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Mendeliome v1.1816 ATXN7L3 Chirag Patel gene: ATXN7L3 was added
gene: ATXN7L3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATXN7L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATXN7L3 were set to PMID: 38753057
Phenotypes for gene: ATXN7L3 were set to Neurodevelopmental disorder, MONDO_0100500
Review for gene: ATXN7L3 was set to GREEN
gene: ATXN7L3 was marked as current diagnostic
Added comment: This study reports 9 unrelated individuals with de novo heterozygous variants in ATXN7L3 identified through WES testing and GeneMatcher. Core clinical features included: global motor and language developmental delay, hypotonia, and dysmorphic features (hypertelorism, epicanthal folds, blepharoptosis, small nose, small mouth, and low-set posteriorly rotated ears). Variable features included: feeding difficulties, seizures, mild periventricular leukomalacia, and structural cardiac abnormalities.

A recurrent nonsense variant [p.(Arg114Ter)] was found in 5/9 individuals. The other variants were 1 frameshift [p.(Ser112LysfsTer12)] and 3 missense variants [p.(Ile71Thr), p.(Ser92Arg), and p.(Leu106Pro)]. They investigated the effects of the recurrent nonsense variant [p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired (as indicated by an increase in histone H2Bub1 levels). This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality.

Pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51).
Sources: Literature
Mendeliome v1.1787 AGTR2 Zornitza Stark changed review comment from: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review; to: DISPUTED by ClinGen:

Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review
Mendeliome v1.1787 AGTR2 Zornitza Stark gene: AGTR2 was added
gene: AGTR2 was added to Mendeliome. Sources: Expert Review
disputed tags were added to gene: AGTR2.
Mode of inheritance for gene: AGTR2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: AGTR2 were set to X-linked complex neurodevelopmental disorder MONDO:0100148
Review for gene: AGTR2 was set to RED
Added comment: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review
Mendeliome v1.1746 SHH Ain Roesley Phenotypes for gene: SHH were changed from Holoprosencephaly 3, MIM#142945; Microphthalmia with coloboma 5, MIM#611638; Single median maxillary central incisor, MIM#147250 to Holoprosencephaly 3, MIM#142945; Microphthalmia with coloboma 5, MIM#611638; Single median maxillary central incisor, MIM#147250; Hypertelorism, ACC, intellectual disability
Mendeliome v1.1744 SHH Ain Roesley reviewed gene: SHH: Rating: GREEN; Mode of pathogenicity: None; Publications: 38562108, 29321670, 32703609; Phenotypes: Hypertelorism, ACC, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1283 MCM9 Natalie Tan changed review comment from: Emerging association in individuals with biallelic variants of a combined phenotype of primary ovarian insufficiency and a Lynch-like syndrome/early-onset colorectal cancer (PMID: 26806154, 34556653). Monoallelic carriers have also been reported with a Lynch-like syndrome (32841224). Association of primary ovarian insufficiency with other malignancies is less clear (32613604, 34556653). See PMID 37378315 for review of literature to April 2023.; to: Emerging association in individuals with biallelic variants of a combined phenotype of primary ovarian insufficiency and a Lynch-like syndrome/early-onset colorectal cancer (PMID: 26806154, 34556653). Monoallelic carriers have also been reported with a Lynch-like syndrome (32841224). Association of primary ovarian insufficiency with other malignancies is less clear (32613604, 34556653). See PMID 37378315 for review of literature to April 2023.
Mendeliome v1.1283 MCM9 Natalie Tan reviewed gene: MCM9: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26806154, 34556653, 32841224, 32613604, 37378315); Phenotypes: Primary ovarian insufficiency, Lynch-like syndrome/colorectal cancer; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.962 RAB34 Elena Savva Phenotypes for gene: RAB34 were changed from Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies to Multiple congenital anomalies, (MONDO:0019042), RAB34-related
Mendeliome v1.956 RAB34 Sarah Pantaleo gene: RAB34 was added
gene: RAB34 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB34 were set to PMID: 37384395
Phenotypes for gene: RAB34 were set to Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies
Penetrance for gene: RAB34 were set to Complete
Review for gene: RAB34 was set to GREEN
Added comment: Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogenous disorders characterised by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in >20 genes encoding ciliary proteins have been found to cause OFDS.

