked gene: RHOB as ready
Mendeliome v0.5259 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979 to Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant
Mendeliome v0.5258 DHX32 Dean Phelan gene: DHX32 was added
gene: DHX32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX32 were set to PMID: 32989326
Phenotypes for gene: DHX32 were set to Intellectual disability, spastic diplegia, dystonia, brain abnormalities
Review for gene: DHX32 was set to AMBER
Added comment: PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two unrelated patients with intellectual disability, one with spastic diplegia, and the other characterised as generalised dystonia. Brain abnormalities were identified also.
Sources: Literature
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).
Mendeliome v0.5254 NHLRC2 Zornitza Stark Marked gene: NHLRC2 as ready
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
Mendeliome v0.5251 CTLA4 Zornitza Stark Marked gene: CTLA4 as ready
Mendeliome v0.5249 VIM Zornitza Stark Marked gene: VIM as ready
Mendeliome v0.5249 VIM Zornitza Stark Phenotypes for gene: VIM were changed from to Cataract 30, pulverulent 116300; frontonasal dysostosis and premature aging
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.
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.
Mendeliome v0.5246 VIM Zornitza Stark reviewed gene: VIM: Rating: GREEN; Mode of pathogenicity: None; Publications: 19126778, 26694549, 28450710; Phenotypes: Cataract 30, pulverulent 116300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5244 ITPR3 Zornitza Stark Marked gene: ITPR3 as ready
Mendeliome v0.5243 ITPR3 Zornitza Stark gene: ITPR3 was added
gene: ITPR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITPR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ITPR3 were set to 32949214
Phenotypes for gene: ITPR3 were set to Charcot-Marie-Tooth disease
Review for gene: ITPR3 was set to AMBER
Added comment: Two unrelated families reported: variant segregated in four affected individuals in one family and was de novo in the second family where there was a single affected person. Some evidence for dominant-negative effect.
Sources: Literature
Mendeliome v0.5242 SOCS1 Zornitza Stark Phenotypes for gene: SOCS1 were changed from Common variable immunodeficiency to Common variable immunodeficiency; Early-onset autoimmunity
Mendeliome v0.5240 SOCS1 Zornitza Stark reviewed gene: SOCS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33087723; Phenotypes: Early-onset autoimmunity; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5240 AMOTL1 Zornitza Stark Marked gene: AMOTL1 as ready
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
Mendeliome v0.5239 KIRREL1 Zornitza Stark Marked gene: KIRREL1 as ready
Mendeliome v0.5238 KIRREL1 Zornitza Stark gene: KIRREL1 was added
gene: KIRREL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIRREL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIRREL1 were set to 31472902
Phenotypes for gene: KIRREL1 were set to Steroid-resistant nephrotic syndrome
Review for gene: KIRREL1 was set to AMBER
Added comment: Two unrelated families reported with bi-allelic variants and limited functional data.
Sources: Literature
Mendeliome v0.5237 GFRA1 Zornitza Stark Marked gene: GFRA1 as ready
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
Mendeliome v0.5235 GNB2 Bryony Thompson reviewed gene: GNB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194; Phenotypes: Developmental disorder, sinus node dysfunction and atrioventricular block; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5235 GIGYF1 Bryony Thompson Marked gene: GIGYF1 as ready
Mendeliome v0.5234 GIGYF1 Bryony Thompson gene: GIGYF1 was added
gene: GIGYF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GIGYF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIGYF1 were set to 33057194
Phenotypes for gene: GIGYF1 were set to Developmental disorder
Review for gene: GIGYF1 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. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5233 FBXW7 Bryony Thompson Marked gene: FBXW7 as ready
Mendeliome v0.5232 FBXW7 Bryony Thompson gene: FBXW7 was added
gene: FBXW7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXW7 were set to 33057194
Phenotypes for gene: FBXW7 were set to Developmental disorder
Review for gene: FBXW7 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 12 de novo missense and 1 de novo synonymous variant identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Sources: Literature
Mendeliome v0.5231 TKFC Zornitza Stark Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, MIM#618805; Developmental delay; cataracts; liver dysfunction
Mendeliome v0.5230 TKFC Zornitza Stark edited their review of gene: TKFC: Changed phenotypes: Triokinase and FMN cyclase deficiency syndrome, MIM#618805, Developmental delay, cataracts, liver dysfunction
Mendeliome v0.5230 PRKAR1B Zornitza Stark Marked gene: PRKAR1B as ready
Mendeliome v0.5230 PRKAR1B Zornitza Stark Gene: prkar1b has been classified as Green List (High Evidence).
Mendeliome v0.5230 PRKAR1B Zornitza Stark Classified gene: PRKAR1B as Green List (high evidence)
Mendeliome v0.5230 PRKAR1B Zornitza Stark Gene: prkar1b has been classified as Green List (High Evidence).
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
Mendeliome v0.5229 NR1H4 Zornitza Stark Marked gene: NR1H4 as ready
Mendeliome v0.5226 PTF1A Zornitza Stark Marked gene: PTF1A as ready
Mendeliome v0.5226 PTF1A Zornitza Stark Phenotypes for gene: PTF1A were changed from to Pancreatic agenesis 2, MIM# 615935; Pancreatic and cerebellar agenesis, MIM# 609069
Mendeliome v0.5223 PTF1A Zornitza Stark reviewed gene: PTF1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24212882, 21749365, 10507728, 15543146, 19650412; Phenotypes: Pancreatic agenesis 2, MIM# 615935, Pancreatic and cerebellar agenesis, MIM# 609069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5223 MPP5 Zornitza Stark Marked gene: MPP5 as ready
Mendeliome v0.5222 MPP5 Konstantinos Varvagiannis gene: MPP5 was added
gene: MPP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MPP5 were set to 33073849
Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality
Penetrance for gene: MPP5 were set to unknown
Review for gene: MPP5 was set to GREEN
Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features.

All were investigated by exome sequencing (previous investigations not mentioned).

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro). All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK p55 subfamily), determining cell polarity at tight junctions.

Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided]

The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness.

Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision.

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Mendeliome v0.5222 AKR1D1 Zornitza Stark Marked gene: AKR1D1 as ready
Mendeliome v0.5219 SCYL1 Zornitza Stark Marked gene: SCYL1 as ready
Mendeliome v0.5219 SCYL1 Zornitza Stark Phenotypes for gene: SCYL1 were changed from to Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719
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 v0.5216 SLC30A10 Zornitza Stark Marked gene: SLC30A10 as ready
Mendeliome v0.5212 DDX23 Bryony Thompson gene: DDX23 was added
gene: DDX23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX23 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX23 were set to 33057194
Phenotypes for gene: DDX23 were set to Developmental disorder
Review for gene: DDX23 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 6 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Sources: Literature
Mendeliome v0.5210 ATP6V0A1 Bryony Thompson gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like
Review for gene: ATP6V0A1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: Literature
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Marked gene: ARHGAP35 as ready
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Classified gene: ARHGAP35 as Amber List (moderate evidence)
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5208 ARHGAP35 Bryony Thompson gene: ARHGAP35 was added
gene: ARHGAP35 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 33057194
Phenotypes for gene: ARHGAP35 were set to Developmental disorder
Review for gene: ARHGAP35 was set to AMBER
Added comment: Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 16 de novo variants (3 frameshift, 2 in-frame, 10 missense, 1 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5207 AP2S1 Bryony Thompson Added comment: Comment on phenotypes: Established hypercalcaemia gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 5 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Mendeliome v0.5204 ASCL1 Zornitza Stark Marked gene: ASCL1 as ready
Mendeliome v0.5198 ODC1 Zornitza Stark commented on gene: ODC1: Fifth individual reported in PMID 30239107: de novo nonsense variant identified, molecular modeling suggested that due to lack of a C terminus in the mutant protein, antizyme binding does not induce ODC degradation, leading to accumulation of active protein.
Mendeliome v0.5198 ODC1 Zornitza Stark changed review comment from: Four individuals with de novo GoF variants in this gene reported.
Sources: Literature; to: Four individuals with de novo GoF variants in this gene reported.
Sources: Literature
Mendeliome v0.5198 KDELR2 Zornitza Stark Marked gene: KDELR2 as ready
Mendeliome v0.5197 KDELR2 Zornitza Stark gene: KDELR2 was added
gene: KDELR2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KDELR2 were set to 33053334
Phenotypes for gene: KDELR2 were set to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms
Review for gene: KDELR2 was set to GREEN
Added comment: 4 families with osteogenesis imperfecta reported with functional studies.
Sources: Expert list
Mendeliome v0.5196 SCN8A Zornitza Stark Marked gene: SCN8A as ready
Mendeliome v0.5196 SCN8A Zornitza Stark Phenotypes for gene: SCN8A were changed from to Developmental and epileptic encephalopathy 13, MIM#614558, dominant and recessive; Myoclonus, familial, 2, MIM# 618364; paroxysmal kinesigenic dyskinesias; Cognitive impairment with or without cerebellar ataxia, MIM# 614306
Mendeliome v0.5192 SCN8A Zornitza Stark reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31625145, 29726066, 27098556, 28702509, 16236810, 31904124, 31887642, 31675620; Phenotypes: Developmental and epileptic encephalopathy 13, MIM#614558, dominant and recessive, Myoclonus, familial, 2, MIM# 618364, paroxysmal kinesigenic dyskinesias, Cognitive impairment with or without cerebellar ataxia, MIM# 614306; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5191 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH) syndrome, MIM#614979
Mendeliome v0.5190 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome ROSAH syndrome, MIM#614979 to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH) syndrome, MIM#614979
Mendeliome v0.5189 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome ROSAH syndrome, MIM#614979
Mendeliome v0.5188 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndromeROSAH syndrome, MIM#614979
Mendeliome v0.5188 NUS1 Zornitza Stark Phenotypes for gene: NUS1 were changed from Epilepsy; intellectual disability to Congenital disorder of glycosylation, type 1aa 617082; Mental retardation, autosomal dominant 55, with seizures 617831
Mendeliome v0.5185 COG8 Zornitza Stark Marked gene: COG8 as ready
Mendeliome v0.5182 HBB Zornitza Stark Marked gene: HBB as ready
Mendeliome v0.5182 HBB Zornitza Stark Phenotypes for gene: HBB were changed from to 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
Mendeliome v0.5180 SCN8A Elena Savva reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 30615093, 31904124; Phenotypes: ?Myoclonus, familial, 2 618364, Cognitive impairment with or without cerebellar ataxia 614306, Epileptic encephalopathy, early infantile, 13 614558, Seizures, benign familial infantile, 5 617080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5178 RAD51D Zornitza Stark Marked gene: RAD51D as ready
Mendeliome v0.5178 RAD51D Zornitza Stark Phenotypes for gene: RAD51D were changed from to {Breast-ovarian cancer, familial, susceptibility to, 4} 614291
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 v0.5174 ISPD Elena Savva reviewed gene: ISPD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28688748, 30060766, 22522420; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 614643, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7 616052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5174 TPO Zornitza Stark Marked gene: TPO as ready
Mendeliome v0.5171 RAD51D Elena Savva reviewed gene: RAD51D: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 28646019, 31937788, 26057125; Phenotypes: {Breast-ovarian cancer, familial, susceptibility to, 4} 614291; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5171 SLC35A3 Zornitza Stark Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures; OMIM #615553 to Arthrogryposis, mental retardation, and seizures OMIM #615553; Skeletal dysplasia; Congenital disorder of glycosylation
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 v0.5168 VAC14 Zornitza Stark Marked gene: VAC14 as ready
Mendeliome v0.5164 PHOX2A Zornitza Stark reviewed gene: PHOX2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16815872; Phenotypes: Fibrosis of extraocular muscles, congenital, 2 602078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5163 COL25A1 Zornitza Stark Marked gene: COL25A1 as ready
Mendeliome v0.5163 COL25A1 Zornitza Stark Phenotypes for gene: COL25A1 were changed from to Fibrosis of extraocular muscles, congenital, 5, MIM# 616219
Mendeliome v0.5159 COL25A1 Zornitza Stark reviewed gene: COL25A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25500261, 26486031; Phenotypes: Fibrosis of extraocular muscles, congenital, 5, MIM# 616219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5159 KIF21A Zornitza Stark Marked gene: KIF21A as ready
Mendeliome v0.5159 KIF21A Zornitza Stark Phenotypes for gene: KIF21A were changed from to Fibrosis of extraocular muscles, congenital, 1/3B, MIM# 135700
Mendeliome v0.5156 KIF21A Zornitza Stark reviewed gene: KIF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: 15621876, 15223798, 15621877, 18332320, 28930843, 27513105, 26190014, 24656932; Phenotypes: Fibrosis of extraocular muscles, congenital, 1/3B, MIM# 135700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5156 NDUFAF6 Zornitza Stark Marked gene: NDUFAF6 as ready
Mendeliome v0.5156 NDUFAF6 Zornitza Stark Phenotypes for gene: NDUFAF6 were changed from to Mitochondrial complex I deficiency, nuclear type 17 (MIM#618239)
Mendeliome v0.5153 NDUFAF6 Ain Roesley reviewed gene: NDUFAF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 30642748; Phenotypes: Mitochondrial complex I deficiency, nuclear type 17 (MIM#618239); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5153 WNT5A Zornitza Stark Marked gene: WNT5A as ready
Mendeliome v0.5150 CYP3A4 Zornitza Stark Marked gene: CYP3A4 as ready
Mendeliome v0.5146 KCTD17 Zornitza Stark Marked gene: KCTD17 as ready
Mendeliome v0.5143 TAF1 Zornitza Stark Marked gene: TAF1 as ready
Mendeliome v0.5143 TAF1 Zornitza Stark Phenotypes for gene: TAF1 were changed from to Dystonia-Parkinsonism, X-linked, MIM# 314250; Mental retardation, X-linked, syndromic 33, MIM# 300966
Mendeliome v0.5140 TAF1 Zornitza Stark reviewed gene: TAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17273961, 31646703; Phenotypes: Dystonia-Parkinsonism, X-linked, MIM# 314250, Mental retardation, X-linked, syndromic 33, MIM# 300966; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5140 CTNNA3 Bryony Thompson Marked gene: CTNNA3 as ready
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
Mendeliome v0.5138 STXBP1 Zornitza Stark Phenotypes for gene: STXBP1 were changed from Epileptic encephalopathy, early infantile, 4 612164; Rett syndrome; Rett-like phenotypes to Developmental and epileptic encephalopathy 4, MIM# 612164; Rett syndrome; Rett-like phenotypes
Mendeliome v0.5135 CHRNE Zornitza Stark Marked gene: CHRNE as ready
Mendeliome v0.5132 COLQ Zornitza Stark Marked gene: COLQ as ready
Mendeliome v0.5129 NDUFA4 Zornitza Stark Phenotypes for gene: NDUFA4 were changed from Leigh syndrome; Complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 21, MIM#619065; Leigh syndrome; Complex IV deficiency
Mendeliome v0.5128 NDUFA4 Zornitza Stark edited their review of gene: NDUFA4: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 21, MIM#619065, Leigh syndrome, Complex IV deficiency
Mendeliome v0.5128 COX5A Zornitza Stark Phenotypes for gene: COX5A were changed from pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 20, MIM#619064; pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency
Mendeliome v0.5127 COX5A Zornitza Stark edited their review of gene: COX5A: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 20, MIM#619064, pulmonary arterial hypertension, lactic acidemia, failure to thrive, isolated complex IV deficiency
Mendeliome v0.5127 PET117 Zornitza Stark Phenotypes for gene: PET117 were changed from Developmental delay; Regression; Complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 19, MIM#619063; Developmental delay; Regression; Complex IV deficiency
Mendeliome v0.5126 PET117 Zornitza Stark edited their review of gene: PET117: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 19, MIM#619063, Developmental delay, Regression, Complex IV deficiency
Mendeliome v0.5126 COX6A2 Zornitza Stark Phenotypes for gene: COX6A2 were changed from Mitochondrial complex IV deficiency, MIM# 220110 to Mitochondrial complex IV deficiency, nuclear type 18, MIM#619062
Mendeliome v0.5125 COX6A2 Zornitza Stark edited their review of gene: COX6A2: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 18, MIM#619062
Mendeliome v0.5125 APOPT1 Zornitza Stark Marked gene: APOPT1 as ready
Mendeliome v0.5125 APOPT1 Zornitza Stark Phenotypes for gene: APOPT1 were changed from to Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061
Mendeliome v0.5122 APOPT1 Zornitza Stark reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347]; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5122 COX4I1 Zornitza Stark Marked gene: COX4I1 as ready
Mendeliome v0.5121 COX4I1 Zornitza Stark gene: COX4I1 was added
gene: COX4I1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COX4I1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX4I1 were set to 28766551; 22592081; 31290619
Phenotypes for gene: COX4I1 were set to Mitochondrial complex IV deficiency, nuclear type 16, MIM#619060
Review for gene: COX4I1 was set to AMBER
Added comment: Two unrelated families reported.

Two more variants reported in PMID: 22592081: one is non-coding and the other rare missense, appear to have been identified in separate individuals, i.e. heterozygous in each individual.
Sources: Expert list
Mendeliome v0.5120 COX8A Zornitza Stark Phenotypes for gene: COX8A were changed from Mitochondrial complex IV deficiency, MIM# 220110 to Mitochondrial complex IV deficiency, nuclear type 15, MIM#619059
Mendeliome v0.5119 COX8A Zornitza Stark edited their review of gene: COX8A: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 15, MIM#619059
Mendeliome v0.5119 COA3 Zornitza Stark Phenotypes for gene: COA3 were changed from Mitochondrial complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 14, MIM# 619058
Mendeliome v0.5118 COA3 Zornitza Stark edited their review of gene: COA3: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 14, MIM# 619058
Mendeliome v0.5118 PET100 Zornitza Stark Marked gene: PET100 as ready
Mendeliome v0.5118 PET100 Zornitza Stark Phenotypes for gene: PET100 were changed from to Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055
Mendeliome v0.5115 PET100 Zornitza Stark reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5115 COX20 Zornitza Stark Marked gene: COX20 as ready
Mendeliome v0.5115 COX20 Zornitza Stark Phenotypes for gene: COX20 were changed from to Mitochondrial complex IV deficiency, nuclear type 11, MIM#619054
Mendeliome v0.5112 COX20 Zornitza Stark reviewed gene: COX20: Rating: GREEN; Mode of pathogenicity: None; Publications: 24202787, 31079202, 30656193, 23125284, 32606554; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 11, MIM#619054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5112 COX14 Zornitza Stark Phenotypes for gene: COX14 were changed from Mitochondrial complex IV deficiency, MIM#220110 to Mitochondrial complex IV deficiency, nuclear type 10, MIM#619053
Mendeliome v0.5111 COX14 Zornitza Stark edited their review of gene: COX14: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 10, MIM#619053
Mendeliome v0.5111 TACO1 Zornitza Stark Marked gene: TACO1 as ready
Mendeliome v0.5111 TACO1 Zornitza Stark Phenotypes for gene: TACO1 were changed from to Mitochondrial complex IV deficiency, nuclear type 8, MIM# 619052
Mendeliome v0.5108 TACO1 Zornitza Stark reviewed gene: TACO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19503089, 20727754, 25044680, 27319982; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 8, MIM# 619052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5108 PRKACA Zornitza Stark Marked gene: PRKACA as ready
Mendeliome v0.5106 CNGA2 Zornitza Stark Marked gene: CNGA2 as ready
Mendeliome v0.5106 CNGA2 Zornitza Stark gene: CNGA2 was added
gene: CNGA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNGA2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CNGA2 were set to 28572688
Phenotypes for gene: CNGA2 were set to Congenital anosmia
Review for gene: CNGA2 was set to RED
Added comment: Single multiplex family with high-impact variant segregating with anosmia.
Sources: Literature
Mendeliome v0.5105 COX6B1 Zornitza Stark Marked gene: COX6B1 as ready
Mendeliome v0.5105 COX6B1 Zornitza Stark Phenotypes for gene: COX6B1 were changed from to Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051
Mendeliome v0.5102 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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
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
Mendeliome v0.5102 SCO1 Zornitza Stark Marked gene: SCO1 as ready
Mendeliome v0.5102 SCO1 Zornitza Stark Phenotypes for gene: SCO1 were changed from to Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048
Mendeliome v0.5099 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5099 COX10 Zornitza Stark Marked gene: COX10 as ready
Mendeliome v0.5099 COX10 Zornitza Stark Phenotypes for gene: COX10 were changed from to Mitochondrial complex IV deficiency, nuclear type 3, MIM# 619046
Mendeliome v0.5096 COX10 Zornitza Stark reviewed gene: COX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 10767350, 12928484, 15455402, 27290639; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 3, MIM# 619046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5096 GFPT1 Zornitza Stark Marked gene: GFPT1 as ready
Mendeliome v0.5096 GFPT1 Zornitza Stark Phenotypes for gene: GFPT1 were changed from to Myasthenia, congenital, 12, with tubular aggregates, 610542; Limb-girdle congenital myasthenic syndrome; Leukoencephalopathy
Mendeliome v0.5093 GFPT1 Zornitza Stark reviewed gene: GFPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21310273, 30635494; Phenotypes: Myasthenia, congenital, 12, with tubular aggregates, 610542, Limb-girdle congenital myasthenic syndrome, Leukoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5093 BMP7 Zornitza Stark Marked gene: BMP7 as ready
Mendeliome v0.5093 BMP7 Zornitza Stark gene: BMP7 was added
gene: BMP7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP7 were set to 32266521; 24429398
Phenotypes for gene: BMP7 were set to Non-syndromic metopic craniosynostosis
Mode of pathogenicity for gene: BMP7 was set to Other
Review for gene: BMP7 was set to RED
Added comment: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature
Mendeliome v0.5092 SMARCC1 Zornitza Stark Publications for gene: SMARCC1 were set to 33077954
Mendeliome v0.5091 SMARCC1 Zornitza Stark changed review comment from: Three de novo variants, two LOF, one missense, reported in this hydrocephalus cohort.
Sources: Literature; to: Three de novo variants, two LOF, one missense, reported in this hydrocephalus cohort. Supportive mouse model.
Sources: Literature
Mendeliome v0.5091 SMARCC1 Zornitza Stark edited their review of gene: SMARCC1: Changed publications: 33077954, 24170322
Mendeliome v0.5091 SMARCC1 Zornitza Stark Marked gene: SMARCC1 as ready
Mendeliome v0.5091 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Mendeliome v0.5091 SMARCC1 Zornitza Stark Classified gene: SMARCC1 as Green List (high evidence)
Mendeliome v0.5091 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Mendeliome v0.5090 SMARCC1 Zornitza Stark gene: SMARCC1 was added
gene: SMARCC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMARCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCC1 were set to 33077954
Phenotypes for gene: SMARCC1 were set to Congenital hydrocephalus
Review for gene: SMARCC1 was set to GREEN
Added comment: Three de novo variants, two LOF, one missense, reported in this hydrocephalus cohort.
Sources: Literature
Mendeliome v0.5089 SLC18A3 Zornitza Stark Marked gene: SLC18A3 as ready
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.
Mendeliome v0.5085 SYT2 Zornitza Stark Marked gene: SYT2 as ready
Mendeliome v0.5082 CHAT Zornitza Stark Marked gene: CHAT as ready
Mendeliome v0.5079 ALG2 Zornitza Stark Marked gene: ALG2 as ready
Mendeliome v0.5079 ALG2 Zornitza Stark Phenotypes for gene: ALG2 were changed from to Myasthenic syndrome, congenital, 14, with tubular aggregates, MIM# 616228; Congenital disorder of glycosylation, type Ii, MIM# 607906
Mendeliome v0.5075 ALG2 Zornitza Stark reviewed gene: ALG2: Rating: AMBER; Mode of pathogenicity: None; Publications: 23404334, 24461433, 12684507; Phenotypes: Myasthenic syndrome, congenital, 14, with tubular aggregates, MIM# 616228, Congenital disorder of glycosylation, type Ii, MIM# 607906; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5075 AGRN Zornitza Stark Marked gene: AGRN as ready
Mendeliome v0.5072 DPH1 Zornitza Stark Marked gene: DPH1 as ready
Mendeliome v0.5072 DPH1 Zornitza Stark Phenotypes for gene: DPH1 were changed from to Developmental delay with short stature, dysmorphic facial features, and sparse hair, MIM# 616901
Mendeliome v0.5069 DPH1 Zornitza Stark reviewed gene: DPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29362492, 29410513, 25558065, 26220823]; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair, MIM# 616901; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5068 LRP8 Bryony Thompson Marked gene: LRP8 as ready
Mendeliome v0.5067 LRP8 Bryony Thompson reviewed gene: LRP8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myocardial infarction, susceptibility to MIM#608446; Mode of inheritance: Unknown
Mendeliome v0.5067 TCF21 Bryony Thompson Marked gene: TCF21 as ready
Mendeliome v0.5066 TCF21 Bryony Thompson reviewed gene: TCF21: Rating: RED; Mode of pathogenicity: None; Publications: 16156022, 10769282, 24875298; Phenotypes: Sensorineural hearing loss, dilated cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5066 SETD1A Zornitza Stark changed review comment from: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; to: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.
Mendeliome v0.5066 SETD1A Zornitza Stark Phenotypes for gene: SETD1A were changed from Epilepsy, early-onset, with or without developmental delay, MIM# 618832 to Epilepsy, early-onset, with or without developmental delay, MIM# 618832; Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Mendeliome v0.5065 SETD1A Zornitza Stark edited their review of gene: SETD1A: Added comment: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; Changed phenotypes: Epilepsy, early-onset, with or without developmental delay, MIM# 618832, Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Mendeliome v0.5065 JARID2 Zornitza Stark Publications for gene: JARID2 were set to 23294540
Mendeliome v0.5064 JARID2 Zornitza Stark Classified gene: JARID2 as Green List (high evidence)
Mendeliome v0.5064 JARID2 Zornitza Stark Gene: jarid2 has been classified as Green List (High Evidence).
Mendeliome v0.5063 JARID2 Zornitza Stark edited their review of gene: JARID2: Added comment: 13 additional individuals reported, note CNVs common but LOF sequence variants identified too.; Changed rating: GREEN; Changed publications: 23294540, 33077894
Mendeliome v0.5063 NUDT2 Zornitza Stark Phenotypes for gene: NUDT2 were changed from Muscular hypotonia; Global developmental delay; Intellectual disability to Muscular hypotonia; Global developmental delay; Intellectual disability; Polyneuropathy
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 v0.5060 AFF2 Zornitza Stark changed review comment from: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar.; to: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar. Missense variants found to be over-represented in an autism cohort.
Mendeliome v0.5060 AFF2 Zornitza Stark Marked gene: AFF2 as ready
Mendeliome v0.5060 AFF2 Zornitza Stark Phenotypes for gene: AFF2 were changed from to Mental retardation, X-linked, FRAXE type 309548
Mendeliome v0.5057 AFF2 Zornitza Stark commented on gene: AFF2: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar.
Mendeliome v0.5057 AFF2 Zornitza Stark reviewed gene: AFF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8334699, 21739600; Phenotypes: Mental retardation, X-linked, FRAXE type 309548; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5057 AUTS2 Zornitza Stark Marked gene: AUTS2 as ready
Mendeliome v0.5057 AUTS2 Zornitza Stark Phenotypes for gene: AUTS2 were changed from to Mental retardation, autosomal dominant 26, MIM#615834
Mendeliome v0.5054 AUTS2 Zornitza Stark reviewed gene: AUTS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23332918, 25205402, 31474318; Phenotypes: Mental retardation, autosomal dominant 26, MIM#615834; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5051 ITSN2 Zornitza Stark Marked gene: ITSN2 as ready
Mendeliome v0.5050 ITSN2 Elena Savva gene: ITSN2 was added
gene: ITSN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITSN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITSN2 were set to PMID: 29773874
Phenotypes for gene: ITSN2 were set to Nephrotic syndrome
Review for gene: ITSN2 was set to GREEN
Added comment: PMID: 29773874: 2 families (3 patients) with homozygous missense or chet missense/PTC + null mice recapitulating the human phenotype.
Functional analysis of all variants shows an inability for Cdc42 activation as shown by wildtype overexpression
Sources: Literature
Mendeliome v0.5050 PI4K2A Zornitza Stark Marked gene: PI4K2A as ready
Mendeliome v0.5050 PI4K2A Zornitza Stark gene: PI4K2A was added
gene: PI4K2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 32418222
Phenotypes for gene: PI4K2A were set to Cutis laxa, intellectual disability, movement disorder
Review for gene: PI4K2A was set to RED
Added comment: Single individual reported with homozygous missense variant and functional data including mouse model.
Sources: Literature
Mendeliome v0.5049 NR5A1 Zornitza Stark Marked gene: NR5A1 as ready
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 v0.5046 HECW2 Zornitza Stark Marked gene: HECW2 as ready
Mendeliome v0.5042 ARHGEF9 Zornitza Stark Mode of inheritance for gene: ARHGEF9 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5041 ARHGEF9 Zornitza Stark edited their review of gene: ARHGEF9: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5041 ZMYND10 Zornitza Stark Marked gene: ZMYND10 as ready
Mendeliome v0.5041 ZMYND10 Zornitza Stark Phenotypes for gene: ZMYND10 were changed from to Ciliary dyskinesia, primary, 22, MIM#615444
Mendeliome v0.5038 ZMYND10 Zornitza Stark reviewed gene: ZMYND10: Rating: GREEN; Mode of pathogenicity: None; Publications: 23891471, 23891469; Phenotypes: Ciliary dyskinesia, primary, 22, MIM#615444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5038 SPAG1 Zornitza Stark Marked gene: SPAG1 as ready
Mendeliome v0.5038 SPAG1 Zornitza Stark Phenotypes for gene: SPAG1 were changed from to Ciliary dyskinesia, primary, 28 (MIM#615505)
Mendeliome v0.5035 SPAG1 Zornitza Stark reviewed gene: SPAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622824, 32502479, 24055112; Phenotypes: Ciliary dyskinesia, primary, 28 (MIM#615505); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5035 MMP21 Zornitza Stark Marked gene: MMP21 as ready
Mendeliome v0.5032 DNAAF1 Zornitza Stark Marked gene: DNAAF1 as ready
Mendeliome v0.5032 DNAAF1 Zornitza Stark Phenotypes for gene: DNAAF1 were changed from to Ciliary dyskinesia, primary, 13, MIM# 613193
Mendeliome v0.5029 DNAAF1 Zornitza Stark reviewed gene: DNAAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19944400, 19944405, 32502479, 29228333, 27261005; Phenotypes: Ciliary dyskinesia, primary, 13, MIM# 613193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5029 LRRC6 Zornitza Stark Marked gene: LRRC6 as ready
Mendeliome v0.5029 LRRC6 Zornitza Stark Phenotypes for gene: LRRC6 were changed from to Ciliary dyskinesia, primary, 19, MIM# 614935
Mendeliome v0.5026 LRRC6 Zornitza Stark reviewed gene: LRRC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23122589, 23891469, 32622824, 29511670; Phenotypes: Ciliary dyskinesia, primary, 19, MIM# 614935; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5026 GAS8 Zornitza Stark Marked gene: GAS8 as ready
Mendeliome v0.5026 GAS8 Zornitza Stark Phenotypes for gene: GAS8 were changed from to Ciliary dyskinesia, primary, 33, MIM#616726
Mendeliome v0.5023 GAS8 Zornitza Stark reviewed gene: GAS8: Rating: GREEN; Mode of pathogenicity: None; Publications: 26387594, 27120127; Phenotypes: Ciliary dyskinesia, primary, 33, mIM# 616726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5023 DNAI2 Zornitza Stark Marked gene: DNAI2 as ready
Mendeliome v0.5023 DNAI2 Zornitza Stark Phenotypes for gene: DNAI2 were changed from to Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM# 612444
Mendeliome v0.5020 DNAI2 Zornitza Stark reviewed gene: DNAI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18950741, 23261302; Phenotypes: Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM# 612444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5020 DNAI1 Zornitza Stark Marked gene: DNAI1 as ready
Mendeliome v0.5020 DNAI1 Zornitza Stark Phenotypes for gene: DNAI1 were changed from to Ciliary dyskinesia, primary, 1, with or without situs inversus, MIM# 244400
Mendeliome v0.5017 DNAI1 Zornitza Stark reviewed gene: DNAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10577904, 11231901, 32502479, 31765523, 30622330; Phenotypes: Ciliary dyskinesia, primary, 1, with or without situs inversus, MIM# 244400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5016 DNAH11 Zornitza Stark reviewed gene: DNAH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 12142464, 18022865, 22102620, 32633470, 31879361, 31765523, 31040315; Phenotypes: Ciliary dyskinesia, primary, 7, with or without situs inversus, MIM#611884; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5016 DNAAF5 Zornitza Stark Marked gene: DNAAF5 as ready
Mendeliome v0.5016 DNAAF5 Zornitza Stark Phenotypes for gene: DNAAF5 were changed from to Ciliary dyskinesia, primary, 18, MIM# 614874
Mendeliome v0.5013 DNAAF5 Zornitza Stark reviewed gene: DNAAF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23040496, 29363216, 25232951; Phenotypes: Ciliary dyskinesia, primary, 18, MIM# 614874; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5013 DNAAF3 Zornitza Stark Marked gene: DNAAF3 as ready
Mendeliome v0.5013 DNAAF3 Zornitza Stark Phenotypes for gene: DNAAF3 were changed from to Ciliary dyskinesia, primary, 2, MIM# 606763
Mendeliome v0.5010 DNAAF3 Zornitza Stark reviewed gene: DNAAF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22387996, 32622824, 31186518; Phenotypes: Ciliary dyskinesia, primary, 2, MIM# 606763; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5010 RAB27A Zornitza Stark Marked gene: RAB27A as ready
Mendeliome v0.5007 DNAAF2 Zornitza Stark Marked gene: DNAAF2 as ready
Mendeliome v0.5007 DNAAF2 Zornitza Stark Phenotypes for gene: DNAAF2 were changed from to Ciliary dyskinesia, primary, 10, MIM# 612518
Mendeliome v0.5004 DNAAF2 Zornitza Stark reviewed gene: DNAAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19052621, 32638265, 31107948; Phenotypes: Ciliary dyskinesia, primary, 10, MIM# 612518; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5004 PPP1R13L Zornitza Stark Marked gene: PPP1R13L as ready
Mendeliome v0.5003 PPP1R13L Zornitza Stark gene: PPP1R13L was added
gene: PPP1R13L was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PPP1R13L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R13L were set to 32666529; 28864777
Phenotypes for gene: PPP1R13L were set to Dilated cardiomyopathy, onset in infancy
Review for gene: PPP1R13L was set to GREEN
Added comment: Four families reported in PMID 28864777, but same homozygous variant, identity by descent. Five unrelated families reported in PMID 32666529. Severe progressive DCM with onset in infancy.
Sources: Expert list
Mendeliome v0.5002 CCNO Zornitza Stark Marked gene: CCNO as ready
Mendeliome v0.5002 CCNO Zornitza Stark Phenotypes for gene: CCNO were changed from to Ciliary dyskinesia, primary, 29, MIM# 615872