Identified by WES biallelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families (aided by GeneMatcher).

Affected individuals presented a novel form of OFDS accompanied by cardiac, cerebral, skeletal (eg. Shortening of long bones), and anorectal defects.

RAB34 encodes a member of the Lab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Protein products of pathogenic variants clustered near the RAB34 C-terminus exhibit a strong loss of function.

Onset is prenatal (multiple developmental defects including short femur, polydactyly, heart malformations, kidney malformations, brain malformations), resulting in medical termination for three probands.

In the fourth, the only one alive at birth, proband born at 39+5 weeks, normal growth parameters after pregnancy with polyhydramnios, corpus callosum agenesis and polydactyly. Respiratory distress at birth.

All four probands presented typical features of ciliopathy disorders, overlapping with oral, facial and digital abnormalities.

All with homozygous missense variants. All absent in gnomAD (in homozygous state). Sanger sequencing confirmed mode of inheritance.
Sources: Literature
Mendeliome v1.807 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Congenital heart disease; Pituitary anomalies; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; intellectual disability, MONDO:0001071 to Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.806 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303, Nystagmus 8, congenital, autosomal recessive, MIM# 257400, Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.629 HTR2C Zornitza Stark gene: HTR2C was added
gene: HTR2C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HTR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HTR2C were set to 36536256
Phenotypes for gene: HTR2C were set to Obesity disorder, MONDO:0011122, HTR2C-related
Review for gene: HTR2C was set to GREEN
Added comment: Exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Obesity was severe, childhood-onset. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Sources: Literature
Mendeliome v1.477 CLEC3B Chirag Patel gene: CLEC3B was added
gene: CLEC3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLEC3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLEC3B were set to PMID: 35331648
Phenotypes for gene: CLEC3B were set to Macular dystrophy, retinal, 4, OMIM #619977
Review for gene: CLEC3B was set to GREEN
Added comment: 12 affected individuals from 5 multigenerational Japanese families in a small village in Miyazaki diagnosed with autosomal dominant maculoretinopathy. WES identified a pathogenic variant (p.Ala180Asp) in CLEC3B, which encodes tetranectin, a plasminogen kringle-4 binding protein. Variant cosegregated with the ocular phenotype.

Mice that received subretinal injections with CLEC3B variant displayed multiple subretinal hyperreflective deposits, reduced retinal thickness, and decreased electroretinographic responses. The optokinetic tracking response indicated that spatial frequency was significantly lower (P < .05), implying impaired visual function in the mice.
Sources: Literature
Mendeliome v1.459 RPS6KB1 Arina Puzriakova gene: RPS6KB1 was added
gene: RPS6KB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS6KB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPS6KB1 were set to 34916228
Phenotypes for gene: RPS6KB1 were set to Hypertrophic cardiomyopathy
Review for gene: RPS6KB1 was set to GREEN
Added comment: Jain et al. 2022 (PMID: 34916228) reported on two unrelated HCM families with the same heterozygous missense RPS6KB1 variant (p.G47W), and subsequently three further unrelated probands with HCM harbouring distinct heterozygous variants (p.Q49K, p.Y62H, respectively). Variants segregated with disease, were predicted pathogenic by silico analyses and were ultrarare or absent in population databases. Functional studies in the HL-1 (mouse cardiomyocytes) cells showed that the patient-specific RPS6KB1 mutant significantly increased cell size and activated rpS6 and ERK1/2 signalling cascades. The relationship between RPS6KB1 and cardiac hypertrophy has also been explored in feline and mice models (PMID: 15226426; 17976640)
Sources: Literature
Mendeliome v1.342 ATP7A Zornitza Stark changed review comment from: ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein.; to: ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein.

Treatment for Menkes disease: subcutaneous injections of copper histidine or copper chloride

ClinGen has assessed as moderate evidence for actionability.

Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.
Mendeliome v1.338 AQP2 Zornitza Stark changed review comment from: Dominant disease is caused by variants exerting a dominant negative effect, whereas recessive disease is caused by bi-allelic loss of function variants.; to: Dominant disease is caused by variants exerting a dominant negative effect, whereas recessive disease is caused by bi-allelic loss of function variants.

Onset in infancy. Causes severe dehydration, can be life-threatening.

Treatment: hydration, low-salt, low-protein diet, thiazide diuretics, amiloride, indomethacin.

Clinical trials.
Mendeliome v1.147 CLDN5 Zornitza Stark gene: CLDN5 was added
gene: CLDN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN5 were set to 35714222
Phenotypes for gene: CLDN5 were set to alternating hemiplegia, MONDO:0016210, CLDN5-related
Mode of pathogenicity for gene: CLDN5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: CLDN5 was set to AMBER
Added comment: PMID: 35714222; Hashimoto, Y. et al. (2022): Two unrelated cases (early-onset) with alternating hemiplegia with microcephaly were shown to have the same de novo variant, NM_001363066.2:c.178G>A, p.(Gly60Arg).

One with Jewish / Tunisian ancestry: Onset was at 8 months, three episodes of febrile tonic-clonic 1 seizures of the four limbs, with eye rolling, loss of consciousness, transient left and right post-2 ictal hemiparesis and vomiting. The other with Asian / European ancestry: Onset was at 30 months with three iterative episodes of febrile and non-febrile hemiplegia and loss of 18 consciousness. The recurrent episodes alternatively involved the left-and 19 right-hand side, then generalised and were followed by post ictal hemiparesis.

CT scans of both showed brain calcifications and aberrant blood flow patterns. Transfected cell lines with this variant, c178G>A, showed higher chloride ion permeability and lower sodium ion permeability when compared to wildtype.
Sources: Literature
Mendeliome v0.13702 HOXA1 Zornitza Stark Phenotypes for gene: HOXA1 were changed from to Athabaskan brainstem dysgenesis syndrome MIM#601536; Bosley-Salih-Alorainy syndrome MIM#601536
Mendeliome v0.13699 HOXA1 Zornitza Stark reviewed gene: HOXA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16155570, 18412118, 32864817; Phenotypes: Athabaskan brainstem dysgenesis syndrome MIM#601536, Bosley-Salih-Alorainy syndrome MIM#601536; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13119 GLRA2 Zornitza Stark gene: GLRA2 was added
gene: GLRA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GLRA2 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: GLRA2 were set to 26370147; 20479760; 35294868
Phenotypes for gene: GLRA2 were set to Intellectual developmental disorder, X-linked, syndromic, Pilorge type, MIM# 301076
Review for gene: GLRA2 was set to GREEN
Added comment: More than 10 unrelated families reported. Both males and females affected, though some mothers are asymptomatic or mild. Zebrafish model.
Sources: Expert list
Mendeliome v0.12634 SPECC1L Zornitza Stark Phenotypes for gene: SPECC1L were changed from to Hypertelorism, Teebi type, MIM# 145420; Opitz GBBB syndrome, type II, MIM#145410
Mendeliome v0.12631 SPECC1L Zornitza Stark edited their review of gene: SPECC1L: Added comment: Well established gene-disease associations with Teebi and Opitz GBBB.