Mendeliome v0.4999 CCNO Zornitza Stark reviewed gene: CCNO: Rating: GREEN; Mode of pathogenicity: None; Publications: 24747639, 31765523, 28801648; Phenotypes: Ciliary dyskinesia, primary, 29, MIM# 615872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4999 CSNK1G1 Zornitza Stark Marked gene: CSNK1G1 as ready
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
Mendeliome v0.4997 LMNB2 Zornitza Stark Marked gene: LMNB2 as ready
Mendeliome v0.4997 LMNB2 Zornitza Stark Phenotypes for gene: LMNB2 were changed from to {Lipodystrophy, partial, acquired, susceptibility to} 608709; Congenital microcephaly, Intellectual disability
Mendeliome v0.4994 LMNB2 Zornitza Stark reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826530, 22768673, 33033404; Phenotypes: {Lipodystrophy, partial, acquired, susceptibility to} 608709, Congenital microcephaly, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v0.4993 SREBF1 Zornitza Stark Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016 to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016; Mucoepithelial dysplasia, hereditary, MIM#158310
Mendeliome v0.4991 SREBF1 Zornitza Stark edited their review of gene: SREBF1: Added comment: HMD phenotype: 5 unrelated families reported with heterozygous variants at same residue (p.Arg557Cys and p.Arg557His) and a panepithelial defect involving the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral, and bladder mucosa. Individuals developed cataracts, blindness, nonscarring alopecia, perineal psoriasiform lesions, and follicular keratoses.; Changed publications: 32497488, 31790666, 32902915; Changed phenotypes: IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016, Mucoepithelial dysplasia, hereditary, MIM#158310
Mendeliome v0.4991 CCDC40 Zornitza Stark Marked gene: CCDC40 as ready
Mendeliome v0.4991 CCDC40 Zornitza Stark Phenotypes for gene: CCDC40 were changed from to Ciliary dyskinesia, primary, 15, MIM#613808
Mendeliome v0.4988 CCDC40 Zornitza Stark reviewed gene: CCDC40: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131974, 23255504, 31879361, 31765523, 31650533; Phenotypes: Ciliary dyskinesia, primary, 15, MIM#613808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4988 CCDC39 Zornitza Stark Marked gene: CCDC39 as ready
Mendeliome v0.4988 CCDC39 Zornitza Stark Phenotypes for gene: CCDC39 were changed from to Ciliary dyskinesia, primary, 14, MIM# 613807
Mendeliome v0.4985 CCDC39 Zornitza Stark reviewed gene: CCDC39: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131972, 23255504; Phenotypes: Ciliary dyskinesia, primary, 14, MIM# 613807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4985 CCDC151 Zornitza Stark Marked gene: CCDC151 as ready
Mendeliome v0.4985 CCDC151 Zornitza Stark Phenotypes for gene: CCDC151 were changed from to Ciliary dyskinesia, primary, 30, MIM# 616037
Mendeliome v0.4982 CCDC151 Zornitza Stark reviewed gene: CCDC151: Rating: GREEN; Mode of pathogenicity: None; Publications: 25192045, 25224326, 32490514, 32286033, 30504913; Phenotypes: Ciliary dyskinesia, primary, 30, MIM# 616037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4982 CCDC114 Zornitza Stark Marked gene: CCDC114 as ready
Mendeliome v0.4982 CCDC114 Zornitza Stark Phenotypes for gene: CCDC114 were changed from to Ciliary dyskinesia, primary, 20, MIM# 615067
Mendeliome v0.4979 CCDC114 Zornitza Stark reviewed gene: CCDC114: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261303, 23261302, 32855706, 23506398; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4979 CCDC103 Zornitza Stark Marked gene: CCDC103 as ready
Mendeliome v0.4979 CCDC103 Zornitza Stark Phenotypes for gene: CCDC103 were changed from to Ciliary dyskinesia, primary, 17, MIM# 614679
Mendeliome v0.4976 CCDC103 Zornitza Stark reviewed gene: CCDC103: Rating: GREEN; Mode of pathogenicity: None; Publications: 22581229, 32447765, 31858719, 28790179; Phenotypes: Ciliary dyskinesia, primary, 17, MIM# 614679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4976 GARS Zornitza Stark Marked gene: GARS as ready
Mendeliome v0.4976 GARS Zornitza Stark Gene: gars has been classified as Green List (High Evidence).
Mendeliome v0.4976 GARS Zornitza Stark Phenotypes for gene: GARS were changed from to Spinal muscular atrophy, infantile, James type, MIM# 619042; Charcot-Marie-Tooth disease, type 2D, MIM# 601472; Neuronopathy, distal hereditary motor, type VA, MIM# 600794; Multi-system mitochondrial disorder
Mendeliome v0.4975 GARS Zornitza Stark Publications for gene: GARS were set to
Mendeliome v0.4974 GARS Zornitza Stark Mode of inheritance for gene: GARS was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4973 GARS Zornitza Stark Tag new gene name tag was added to gene: GARS.
Mendeliome v0.4973 GARS Zornitza Stark reviewed gene: GARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 17101916, 22462675, 31985473, 32181591, 12690580, 25168514, 26503042, 29648643, 16982418, 24669931, 28594869; Phenotypes: Spinal muscular atrophy, infantile, James type, MIM# 619042, Charcot-Marie-Tooth disease, type 2D, MIM# 601472, Neuronopathy, distal hereditary motor, type VA, MIM# 600794, Multi-system mitochondrial disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4973 SELENON Zornitza Stark Marked gene: SELENON as ready
Mendeliome v0.4973 SELENON Zornitza Stark Phenotypes for gene: SELENON were changed from to Myopathy, congenital, with fiber-type disproportion, MIM# 255310; Muscular dystrophy, rigid spine, 1, MIM# 602771
Mendeliome v0.4970 SELENON Zornitza Stark reviewed gene: SELENON: Rating: GREEN; Mode of pathogenicity: None; Publications: 11528383, 12192640, 16365872, 21131290, 21131290, 32154989, 32796131; Phenotypes: Myopathy, congenital, with fiber-type disproportion, MIM# 255310, Muscular dystrophy, rigid spine, 1, MIM# 602771; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4970 TNNT1 Zornitza Stark Marked gene: TNNT1 as ready
Mendeliome v0.4968 TNNT3 Zornitza Stark Marked gene: TNNT3 as ready
Mendeliome v0.4968 TNNT3 Zornitza Stark Phenotypes for gene: TNNT3 were changed from to Arthrogryposis, distal, type 2B2, MIM# 618435
Mendeliome v0.4964 TNNT3 Zornitza Stark reviewed gene: TNNT3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 12865991, 19142688, 21402185, 25337069, 17194691; Phenotypes: Arthrogryposis, distal, type 2B2, MIM# 618435; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4964 STAC3 Zornitza Stark Marked gene: STAC3 as ready
Mendeliome v0.4961 SPEG Zornitza Stark Marked gene: SPEG as ready
Mendeliome v0.4961 SPEG Zornitza Stark Phenotypes for gene: SPEG were changed from to Centronuclear myopathy 5, MIM# 615959
Mendeliome v0.4958 SPEG Zornitza Stark reviewed gene: SPEG: Rating: GREEN; Mode of pathogenicity: None; Publications: 25087613, 31625632, 30412272, 30157964, 29614691, 29474540, 28624463, 26578207, 25087613; Phenotypes: Centronuclear myopathy 5, MIM# 615959; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4958 TPM3 Zornitza Stark Marked gene: TPM3 as ready
Mendeliome v0.4954 MICU1 Zornitza Stark Marked gene: MICU1 as ready
Mendeliome v0.4951 LMOD3 Zornitza Stark Marked gene: LMOD3 as ready
Mendeliome v0.4947 MYH2 Zornitza Stark Marked gene: MYH2 as ready
Mendeliome v0.4944 KLHL41 Zornitza Stark Marked gene: KLHL41 as ready
Mendeliome v0.4941 KLHL40 Zornitza Stark Marked gene: KLHL40 as ready
Mendeliome v0.4938 MYO18B Zornitza Stark Marked gene: MYO18B as ready
Mendeliome v0.4935 MEGF10 Zornitza Stark Marked gene: MEGF10 as ready
Mendeliome v0.4935 MEGF10 Zornitza Stark Phenotypes for gene: MEGF10 were changed from to Myopathy, areflexia, respiratory distress, and dysphagia, early-onset, MIM# 614399
Mendeliome v0.4932 MEGF10 Zornitza Stark reviewed gene: MEGF10: Rating: GREEN; Mode of pathogenicity: None; Publications: 22101682, 22371254, 30802937; Phenotypes: Myopathy, areflexia, respiratory distress, and dysphagia, early-onset, MIM# 614399; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4930 WDPCP Zornitza Stark edited their review of gene: WDPCP: Changed rating: GREEN; Changed publications: 20671153, 25427950, 32055034, 29588463, 28289185; Changed phenotypes: Bardet-Biedl syndrome 15, MIM# 615992, OFD, Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085
Mendeliome v0.4930 WDPCP Zornitza Stark Marked gene: WDPCP as ready
Mendeliome v0.4930 WDPCP Zornitza Stark Phenotypes for gene: WDPCP were changed from Bardet-Biedl syndrome 15, MIM# 615992; OFD; Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085 to Bardet-Biedl syndrome 15, MIM# 615992; OFD; Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085
Mendeliome v0.4930 WDPCP Zornitza Stark Phenotypes for gene: WDPCP were changed from to Bardet-Biedl syndrome 15, MIM# 615992; OFD; Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085
Mendeliome v0.4926 WDPCP Zornitza Stark reviewed gene: WDPCP: Rating: AMBER; Mode of pathogenicity: None; Publications: 20671153, 25427950; Phenotypes: Bardet-Biedl syndrome 15, MIM# 615992, OFD; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4926 TUBGCP4 Zornitza Stark Marked gene: TUBGCP4 as ready
Mendeliome v0.4923 DYNC2LI1 Zornitza Stark Marked gene: DYNC2LI1 as ready
Mendeliome v0.4920 SLC20A2 Zornitza Stark Phenotypes for gene: SLC20A2 were changed from Basal ganglia calcification, idiopathic, 1, MIM# 213600 to Basal ganglia calcification, idiopathic, 1, MIM# 213600; ?hereditary multiple exostoses
Mendeliome v0.4917 SLC20A2 Elena Savva reviewed gene: SLC20A2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 24209445, 23437308, 32705272, 27943094; Phenotypes: Basal ganglia calcification, idiopathic, 1213600, ?hereditary multiple exostoses; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4916 FKBP14 Zornitza Stark Marked gene: FKBP14 as ready
Mendeliome v0.4913 EPG5 Zornitza Stark Marked gene: EPG5 as ready
Mendeliome v0.4910 EPG5 Zornitza Stark reviewed gene: EPG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23222957, 26917586; Phenotypes: Vici syndrome, MIM# 242840, vacuolar myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4910 LMX1B Zornitza Stark Marked gene: LMX1B as ready
Mendeliome v0.4907 SEMA4A Zornitza Stark Marked gene: SEMA4A as ready
Mendeliome v0.4903 JPH2 Zornitza Stark Marked gene: JPH2 as ready
Mendeliome v0.4903 JPH2 Zornitza Stark Phenotypes for gene: JPH2 were changed from to Cardiomyopathy, hypertrophic, MIM#613873; dilated cardiomyopathy
Mendeliome v0.4899 JPH2 Zornitza Stark reviewed gene: JPH2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30681346, 17509612, 23973696, 26869393, 28393127, 30235249, 31227780; Phenotypes: Cardiomyopathy, hypertrophic, MIM#613873, dilated cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4899 RGR Zornitza Stark Marked gene: RGR as ready
Mendeliome v0.4895 RDH11 Zornitza Stark Marked gene: RDH11 as ready
Mendeliome v0.4895 RDH11 Zornitza Stark gene: RDH11 was added
gene: RDH11 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 15634683; 30731079; 18326732
Phenotypes for gene: RDH11 were set to Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108
Review for gene: RDH11 was set to RED
Added comment: Single family reported with compound heterozygous LOF variants segregating with disease in three siblings. Some functional data, but note mouse KO did not have eye phenotype.
Sources: Expert list
Mendeliome v0.4894 CEP112 Zornitza Stark Marked gene: CEP112 as ready
Mendeliome v0.4893 SVIL Zornitza Stark Phenotypes for gene: SVIL were changed from myopathy to Myofibrillar myopathy, MIM#619040
Mendeliome v0.4892 SVIL Zornitza Stark edited their review of gene: SVIL: Changed rating: AMBER; Changed phenotypes: Myofibrillar myopathy, MIM#619040
Mendeliome v0.4892 GPC6 Zornitza Stark Marked gene: GPC6 as ready
Mendeliome v0.4892 GPC6 Zornitza Stark Phenotypes for gene: GPC6 were changed from to Omodysplasia 1 (MIM#258315), AR
Mendeliome v0.4889 GPC6 Kristin Rigbye reviewed gene: GPC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 19481194; Phenotypes: Omodysplasia 1 (MIM#258315), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4889 SPATA7 Zornitza Stark Marked gene: SPATA7 as ready
Mendeliome v0.4886 KIRREL3 Zornitza Stark Marked gene: KIRREL3 as ready
Mendeliome v0.4886 KIRREL3 Zornitza Stark gene: KIRREL3 was added
gene: KIRREL3 was added to Mendeliome. Sources: Expert list
refuted tags were added to gene: KIRREL3.
Mode of inheritance for gene: KIRREL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIRREL3 were set to 19012874
Phenotypes for gene: KIRREL3 were set to Intellectual disability
Review for gene: KIRREL3 was set to RED
Added comment: Variants associated with ID have now been re-classified based on population frequency.
Sources: Expert list
Mendeliome v0.4885 NEUROD1 Zornitza Stark Marked gene: NEUROD1 as ready
Mendeliome v0.4882 DNAAF4 Zornitza Stark Marked gene: DNAAF4 as ready
Mendeliome v0.4882 DNAAF4 Zornitza Stark Phenotypes for gene: DNAAF4 were changed from to Ciliary dyskinesia, primary, 25, MIM# 615482
Mendeliome v0.4879 DNAAF4 Zornitza Stark reviewed gene: DNAAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23872636; Phenotypes: Ciliary dyskinesia, primary, 25, MIM# 615482; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4879 MAG Zornitza Stark Phenotypes for gene: MAG were changed from Spastic paraplegia 75, autosomal recessive, MIM# 616680 to Spastic paraplegia 75, autosomal recessive, MIM# 616680; Cerebellar ataxia
Mendeliome v0.4878 MAG Zornitza Stark changed review comment from: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported.; to: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms.
Mendeliome v0.4878 GZF1 Zornitza Stark Marked gene: GZF1 as ready
Mendeliome v0.4878 GZF1 Zornitza Stark Phenotypes for gene: GZF1 were changed from to Joint laxity, short stature, and myopia, MIM# 617662; Larsen-like syndrome
Mendeliome v0.4875 GZF1 Zornitza Stark reviewed gene: GZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33009817, 28475863; Phenotypes: Joint laxity, short stature, and myopia, MIM# 617662, Larsen-like syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4875 ITFG2 Zornitza Stark Marked gene: ITFG2 as ready
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
Mendeliome v0.4873 SHMT2 Zornitza Stark Marked gene: SHMT2 as ready
Mendeliome v0.4872 SHMT2 Zornitza Stark gene: SHMT2 was added
gene: SHMT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).
Sources: Literature
Mendeliome v0.4871 DHX38 Zornitza Stark Marked gene: DHX38 as ready
Mendeliome v0.4867 CCT2 Zornitza Stark Marked gene: CCT2 as ready
Mendeliome v0.4867 CCT2 Zornitza Stark gene: CCT2 was added
gene: CCT2 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: CCT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCT2 were set to 27645772; 29450543
Phenotypes for gene: CCT2 were set to Leber's congenital amaurosis
Review for gene: CCT2 was set to RED
Added comment: Single family reported with compound het missense variants, functional data, including animal model.
Sources: NHS GMS
Mendeliome v0.4866 CA4 Zornitza Stark Marked gene: CA4 as ready
Mendeliome v0.4862 VPS41 Zornitza Stark Marked gene: VPS41 as ready
Mendeliome v0.4862 VPS41 Zornitza Stark gene: VPS41 was added
gene: VPS41 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683
Phenotypes for gene: VPS41 were set to Dystonia; intellectual disability
Review for gene: VPS41 was set to RED
Added comment: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.
Sources: Literature
Mendeliome v0.4861 VPS16 Zornitza Stark Marked gene: VPS16 as ready
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
Mendeliome v0.4859 KRIT1 Zornitza Stark Marked gene: KRIT1 as ready
Mendeliome v0.4859 KRIT1 Zornitza Stark Phenotypes for gene: KRIT1 were changed from to Cavernous malformations of CNS and retina, 116860; Cerebral cavernous malformations-1, 116860; Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations, 116860
Mendeliome v0.4856 SH3TC2 Zornitza Stark Marked gene: SH3TC2 as ready
Mendeliome v0.4856 SH3TC2 Zornitza Stark Phenotypes for gene: SH3TC2 were changed from to Charcot-Marie-Tooth disease, type 4C MIM#601596, Mononeuropathy of the median nerve, mild MIM#613353
Mendeliome v0.4853 ABCC6 Zornitza Stark Marked gene: ABCC6 as ready
Mendeliome v0.4853 ABCC6 Zornitza Stark Added comment: Comment when marking as ready: Evidence for mono-allelic variants causing disease is limited.
Mendeliome v0.4853 CAPN3 Zornitza Stark Marked gene: CAPN3 as ready
Mendeliome v0.4853 CAPN3 Zornitza Stark Phenotypes for gene: CAPN3 were changed from to Muscular dystrophy, limb-girdle, autosomal dominant 4, MIM# 618129; Muscular dystrophy, limb-girdle, autosomal recessive 1, MIM# 253600
Mendeliome v0.4850 CAPN3 Zornitza Stark reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31937337, 28881388, 32342993, 32557990; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 4, MIM# 618129, Muscular dystrophy, limb-girdle, autosomal recessive 1, MIM# 253600; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4850 SLC6A5 Zornitza Stark Marked gene: SLC6A5 as ready
Mendeliome v0.4849 KRIT1 Elena Savva reviewed gene: KRIT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16571644, 29593473; Phenotypes: Cavernous malformations of CNS and retina, 116860, Cerebral cavernous malformations-1, 116860, Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations, 116860; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4846 ARX Zornitza Stark Marked gene: ARX as ready
Mendeliome v0.4846 ARX Zornitza Stark Gene: arx has been classified as Green List (High Evidence).
Mendeliome v0.4846 ARX Zornitza Stark Phenotypes for gene: ARX were changed from to 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
Mendeliome v0.4845 ARX Zornitza Stark Publications for gene: ARX were set to
Mendeliome v0.4844 ARX Zornitza Stark Mode of inheritance for gene: ARX was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.4843 SH3TC2 Elena Savva reviewed gene: SH3TC2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19744956, 20220177, 19744956, 20028792; Phenotypes: Charcot-Marie-Tooth disease, type 4C MIM#601596, Mononeuropathy of the median nerve, mild MIM#613353; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4843 ABCC6 Kristin Rigbye changed review comment from: All conditions are regarded as a single disorder at variable ends of the phenotypic spectrum. The same variants have been reported in all three conditions, however reports for AD PE are consistently from older papers (pre-2005) and may have missed a 2nd hit (OMIM). More recent papers consistently report this condition as autosomal recessive (PMID: 28102862).; to: All conditions are regarded as a single disorder at variable ends of the phenotypic spectrum. The same variants have been reported in all three conditions, however reports for AD PXE are consistently from older papers (pre-2005) and may have missed a 2nd hit (OMIM). More recent papers consistently report this condition as autosomal recessive (PMID: 28102862).