Single individual reported with oblique facial cleft, some supportive functional data.; Changed publications: 25412741, 26111080, 21703590; Changed phenotypes: Hypertelorism, Teebi type, MIM# 145420, Opitz GBBB syndrome, type II, MIM#145410
Mendeliome v0.12631 SPECC1L Zornitza Stark edited their review of gene: SPECC1L: Changed phenotypes: Hypertelorism, Teebi type, MIM# 145420, Opitz GBBB syndrome, type II, MIM#145410, Craniosynostosis
Mendeliome v0.12631 SPECC1L Zornitza Stark reviewed gene: SPECC1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 25412741; Phenotypes: Hypertelorism, Teebi type, MIM# 145420, Opitz GBBB syndrome, type II, MIM#145410; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12598 PAX6 Zornitza Stark Phenotypes for gene: PAX6 were changed from to Coloboma of optic nerve - MIM# 120430; Coloboma, ocular - MIM#120200; Morning glory disc anomaly - MIM#120430; Aniridia - MIM#106210; Anterior segment dysgenesis 5, multiple subtypes - MIM#604229; Cataract with late-onset corneal dystrophy - MIM#106210; Foveal hypoplasia 1- MIM#136520; Keratitis - MIM#148190; Optic nerve hypoplasia - MIM#165550
Mendeliome v0.12595 PAX2 Zornitza Stark Phenotypes for gene: PAX2 were changed from to Papillorenal syndrome, MIM# 120330; Renal coloboma syndrome, MONDO:0007352; Glomerulosclerosis, focal segmental, 7 - MIM#616002
Mendeliome v0.12573 PAX6 Krithika Murali reviewed gene: PAX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31700164, 30986449, 29930474, 22171686; Phenotypes: ?Coloboma of optic nerve - MIM# 120430, ?Coloboma, ocular - MIM#120200, ?Morning glory disc anomaly - MIM#120430, Aniridia - MIM#106210, Anterior segment dysgenesis 5, multiple subtypes - MIM#604229, Cataract with late-onset corneal dystrophy - MIM#106210, Foveal hypoplasia 1- MIM#136520, Keratitis - MIM#148190, Optic nerve hypoplasia - MIM#165550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12573 PAX2 Krithika Murali reviewed gene: PAX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21654726, 24676634, 31060108, 32203253; Phenotypes: Papillorenal syndrome, MIM# 120330, Renal coloboma syndrome, MONDO:0007352, Glomerulosclerosis, focal segmental, 7 - MIM#616002; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12224 OPN1SW Krithika Murali reviewed gene: OPN1SW: Rating: GREEN; Mode of pathogenicity: None; Publications: 1531728, 2937147, 22065927, 32400513, 31944634; Phenotypes: Colorblindness, tritan - MIM#190900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12224 OPN1MW Krithika Murali reviewed gene: OPN1MW: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168334, 32860923; Phenotypes: Blue cone monochromacy - MIM#303700, Colorblindness, deutan - MIM#303800; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.12224 OPN1LW Krithika Murali reviewed gene: OPN1LW: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168334, 32860923; Phenotypes: Blue cone monochromacy - MIM#303700, Colorblindness, protan - MIM#303900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.12082 CA12 Ain Roesley Phenotypes for gene: CA12 were changed from to Hyperchlorhidrosis, isolated MIM#143860
Mendeliome v0.12080 CA12 Ain Roesley reviewed gene: CA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21035102, 21184099, 26911677; Phenotypes: Hyperchlorhidrosis, isolated MIM#143860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12059 LEMD3 Alison Yeung Phenotypes for gene: LEMD3 were changed from to Buschke-Ollendorff syndrome MIM#166700; Osteopoikilosis with or without melorheostosis MIM#166700
Mendeliome v0.11639 SMAD7 Zornitza Stark Phenotypes for gene: SMAD7 were changed from to {Colorectal cancer, susceptibility to, 3} 612229
Mendeliome v0.11636 SMAD7 Zornitza Stark edited their review of gene: SMAD7: Changed phenotypes: {Colorectal cancer, susceptibility to, 3} 612229
Mendeliome v0.11286 KIF5A Zornitza Stark edited their review of gene: KIF5A: Added comment: Neonatal intractable myoclonus is a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants have intermittent apnea, abnormal eye movements, pallor of the optic nerve, and lack of developmental progress. Brain imaging shows a progressive leukoencephalopathy. At least 3 unrelated individuals with de novo LoF variants.

SPG10/CMT: variants are generally in the motor domain.; Changed publications: 30057544, 29892902, 28902413, 26403765, 25695920, 25008398, 27463701, 27414745; Changed phenotypes: Neuropathy, Spastic paraplegia 10, autosomal dominant, MIM# 604187, Myoclonus, intractable, neonatal, MIM# 617235
Mendeliome v0.10875 CCND1 Zornitza Stark Phenotypes for gene: CCND1 were changed from to {Colorectal cancer, susceptibility to} MIM#114500; {Multiple myeloma, susceptibility to} MIM#254500; {von Hippel-Lindau syndrome, modifier of} MIM#193300
Mendeliome v0.10823 CCND1 Paul De Fazio reviewed gene: CCND1: Rating: RED; Mode of pathogenicity: None; Publications: 12097293, 23502783, 21131975, 14657069, 23540573, 20633772; Phenotypes: {Colorectal cancer, susceptibility to} MIM#114500, {Multiple myeloma, susceptibility to} MIM#254500, {von Hippel-Lindau syndrome, modifier of} MIM#193300; Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.10812 LEMD3 Ain Roesley reviewed gene: LEMD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34098227, 33598273, 32519343, 32151766, 32151766; Phenotypes: Buschke-Ollendorff syndrome MIM#166700, Osteopoikilosis with or without melorheostosis MIM#166700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.10051 AXIN2 Zornitza Stark Phenotypes for gene: AXIN2 were changed from to Oligodontia-colorectal cancer syndrome, MIM# 608615
Mendeliome v0.10049 AXIN2 Zornitza Stark reviewed gene: AXIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15042511, 21626677, 21416598, 34637023; Phenotypes: Oligodontia-colorectal cancer syndrome, MIM# 608615; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9682 BMPER Zornitza Stark commented on gene: BMPER: Perinatal lethal skeletal dysplasia.

The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases.

At least 5 unrelated families reported.
Mendeliome v0.9012 RPS6KA3 Zornitza Stark Phenotypes for gene: RPS6KA3 were changed from to Coffin-Lowry syndrome MIM# 303600; Intellectual disability; short stature; delayed bone age; hearing deficit; hypotonia; tapering fingers; abnormal facies (hypertelorism, anteverted nares, prominent frontal region)
Mendeliome v0.9009 RPS6KA3 Zornitza Stark reviewed gene: RPS6KA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 6879200; Phenotypes: Coffin-Lowry syndrome MIM# 303600, Intellectual disability, short stature, delayed bone age, hearing deficit, hypotonia, tapering fingers, abnormal facies (hypertelorism, anteverted nares, prominent frontal region); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9003 ROR2 Zornitza Stark Phenotypes for gene: ROR2 were changed from to Robinow syndrome, autosomal recessive MIM# 268310; hypertelorism; short stature; mesomelic shortening of the limbs; hypoplastic genitalia; rib/vertebral anomalies; abnormal morphogenesis of the face; Brachydactyly, type B1 MIM# 113000; hypoplasia/aplasia of distal phalanges and nails (2-5)
Mendeliome v0.9000 ROR2 Zornitza Stark reviewed gene: ROR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10932186, 10932187, 10986040, 19461659; Phenotypes: Robinow syndrome, autosomal recessive MIM# 268310, hypertelorism, short stature, mesomelic shortening of the limbs, hypoplastic genitalia, rib/vertebral anomalies, abnormal morphogenesis of the face, Brachydactyly, type B1 MIM# 113000, hypoplasia/aplasia of distal phalanges and nails (2-5); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8848 TCN2 Zornitza Stark changed review comment from: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homologous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list; to: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homozygous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list
Mendeliome v0.8847 TCN2 Zornitza Stark changed review comment from: Well established gene-disease association.
Sources: Expert list; to: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homologous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list
Mendeliome v0.8657 ACAN Zornitza Stark edited their review of gene: ACAN: Added comment: Patients with SSOAD exhibit a broad phenotypic spectrum involving short stature associated with advanced bone maturation and early-onset osteoarthritis (OA), as well as mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disc disease and osteochondritis dissecans, which is characterized by separation of articular cartilage and subchondral bone from the articular surface. Phenotypes are highly variable even among patients within the same family, and there are no apparent genotype-phenotype correlations.

Well established gene-disease association, multiple families reported.