In addition to missense, PTCs and splice variants, deletions and duplications in this gene comprise a significant proportion of variants and are a recognised mechanism / cause of PXE.
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 v0.4843 TBL1Y Zornitza Stark Phenotypes for gene: TBL1Y were changed from Hearing loss to Deafness, Y-linked 2, MIM# 400047
Mendeliome v0.4842 MCM2 Zornitza Stark Marked gene: MCM2 as ready
Mendeliome v0.4841 ATP1A4 Zornitza Stark Marked gene: ATP1A4 as ready
Mendeliome v0.4841 ATP1A4 Zornitza Stark gene: ATP1A4 was added
gene: ATP1A4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP1A4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP1A4 were set to 32549268
Phenotypes for gene: ATP1A4 were set to Hemiplegic migraine
Review for gene: ATP1A4 was set to RED
Added comment: Single family reported where missense variant segregated with hemiplegic migraine in four affected individuals.
Sources: Literature
Mendeliome v0.4840 BSND Zornitza Stark Marked gene: BSND as ready
Mendeliome v0.4840 BSND Zornitza Stark Phenotypes for gene: BSND were changed from to Bartter syndrome, type 4a, MIM#602522
Mendeliome v0.4837 BSND Zornitza Stark changed review comment from: Some individuals with severe Bartter syndrome have been described as having intellectual disability, whereas others with milder symptoms have normal intellect.
Sources: Expert list; to: Well established gene-disease association.
Sources: Expert list
Mendeliome v0.4837 LTBP2 Zornitza Stark Marked gene: LTBP2 as ready
Mendeliome v0.4837 LTBP2 Zornitza Stark Phenotypes for gene: LTBP2 were changed from to Glaucoma 3, primary congenital, D 613086; Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750
Mendeliome v0.4834 LTBP2 Zornitza Stark reviewed gene: LTBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19656777, 19361779, 20617341, 32165823, 30380740, 30565850; Phenotypes: Glaucoma 3, primary congenital, D 613086, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4833 CYP1B1 Zornitza Stark reviewed gene: CYP1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9463332, 10655546, 12372064, 21081970; Phenotypes: Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, MIM# 231300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4832 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from Lethal congenital contracture syndrome 10, MIM# 617022; Skeletal dysplasia to Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262; Skeletal dysplasia
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 v0.4829 IL11RA Zornitza Stark Marked gene: IL11RA as ready
Mendeliome v0.4825 EFNB1 Zornitza Stark Marked gene: EFNB1 as ready
Mendeliome v0.4822 ABCC6 Kristin Rigbye reviewed gene: ABCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28102862; Phenotypes: Pseudoxanthoma elasticum (MIM#264800), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4822 AGAP1 Zornitza Stark Marked gene: AGAP1 as ready
Mendeliome v0.4821 AGAP1 Zornitza Stark gene: AGAP1 was added
gene: AGAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AGAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGAP1 were set to 31700678; 25666757; 30472483
Phenotypes for gene: AGAP1 were set to Cerebral palsy
Review for gene: AGAP1 was set to AMBER
Added comment: Two individuals reported with de novo variants in this gene and a CP phenotype. Rare variants over-represented in a case-control study. Supportive zebrafish model. Another individual with a deletion (+1 other gene) reported with ID and autism.
Sources: Literature
Mendeliome v0.4820 SMN1 Zornitza Stark Marked gene: SMN1 as ready
Mendeliome v0.4820 SMN1 Zornitza Stark Phenotypes for gene: SMN1 were changed from to Spinal muscular atrophy-1, MIM# 253300
Mendeliome v0.4817 SMN1 Zornitza Stark reviewed gene: SMN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7813012; Phenotypes: Spinal muscular atrophy-1, MIM# 253300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4817 BUB1B Zornitza Stark Marked gene: BUB1B as ready
Mendeliome v0.4817 BUB1B Zornitza Stark Phenotypes for gene: BUB1B were changed from to Mosaic variegated aneuploidy syndrome 1, MIM# 257300; Premature ovarian failure
Mendeliome v0.4814 BUB1B Zornitza Stark reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32716490, 18548531; Phenotypes: Mosaic variegated aneuploidy syndrome 1, MIM# 257300, Premature ovarian failure; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4814 ROM1 Zornitza Stark Marked gene: ROM1 as ready
Mendeliome v0.4811 FOXC1 Zornitza Stark Marked gene: FOXC1 as ready
Mendeliome v0.4808 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Disorder of N-glycosylation to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Disorder of N-glycosylation
Mendeliome v0.4807 ALG14 Zornitza Stark changed review comment from: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype. ALG14 is part of the UDP-GlcNAc transferase, which catalyzes a key step in endoplasmic reticulum N-linked glycosylation; to: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype. ALG14 is part of the UDP-GlcNAc transferase, which catalyzes a key step in endoplasmic reticulum N-linked glycosylation. The three OMIM disorders may represent a spectrum of severity for CDG.
Mendeliome v0.4807 ALG14 Zornitza Stark edited their review of gene: ALG14: Changed phenotypes: Myasthenic syndrome, congenital, 15, without tubular aggregates 616227, Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031, Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036, Disorder of N-glycosylation
Mendeliome v0.4807 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: eye and vascular development; Mode of inheritance: None
Mendeliome v0.4807 BUB1B Eleanor Williams reviewed gene: BUB1B: Rating: ; Mode of pathogenicity: None; Publications: 32716490; Phenotypes: premature ovarian insufficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4807 SMN1 Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: Spinal muscular atrophy; Mode of inheritance: None
Mendeliome v0.4807 ACER3 Zornitza Stark Marked gene: ACER3 as ready
Mendeliome v0.4796 AP1S1 Zornitza Stark Marked gene: AP1S1 as ready
Mendeliome v0.4791 AP1S1 Ee Ming Wong changed review comment from: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants; to: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants
Mendeliome v0.4791 AP1S1 Ee Ming Wong changed review comment from: - 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants; to: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants
Mendeliome v0.4791 AKNA Seb Lunke Marked gene: AKNA as ready
Mendeliome v0.4791 GOLGA3 Zornitza Stark Marked gene: GOLGA3 as ready
Mendeliome v0.4789 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and in mouse it induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the hypomorphic thoc1 in mouse induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4789 GOLGA3 Elena Savva gene: GOLGA3 was added
gene: GOLGA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GOLGA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOLGA3 were set to PMID: 23495255
Phenotypes for gene: GOLGA3 were set to Primary ciliary dyskinesia
Review for gene: GOLGA3 was set to RED
Added comment: https://link.springer.com/article/10.1007/s00439-020-02170-2
Two siblings with a homozygous missense and PCD

PMID: 23495255; null mice have failed spermatogenesis
Sources: Literature
Mendeliome v0.4789 PRICKLE3 Seb Lunke Marked gene: PRICKLE3 as ready
Mendeliome v0.4789 PRICKLE3 Seb Lunke Added comment: Comment on list classification: Single variant only and questionable association due to uncertainty of role around ND4.
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
Mendeliome v0.4788 THOC1 Zornitza Stark Marked gene: THOC1 as ready
Mendeliome v0.4787 GBF1 Seb Lunke Marked gene: GBF1 as ready
Mendeliome v0.4786 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and in mouse it induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4785 RNPC3 Zornitza Stark Marked gene: RNPC3 as ready
Mendeliome v0.4784 RNPC3 Zornitza Stark gene: RNPC3 was added
gene: RNPC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 29866761; 32462814
Phenotypes for gene: RNPC3 were set to Growth hormone deficiency
Review for gene: RNPC3 was set to AMBER
Added comment: Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Sources: Literature
Mendeliome v0.4783 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adulthood-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4783 PRICKLE3 Teresa Zhao gene: PRICKLE3 was added
gene: PRICKLE3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRICKLE3 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: PRICKLE3 were set to 32516135
Phenotypes for gene: PRICKLE3 were set to Leber’s hereditary optic neuropathy MIM#535000
Review for gene: PRICKLE3 was set to AMBER
Added comment: Reported as X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision.