Note fewer families reported with bi-allelic variants in this gene and extreme short stature.; Changed publications: 24762113, 27870580, 19110214, 30124491, 28331218, 20137779; Changed phenotypes: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800, Spondyloepimetaphyseal dysplasia, aggrecan type 612813
Mendeliome v0.8601 CLCN3 Kristin Rigbye gene: CLCN3 was added
gene: CLCN3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to PMID: 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:
- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.
- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.
- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.
- Six have mood or behavioural disorders, particularly anxiety (3/6).
- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.

The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.

Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Mendeliome v0.8065 EP300 Elena Savva reviewed gene: EP300: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29460469, 24381114; Phenotypes: Rubinstein-Taybi syndrome 2 MIM#613684, Menke-Hennekam syndrome 2 MIM#618333, Colorectal cancer, somatic MIM#114500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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 v0.7772 SCNN1B Zornitza Stark Phenotypes for gene: SCNN1B were changed from to Liddle syndrome 1, MIM# 177200; Pseudohypoaldosteronism, type I, MIM# 264350; Bronchiectasis with or without elevated sweat chloride 1 (MIM#211400)
Mendeliome v0.7770 SCNN1B Zornitza Stark reviewed gene: SCNN1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Liddle syndrome 1, MIM# 177200, Pseudohypoaldosteronism, type I, MIM# 264350, Bronchiectasis with or without elevated sweat chloride 1 (MIM#211400); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v0.7078 CDH11 Zornitza Stark Phenotypes for gene: CDH11 were changed from to Elsahy-Waters syndrome, MIM# 211380; Teebi hypertelorism syndrome
Mendeliome v0.7075 CDH11 Zornitza Stark reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811546, 27431290, 28988429, 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome, MIM# 211380, Teebi hypertelorism syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v0.6445 GALNT12 Bryony Thompson reviewed gene: GALNT12: Rating: RED; Mode of pathogenicity: None; Publications: 19617566, 30523343, 29749045; Phenotypes: Colorectal cancer, susceptibility to, 1 MIM#608812; Mode of inheritance: Unknown
Mendeliome v0.6356 ITGB4 Zornitza Stark Phenotypes for gene: ITGB4 were changed from to Epidermolysis bullosa of hands and feet, MIM# 131800; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730
Mendeliome v0.6353 ITGB4 Zornitza Stark reviewed gene: ITGB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11328943, 9670011, 33225458, 30079450, 29380424, 29198538, 28557647; Phenotypes: Epidermolysis bullosa of hands and feet, MIM# 131800, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650, Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6340 ITGA6 Zornitza Stark Phenotypes for gene: ITGA6 were changed from to Epidermolysis bullosa, junctional, with pyloric stenosis, MIM# 226730
Mendeliome v0.6337 ITGA6 Zornitza Stark reviewed gene: ITGA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31502654, 27607025, 9158140; Phenotypes: Epidermolysis bullosa, junctional, with pyloric stenosis, MIM# 226730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v0.6094 LOR Zornitza Stark Marked gene: LOR as ready
Mendeliome v0.6094 LOR Zornitza Stark Gene: lor has been classified as Green List (High Evidence).
Mendeliome v0.6094 LOR Zornitza Stark Phenotypes for gene: LOR were changed from to Vohwinkel syndrome with ichthyosis, MIM# 604117
Mendeliome v0.6093 LOR Zornitza Stark Publications for gene: LOR were set to
Mendeliome v0.6092 LOR Zornitza Stark Mode of inheritance for gene: LOR was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6091 LOR Zornitza Stark reviewed gene: LOR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8673107, 9326398, 9326323, 25234742, 25142840; Phenotypes: Vohwinkel syndrome with ichthyosis, MIM# 604117; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v0.5950 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 v0.5449 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 v0.5400 POLE Zornitza Stark Phenotypes for gene: POLE were changed from to FILS syndrome, 615139; IMAGE-I syndrome, 618336; {Colorectal cancer, susceptibility to, 12}, 615083
Mendeliome v0.5393 POLE Elena Savva reviewed gene: POLE: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 30503519, 23230001; Phenotypes: FILS syndrome, 615139, IMAGE-I syndrome, 618336, {Colorectal cancer, susceptibility to, 12}, 615083; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v0.4520 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 v0.4500 RREB1 Zornitza Stark gene: RREB1 was added
gene: RREB1 was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: RREB1.
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RREB1 were set to 32938917
Phenotypes for gene: RREB1 were set to Noonan syndrome-like disorder
Review for gene: RREB1 was set to RED
Added comment: Single individual reported with Noonan syndrome-like features and a deletion encompassing RREB1. Overlapping deletions in publicly reported databases examined, and RREB1 postulated to be the key gene. Rreb1 hemizygous mice display orbital hypertelorism and age dependent cardiac hypertrophy. RREB1 recruits SIN3A and KDM1A to an RRE in target promoters in human and murine cells to control histone H3K4 methylation of MAPK pathway genes.