Defective assembly, stability, and function of ATP synthase observed using Lymphoblastoid cell lines from one of the families.

This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON.

Prickle3-deficient mice exhibited pronounced ATPase deficiencies.
Sources: Literature
Mendeliome v0.4783 NUAK2 Seb Lunke Marked gene: NUAK2 as ready
Mendeliome v0.4783 GBF1 Paul De Fazio changed review comment from: 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; to: 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).

Age of onset varied from childhood (nonsense variant) to 50s. Authors observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals.
Sources: Literature
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
Mendeliome v0.4782 THOC1 Melanie Marty gene: THOC1 was added
gene: THOC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THOC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THOC1 were set to 32776944
Phenotypes for gene: THOC1 were set to Nonsyndromic hearing loss
Review for gene: THOC1 was set to AMBER
Added comment: Missense variant identified and segregated with adulthood-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4782 MBTPS1 Zornitza Stark Marked gene: MBTPS1 as ready
Mendeliome v0.4781 MBTPS1 Zornitza Stark gene: MBTPS1 was added
gene: MBTPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBTPS1 were set to 32857899; 32420688; 30046013
Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia
Review for gene: MBTPS1 was set to GREEN
Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature.
Sources: Literature
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
Mendeliome v0.4780 ALS2 Ain Roesley gene: ALS2 was added
gene: ALS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALS2 were set to 32214227
Phenotypes for gene: ALS2 were set to Tetraparesis with affection of upper and lower motor neuron
Penetrance for gene: ALS2 were set to unknown
Review for gene: ALS2 was set to RED
Added comment: In a cohort of Palestinian and Israeli Arabs with neurological disorders, a family with 2 affecteds were homozygous for a nonsense variant. Authors classified as likely path by ACMG guidelines
Sources: Literature
Mendeliome v0.4780 QRICH1 Zornitza Stark Marked gene: QRICH1 as ready
Mendeliome v0.4777 GREB1L Zornitza Stark Marked gene: GREB1L as ready
Mendeliome v0.4774 IL1RAP Zornitza Stark Marked gene: IL1RAP as ready
Mendeliome v0.4774 IL1RAP Zornitza Stark gene: IL1RAP was added
gene: IL1RAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL1RAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL1RAP were set to 31954058
Phenotypes for gene: IL1RAP were set to Steroid-sensitive nephrotic syndrome
Review for gene: IL1RAP was set to RED
Added comment: A pair of siblings with compound heterozygous variants in this gene and steroid-sensitive nephrotic syndrome. Functional effect of variants demonstrated but mouse model does not have proteinuria.
Sources: Literature
Mendeliome v0.4770 NEMF Zornitza Stark changed review comment from: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature; to: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.

Single individual with de novo variant reported, postulated dominant negative effect. Evidence for mono allelic variants causing disease is limited.
Sources: Literature
Mendeliome v0.4769 HOMER2 Zornitza Stark Marked gene: HOMER2 as ready
Mendeliome v0.4766 TPRN Zornitza Stark Marked gene: TPRN as ready
Mendeliome v0.4763 TMC1 Zornitza Stark Marked gene: TMC1 as ready
Mendeliome v0.4760 TMIE Zornitza Stark Marked gene: TMIE as ready
Mendeliome v0.4757 TRIOBP Zornitza Stark Marked gene: TRIOBP as ready
Mendeliome v0.4754 STRC Zornitza Stark Marked gene: STRC as ready
Mendeliome v0.4751 NUP188 Zornitza Stark Phenotypes for gene: NUP188 were changed from microcephaly; ID; cataract; structural brain abnormalities; hypoventilation to Sandestig-Stefanova syndrome, 618804; microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Mendeliome v0.4750 NUP188 Zornitza Stark edited their review of gene: NUP188: Changed phenotypes: Sandestig-Stefanova syndrome, 618804, microcephaly, ID, cataract, structural brain abnormalities, hypoventilation
Mendeliome v0.4750 SETD1A Zornitza Stark Marked gene: SETD1A as ready
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
Mendeliome v0.4748 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome to Spastic paraplegia-83 (SPG83), MIM#619027; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Mendeliome v0.4747 HPDL Zornitza Stark edited their review of gene: HPDL: Added comment: Although two distinct distinct disease associations have been assigned by OMIM, these clinical presentations likely represent a continuum of severity for an underlying mitochondrial disorder.; Changed phenotypes: Spastic paraplegia-83 (SPG83), MIM#619027, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026
Mendeliome v0.4747 HPDL Zornitza Stark commented on gene: HPDL: 17 individuals from 13 families, with a spectrum of neurologic impairment ranging from a severe congenital form without any neurological development (n = 2/17, 12%) to infantile-onset presentations (n = 10/17, 59%) with moderate to severe neurodevelopmental issues, partly with a pathology reminiscent of mitochondrial disease (Leigh-like syndrome), to juvenile-onset spastic paraplegia (n = 5/17, 29%).

Frequently observed clinical findings included chronic progression of neurological signs (n = 16/17, 94%), motor developmental delay (n = 12/17, 71%), intellectual impairment (n = 11/17, 65%), microcephaly (n = 9/16, 56%), and seizures/epilepsy (n = 9/17, 53%). Other relevant clinical findings were visual disturbances/strabismus (n = 9/17, 53%) and loss of developmental milestones (n = 6/17, 35%).

Acute central respiratory failure leading to life-threatening events requiring partly mechanically assisted ventilation occurred in half of individuals with infantile presentation (n = 5/10, 50%), respectively one third of all individuals (n = 5/17, 29%).

Demyelinating neuropathy was present in three individuals (n = 3/11, 27%), with reduced sensory nerve conduction velocity (NCV) in all and severely reduced motor NCV in one.
Mendeliome v0.4745 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208 to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208; Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome; Febrile seizures; Arthrogryposis multiplex congenita
Mendeliome v0.4743 SCN1A Zornitza Stark edited their review of gene: SCN1A: Added comment: Note we have reported the association with AMC previously in PMID 29543227 (Supplementary info) in an infant presenting with AMC and severe EE, and de novo p.(Ile1347Asn) variant which at the time was thought to only partially explain the phenotype, but in light of this new report, likely fully explains the phenotype. Given the presence of severe seizure disorder in the two infants who were phenotyped in the newborn period, this likely represents the severe end of the spectrum of SCN1A-related disorders rather than a distinct association.; Changed phenotypes: Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208, Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome, Febrile seizures, Arthrogryposis multiplex congenita
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.
Mendeliome v0.4742 PRKD1 Zornitza Stark reviewed gene: PRKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4742 SCN1A Arina Puzriakova reviewed gene: SCN1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 32928894; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4742 SIX1 Zornitza Stark Marked gene: SIX1 as ready
Mendeliome v0.4739 PTPRQ Zornitza Stark Marked gene: PTPRQ as ready
Mendeliome v0.4736 POU4F3 Zornitza Stark Marked gene: POU4F3 as ready
Mendeliome v0.4733 KPTN Zornitza Stark Marked gene: KPTN as ready
Mendeliome v0.4733 KPTN Zornitza Stark Phenotypes for gene: KPTN were changed from to Mental retardation, autosomal recessive 41 (MIM#615637)
Mendeliome v0.4730 NPHS1 Zornitza Stark Marked gene: NPHS1 as ready
Mendeliome v0.4728 TTI2 Zornitza Stark Marked gene: TTI2 as ready
Mendeliome v0.4728 TTI2 Zornitza Stark Phenotypes for gene: TTI2 were changed from to Mental retardation, autosomal recessive 39, MIM#615541
Mendeliome v0.4725 TTI2 Zornitza Stark reviewed gene: TTI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32061250, 23956177, 31737043; Phenotypes: Mental retardation, autosomal recessive 39, MIM#615541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4725 IGSF10 Bryony Thompson Marked gene: IGSF10 as ready
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
Mendeliome v0.4723 KPTN Melanie Marty reviewed gene: KPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24239382, 32358097, 32808430; Phenotypes: Mental retardation, autosomal recessive 41 (MIM#615637); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4723 PFN1 Zornitza Stark Marked gene: PFN1 as ready
Mendeliome v0.4720 PCDH15 Zornitza Stark Marked gene: PCDH15 as ready
Mendeliome v0.4717 WHRN Zornitza Stark Marked gene: WHRN as ready
Mendeliome v0.4714 OTOGL Zornitza Stark Marked gene: OTOGL as ready
Mendeliome v0.4711 RDX Zornitza Stark Marked gene: RDX as ready
Mendeliome v0.4708 OTOA Zornitza Stark Marked gene: OTOA as ready
Mendeliome v0.4705 MYO7A Zornitza Stark Marked gene: MYO7A as ready
Mendeliome v0.4702 SMPX Zornitza Stark Marked gene: SMPX as ready
Mendeliome v0.4699 MYO6 Zornitza Stark Marked gene: MYO6 as ready
Mendeliome v0.4696 MYO15A Zornitza Stark Marked gene: MYO15A as ready
Mendeliome v0.4693 MYH9 Zornitza Stark Marked gene: MYH9 as ready
Mendeliome v0.4693 MYH9 Zornitza Stark Phenotypes for gene: MYH9 were changed from to Deafness, autosomal dominant 17, MIM# 603622; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100; MYH9-related disorders
Mendeliome v0.4690 MYH9 Zornitza Stark reviewed gene: MYH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 9390828, 24890873, 17146397, 25505834, 16630581, 16162639, 23976996, 21908426; Phenotypes: Deafness, autosomal dominant 17, MIM# 603622, Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100, MYH9-related disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4690 MARVELD2 Zornitza Stark Marked gene: MARVELD2 as ready
Mendeliome v0.4690 MARVELD2 Zornitza Stark Gene: marveld2 has been classified as Green List (High Evidence).
Mendeliome v0.4690 MARVELD2 Zornitza Stark Phenotypes for gene: MARVELD2 were changed from to Deafness, autosomal recessive 49, MIM# 610153
Mendeliome v0.4689 MARVELD2 Zornitza Stark Publications for gene: MARVELD2 were set to
Mendeliome v0.4688 MARVELD2 Zornitza Stark Mode of inheritance for gene: MARVELD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4687 MARVELD2 Zornitza Stark reviewed gene: MARVELD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17186462, 18084694, 22903915, 27344577, 26677943, 23979167; Phenotypes: Deafness, autosomal recessive 49, MIM# 610153; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4687 RPL9 Zornitza Stark Marked gene: RPL9 as ready
Mendeliome v0.4687 RPL9 Zornitza Stark Added comment: Comment when marking as ready: Second individual reported with same c.-2+1G>C variant in the 5′UTR of RPL9, deleterious effect demonstrated, functional data, upgrade to Amber.
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 v0.4685 LRTOMT Zornitza Stark Marked gene: LRTOMT as ready
Mendeliome v0.4682 LHFPL5 Zornitza Stark Marked gene: LHFPL5 as ready
Mendeliome v0.4679 GYS1 Zornitza Stark Marked gene: GYS1 as ready
Mendeliome v0.4676 PIGT Zornitza Stark Marked gene: PIGT as ready
Mendeliome v0.4672 ALG13 Zornitza Stark Marked gene: ALG13 as ready
Mendeliome v0.4669 BLOC1S5 Zornitza Stark Marked gene: BLOC1S5 as ready
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
Mendeliome v0.4667 FOXL2 Zornitza Stark Marked gene: FOXL2 as ready
Mendeliome v0.4667 FOXL2 Zornitza Stark Phenotypes for gene: FOXL2 were changed from to Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100)
Mendeliome v0.4664 FOXL2 Ain Roesley changed review comment from: PMID: 31077882; 19x probands reported, AD.

PMID: 18642388;
BPES type I : Mutations predicted to result in proteins with truncation before the poly-Ala tract
BPES type II: poly-Ala expansions (WT poly-Ala is between aa 221-234)
Exceptions: Truncated proteins with complete forkhead and poly-Ala domains, can be either Type I and II

NOTE: only 1 family reported for AR (PMID: 17089161); to: PMID: 31077882; >100 probands reported, AD.

PMID: 18642388;
BPES type I : Mutations predicted to result in proteins with truncation before the poly-Ala tract
BPES type II: poly-Ala expansions (WT poly-Ala is between aa 221-234)
Exceptions: Truncated proteins with complete forkhead and poly-Ala domains, can be either Type I and II

NOTE: only 1 family reported for AR (PMID: 17089161)
Mendeliome v0.4664 FOXL2 Ain Roesley reviewed gene: FOXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31077882, 18642388, 17089161; Phenotypes: Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4664 ILDR1 Zornitza Stark Marked gene: ILDR1 as ready
Mendeliome v0.4661 HOXA2 Zornitza Stark Marked gene: HOXA2 as ready
Mendeliome v0.4661 HOXA2 Zornitza Stark Phenotypes for gene: HOXA2 were changed from to Microtia with or without hearing impairment, MIM# 612290
Mendeliome v0.4658 HOXA2 Zornitza Stark reviewed gene: HOXA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18394579, 23775976, 27503514, 32649979, 31567444; Phenotypes: Microtia with or without hearing impairment, MIM# 612290; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4658 GRXCR1 Zornitza Stark Marked gene: GRXCR1 as ready
Mendeliome v0.4655 GPSM2 Zornitza Stark Marked gene: GPSM2 as ready
Mendeliome v0.4652 GIPC3 Zornitza Stark Marked gene: GIPC3 as ready
Mendeliome v0.4647 COCH Zornitza Stark changed review comment from: Mono-allelic variants: Over 50 affected individuals from more than 10 families reported, mouse model. Dominant negative effect postulated.

Bi-allelic variants: three families reported with bi-allelic variants in this gene and deafness. All variants are LOF, some functional data. PMIDs 29449721, 32939038, 32562050.; to: Mono-allelic variants: Over 50 affected individuals from more than 10 families reported, mouse model. Dominant negative effect postulated.

Bi-allelic variants: three families reported with bi-allelic variants in this gene and deafness. All variants are LOF, some functional data. PMIDs 29449721, 32939038, 32562050.
Mendeliome v0.4647 COCH Zornitza Stark changed review comment from: Over 50 affected individuals from more than 10 families reported, mouse model. Single family with two siblings reported with bi-allelic variants in this gene and deafness (homozygous LOF) in PMID 29449721, evidence for bi-allelic disease is limited.; to: Mono-allelic variants: Over 50 affected individuals from more than 10 families reported, mouse model. Dominant negative effect postulated.