In summary, single well phenotyped individual with a CNV and experimental data to support gene-disease association.
Sources: Literature
Mendeliome v0.3656 FBXL7 Zornitza Stark Phenotypes for gene: FBXL7 were changed from Hennekam lymphangiectasia-lymphedema syndrome; lymphedema; protein‐losing enteropathy; dental anomalies; camptodactyly; microtia; small auditory canals; ductive hearing loss; middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae. to Hennekam lymphangiectasia-lymphedema syndrome
Mendeliome v0.3648 FBXL7 Hazel Phillimore changed review comment from: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature; to: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature
Mendeliome v0.3647 FBXL7 Hazel Phillimore gene: FBXL7 was added
gene: FBXL7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXL7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL7 were set to PMID: 31633297
Phenotypes for gene: FBXL7 were set to Hennekam lymphangiectasia-lymphedema syndrome; lymphedema; protein‐losing enteropathy; dental anomalies; camptodactyly; microtia; small auditory canals; ductive hearing loss; middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Review for gene: FBXL7 was set to AMBER
Added comment: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature
Mendeliome v0.3631 MAPK1 Zornitza Stark gene: MAPK1 was added
gene: MAPK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to 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
Review for gene: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).
Sources: Literature
Mendeliome v0.1292 PLEC Zornitza Stark Phenotypes for gene: PLEC were changed from to ?Epidermolysis bullosa simplex with nail dystrophy, MIM# 616487; Epidermolysis bullosa simplex with muscular dystrophy, MIM# 226670; Epidermolysis bullosa simplex with pyloric atresia, MIM# 612138; Epidermolysis bullosa simplex, Ogna type MIM#131950; Muscular dystrophy, limb-girdle, autosomal recessive 17, MIM# 613723
Mendeliome v0.1289 PLEC Elena Savva reviewed gene: PLEC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22144912; Phenotypes: ?Epidermolysis bullosa simplex with nail dystrophy, Epidermolysis bullosa simplex with muscular dystrophy, Epidermolysis bullosa simplex with pyloric atresia, Epidermolysis bullosa simplex, Ogna type, Muscular dystrophy, limb-girdle; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.273 GABRA5 Zornitza Stark gene: GABRA5 was added
gene: GABRA5 was added to Mendeliome_VCGS. Sources: Literature
Mode of inheritance for gene: GABRA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRA5 were set to 31056671; 29961870
Phenotypes for gene: GABRA5 were set to Epileptic encephalopathy, early infantile, 79; OMIM #618559
Review for gene: GABRA5 was set to GREEN
Added comment: 3 unrelated patients with de novo heterozygous missense mutations in GABRA5 gene. In vitro functional expression studies in HEK293 cells showed that the mutant subunit was expressed at the surface and incorporated into the channel, but the mutant channel was 10 times more sensitive to GABA compared to wildtype. This increased sensitization resulted in increased receptor desensitization to GABA, with a reduced maximal GABA-evoked current and impaired capacity to pass GABAergic chloride current.
Sources: Literature
Mendeliome v0.0 LOR Zornitza Stark gene: LOR was added
gene: LOR was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: LOR was set to Unknown