Bi-allelic variants: three families reported with bi-allelic variants in this gene and deafness. All variants are LOF, some functional data. PMIDs 29449721, 32939038, 32562050.
Mendeliome v0.4644 COQ5 Zornitza Stark Phenotypes for gene: COQ5 were changed from Cerebellar ataxia; encephalopathy; generalized tonic-clonic seizures; intellectual disability to Coenzyme Q10 deficiency, primary 9, MIM#619028; Cerebellar ataxia; encephalopathy; generalized tonic-clonic seizures; intellectual disability
Mendeliome v0.4643 COQ5 Zornitza Stark edited their review of gene: COQ5: Changed phenotypes: Coenzyme Q10 deficiency, primary 9, MIM#619028, Cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, intellectual disability
Mendeliome v0.4643 GATA3 Zornitza Stark Marked gene: GATA3 as ready
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 v0.4639 FGF3 Zornitza Stark reviewed gene: FGF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21480479, 21306635, 18435799, 17236138, 21306635, 18701883, 8223243, 26995070, 29902227, 30504125; Phenotypes: Deafness, congenital with inner ear agenesis, microtia, and microdontia, MIM# 610706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4639 EYA4 Zornitza Stark Phenotypes for gene: EYA4 were changed from to Deafness, autosomal dominant 10, MIM# 601316; Cardiomyopathy, dilated, 1J, MIM# 605362
Mendeliome v0.4636 EYA4 Zornitza Stark reviewed gene: EYA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11159937, ​17568404, 25681523, 25963406, 25242383, 26331839, 18219393, 27545760, 15735644, 10769282, 30155266; Phenotypes: Deafness, autosomal dominant 10, MIM# 601316, Cardiomyopathy, dilated, 1J, MIM# 605362; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4636 ESPN Zornitza Stark Marked gene: ESPN as ready
Mendeliome v0.4636 ESPN Zornitza Stark Phenotypes for gene: ESPN were changed from to Deafness, autosomal recessive 36, MIM# 609006; Deafness, neurosensory, without vestibular involvement, autosomal dominant, MIM# 609006
Mendeliome v0.4633 ESPN Zornitza Stark reviewed gene: ESPN: Rating: GREEN; Mode of pathogenicity: None; Publications: 15286153, 18973245, 26445815, 28281779, 10975527, 15930085; Phenotypes: Deafness, autosomal recessive 36, MIM# 609006, Deafness, neurosensory, without vestibular involvement, autosomal dominant, MIM# 609006; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4633 DFNB59 Zornitza Stark Marked gene: DFNB59 as ready
Mendeliome v0.4630 DFNA5 Zornitza Stark Marked gene: DFNA5 as ready
Mendeliome v0.4627 RIC3 Bryony Thompson Marked gene: RIC3 as ready
Mendeliome v0.4626 RIC3 Bryony Thompson reviewed gene: RIC3: Rating: RED; Mode of pathogenicity: None; Publications: 27055476, 28153381, 28606768, 32794657; Phenotypes: Parkinson disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4624 MRPS25 Zornitza Stark Phenotypes for gene: MRPS25 were changed from Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum to Combined oxidative phosphorylation deficiency 50, MIM# 619025; Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum
Mendeliome v0.4623 MRPS25 Zornitza Stark edited their review of gene: MRPS25: Changed phenotypes: Combined oxidative phosphorylation deficiency 50, MIM# 619025, Dyskinetic cerebral palsy, Mitochondrial myopathy, Partial agenesis of the corpus callosum
Mendeliome v0.4623 COL4A5 Zornitza Stark Marked gene: COL4A5 as ready
Mendeliome v0.4621 COCH Zornitza Stark Marked gene: COCH as ready
Mendeliome v0.4618 CLRN1 Zornitza Stark Marked gene: CLRN1 as ready
Mendeliome v0.4615 CLPP Zornitza Stark Marked gene: CLPP as ready
Mendeliome v0.4612 CLDN14 Zornitza Stark Marked gene: CLDN14 as ready
Mendeliome v0.4609 CIB2 Zornitza Stark Marked gene: CIB2 as ready
Mendeliome v0.4606 GCM2 Zornitza Stark Marked gene: GCM2 as ready
Mendeliome v0.4606 GCM2 Zornitza Stark Phenotypes for gene: GCM2 were changed from to Hyperparathyroidism 4, OMIM #617343
Mendeliome v0.4602 GCM2 Zornitza Stark reviewed gene: GCM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27745835; Phenotypes: Hyperparathyroidism 4, OMIM #617343; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4602 SECISBP2 Zornitza Stark Marked gene: SECISBP2 as ready
Mendeliome v0.4599 UBA1 Zornitza Stark Marked gene: UBA1 as ready
Mendeliome v0.4599 UBA1 Zornitza Stark Phenotypes for gene: UBA1 were changed from to Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830
Mendeliome v0.4596 UBA1 Zornitza Stark reviewed gene: UBA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18179898, 32181232, 31932168, 29034082, 27699224, 26028276, 23518311; Phenotypes: Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.4596 TRIP4 Zornitza Stark Marked gene: TRIP4 as ready
Mendeliome v0.4596 TRIP4 Zornitza Stark Phenotypes for gene: TRIP4 were changed from to Spinal muscular atrophy with congenital bone fractures 1, MIM# 616866; Muscular dystrophy, congenital, Davignon-Chauveau type 617066
Mendeliome v0.4593 TRIP4 Zornitza Stark reviewed gene: TRIP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26924529, 31794073; Phenotypes: Spinal muscular atrophy with congenital bone fractures 1, MIM# 616866, Muscular dystrophy, congenital, Davignon-Chauveau type 617066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4593 EXOSC9 Zornitza Stark Marked gene: EXOSC9 as ready
Mendeliome v0.4593 EXOSC9 Zornitza Stark Phenotypes for gene: EXOSC9 were changed from to Pontocerebellar hypoplasia, type 1D, MIM# 618065
Mendeliome v0.4590 EXOSC9 Zornitza Stark reviewed gene: EXOSC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30690203, 29727687; Phenotypes: Pontocerebellar hypoplasia, type 1D, MIM# 618065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4590 SLC7A14 Zornitza Stark Marked gene: SLC7A14 as ready
Mendeliome v0.4586 ATP6V1B1 Zornitza Stark Marked gene: ATP6V1B1 as ready
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 v0.4583 C1orf194 Zornitza Stark Phenotypes for gene: C1orf194 were changed from Charcot-Marie-Tooth to Charcot-Marie-Tooth disease, intermediate or demyelinating
Mendeliome v0.4581 ALB Zornitza Stark Marked gene: ALB as ready
Mendeliome v0.4578 TREM2 Zornitza Stark Marked gene: TREM2 as ready
Mendeliome v0.4575 SPG21 Zornitza Stark Marked gene: SPG21 as ready
Mendeliome v0.4572 LMX1A Zornitza Stark Marked gene: LMX1A as ready
Mendeliome v0.4572 LMX1A Zornitza Stark Phenotypes for gene: LMX1A were changed from to Deafness, autosomal dominant 7 MIM#601412; non-syndromic hearing loss
Mendeliome v0.4569 LMX1A Zornitza Stark reviewed gene: LMX1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29754270, 32840933, 29971487; Phenotypes: Deafness, autosomal dominant 7 MIM#601412, non-syndromic hearing loss; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4569 RPS20 Bryony Thompson Marked gene: RPS20 as ready
Mendeliome v0.4568 RPS20 Bryony Thompson gene: RPS20 was added
gene: RPS20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS20 were set to 32790018
Phenotypes for gene: RPS20 were set to Diamond Blackfan anaemia
Mode of pathogenicity for gene: RPS20 was set to Other
Review for gene: RPS20 was set to AMBER
Added comment: Two unrelated cases where a de novo variant involving Ile84 (Ile84Ser and Ile84Asn), and reduce the RPS20 protein level in patient cells. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. Loss of function may not be the mechanism of disease, because loss of function variants appear to be exclusively associated with familial colorectal cancer without the DBA phenotype.
Sources: Literature
Mendeliome v0.4566 ABHD12 Zornitza Stark reviewed gene: ABHD12: Rating: GREEN; Mode of pathogenicity: None; Publications: 20797687, 24697911; Phenotypes: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, MIM# 612674; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4566 SPAST Zornitza Stark Marked gene: SPAST as ready
Mendeliome v0.4566 SPAST Zornitza Stark Phenotypes for gene: SPAST were changed from to Spastic paraplegia 4, autosomal dominant (MIM#182601), AD
Mendeliome v0.4563 TRRAP Zornitza Stark Marked gene: TRRAP as ready
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 UPF3B Zornitza Stark Marked gene: UPF3B as ready
Mendeliome v0.4560 UPF3B Zornitza Stark Phenotypes for gene: UPF3B were changed from to Mental retardation, X-linked, syndromic 14, MIM# 300676
Mendeliome v0.4557 UPF3B Zornitza Stark reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 19377476, 17704778, 31737052, 28948974, 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, MIM# 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.4557 C1orf194 Arina Puzriakova changed review comment from: PMID: 32592472 (2020) - Another knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; to: PMID: 32592472 (2020) - An additional knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.
Mendeliome v0.4557 C1orf194 Arina Puzriakova reviewed gene: C1orf194: Rating: ; Mode of pathogenicity: None; Publications: 32592472; Phenotypes: Charcot-Marie-Tooth; Mode of inheritance: None
Mendeliome v0.4557 XPR1 Zornitza Stark Marked gene: XPR1 as ready
Mendeliome v0.4554 VPS13C Zornitza Stark Marked gene: VPS13C as ready
Mendeliome v0.4554 VPS13C Zornitza Stark Phenotypes for gene: VPS13C were changed from to Early-onset Parkinson disease-23, MIM# 616840
Mendeliome v0.4551 VPS13C Zornitza Stark reviewed gene: VPS13C: Rating: GREEN; Mode of pathogenicity: None; Publications: 26942284 30452786 28862745; Phenotypes: Early-onset Parkinson disease-23, MIM# 616840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4551 KIAA1161 Zornitza Stark Phenotypes for gene: KIAA1161 were changed from Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome to Basal ganglia calcification, idiopathic, 7, MIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome
Mendeliome v0.4548 KIAA1161 Zornitza Stark edited their review of gene: KIAA1161: Added comment: In a cohort study comprising 435 individuals with primary brain calcification, 38 individuals identified with mono-allelic variants in this gene, in addition to 14 with bi-allelic variants. Clinical and imaging penetrance of individuals with bi-allelic variants were 100%, whereas among individuals with heterozygous variants, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG variants, individuals with heterozygous variants had brain calcifications with much lower calcification scores (P < 2e-16). HGNC approved name is MYORG.; Changed publications: 30656188, 30649222, 30460687, 29910000, 31951047; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4548 ALG14 Zornitza Stark Marked gene: ALG14 as ready
Mendeliome v0.4548 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Disorder of N-glycosylation
Mendeliome v0.4545 ALG14 Zornitza Stark reviewed gene: ALG14: Rating: GREEN; Mode of pathogenicity: None; Publications: 30221345, 23404334, 28733338; Phenotypes: Myasthenic syndrome, congenital, 15, without tubular aggregates 616227, Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031, Disorder of N-glycosylation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4545 TCF12 Zornitza Stark Marked gene: TCF12 as ready
Mendeliome v0.4542 RP1L1 Zornitza Stark Marked gene: RP1L1 as ready
Mendeliome v0.4542 RP1L1 Zornitza Stark Phenotypes for gene: RP1L1 were changed from to Occult macular dystrophy (MIM#613587) AD; Retinitis pigmentosa 88 (MIM#618826) AR
Mendeliome v0.4539 CYP11B2 Zornitza Stark Marked gene: CYP11B2 as ready
Mendeliome v0.4536 HPS5 Zornitza Stark Marked gene: HPS5 as ready
Mendeliome v0.4533 IBA57 Zornitza Stark Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3, MIM#615330 to Multiple mitochondrial dysfunctions syndrome 3, MIM#615330; Spastic paraplegia 74, autosomal recessive MIM#616451
Mendeliome v0.4531 IBA57 Zornitza Stark changed review comment from: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.; to: MMDS3: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.

SPG74: Three families with spastic paraparesis as a feature of the condition.
Mendeliome v0.4531 IBA57 Zornitza Stark edited their review of gene: IBA57: Changed phenotypes: Multiple mitochondrial dysfunctions syndrome 3, MIM#615330, Spastic paraplegia 74, autosomal recessive MIM#616451
Mendeliome v0.4531 IBA57 Zornitza Stark Marked gene: IBA57 as ready
Mendeliome v0.4528 RP1L1 Teresa Zhao reviewed gene: RP1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23281133, 30025130, 32360662; Phenotypes: Occult macular dystrophy (MIM#613587) AD, Retinitis pigmentosa 88 (MIM#618826) AR; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4526 NSUN3 Zornitza Stark edited their review of gene: NSUN3: Added comment: Second family reported with early-onset mitochondrial encephalomyopathy and seizures.; Changed publications: 27356879, 32488845; Changed phenotypes: Combined oxidative phosphorylation deficiency 48, MIM# 619012
Mendeliome v0.4525 LIFR Zornitza Stark edited their review of gene: LIFR: Added comment: Bi-allelic variants: At least 28 unique variants (nonsense, frameshift, splicing, missense, gross deletions) have been reported in individuals with Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, 22 of which are predicted to cause LOF, suggesting homozygous LOF is the mechanism of disease for this gene. Variants in this gene have been reported in at least 22 probands in four publications.

Mono-allelic variants: associated with CAKUT in 4 individuals, mouse model recapitulates phenotype.; Changed rating: GREEN; Changed publications: 14740318, 20447141, 24988918, 29620724, 28334964; Changed phenotypes: Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, MIM# 601559, CAKUT; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4525 PAX7 Zornitza Stark Marked gene: PAX7 as ready
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.


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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
Mendeliome v0.4520 VPS37A Zornitza Stark Marked gene: VPS37A as ready
Mendeliome v0.4520 VPS37A Zornitza Stark Phenotypes for gene: VPS37A were changed from to Spastic paraplegia 53, autosomal recessive, MIM# 614898
Mendeliome v0.4516 VPS37A Zornitza Stark reviewed gene: VPS37A: Rating: AMBER; Mode of pathogenicity: None; Publications: 22717650; Phenotypes: Spastic paraplegia 53, autosomal recessive, MIM# 614898; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4516 TECPR2 Zornitza Stark Marked gene: TECPR2 as ready
Mendeliome v0.4516 TECPR2 Zornitza Stark Phenotypes for gene: TECPR2 were changed from to Spastic paraplegia 49, autosomal recessive, MIM# 615031; Autonomic-sensory neuropathy
Mendeliome v0.4513 TECPR2 Zornitza Stark reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176824, 26542466; Phenotypes: Spastic paraplegia 49, autosomal recessive, MIM# 615031, Autonomic-sensory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4513 SMOC2 Zornitza Stark Marked gene: SMOC2 as ready
Mendeliome v0.4510 MAG Zornitza Stark Marked gene: MAG as ready
Mendeliome v0.4510 MAG Zornitza Stark Phenotypes for gene: MAG were changed from to Spastic paraplegia 75, autosomal recessive, MIM# 616680