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| Mendeliome v1.2289 | PTPMT1 |
Bryony Thompson gene: PTPMT1 was added gene: PTPMT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPMT1 were set to 39279645; 37672386 Phenotypes for gene: PTPMT1 were set to inborn mitochondrial metabolism disorder MONDO:0004069 Review for gene: PTPMT1 was set to GREEN Added comment: 6 cases from 3 independent families with biallelic variants in PTPMT1 (a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis). All cases presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome including developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Supporting knockout zebrafish and mouse models. Sources: Literature |
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| Mendeliome v1.2265 | HYAL2 | Zornitza Stark Phenotypes for gene: HYAL2 were changed from Cleft lip and palate; cor triatriatum; congenital cardiac malformations to Muggenthaler-Chowdhury-Chioza syndrome, MIM# 621063 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2250 | EEFSEC |
Zornitza Stark gene: EEFSEC was added gene: EEFSEC was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EEFSEC were set to 39753114 Phenotypes for gene: EEFSEC were set to Neurodevelopmental disorder, MONDO:0700092, EEFSEC-related Review for gene: EEFSEC was set to GREEN Added comment: Nine individuals from 8 unrelated families reported with bi-allelic variants in this gene and progressive neurodevelopmental disorder manifesting with global developmental delay, progressive spasticity, ataxia, and seizures. Cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. In line with the clinical phenotype, an eEFSec-RNAi Drosophila model displays progressive impairment of motor function, which is reflected in the synaptic defects in this model organisms. Sources: Literature |
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| Mendeliome v1.2221 | PIGG | Ain Roesley Phenotypes for gene: PIGG were changed from Mental retardation, autosomal recessive 53, MIM#616917 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy MIM#616917 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2197 | RUNX1T1 |
Chirag Patel gene: RUNX1T1 was added gene: RUNX1T1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RUNX1T1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RUNX1T1 were set to PMID: 39568205, 19172993, 22644616, 31223340 Phenotypes for gene: RUNX1T1 were set to Neurodevelopmental disorder MONDO:0700092 Review for gene: RUNX1T1 was set to GREEN Added comment: RUNX1T1 encodes a transcription regulator for hematopoietic genes and is well-known for its involvement in hematologic malignancies. Germline RUNX1T1 variants may also play a role in human congenital neurodevelopmental disorders. PMID: 39568205 3 unrelated individuals with developmental delay, learning disability, ASD, ADHD, and dysmorphism (1 x heart defects). Trio WES identified de novo variants in RUNX1T1 gene (1 x nonsense variant in 5' region [p.Gln36Ter], 2 x missense variants in C-terminus [p.Gly412Arg and p.His521Tyr]). PMID: 19172993 1 individual with mild-moderate ID and congenital heart disease, and chromosome t(5;8)(q32;q21.3) translocation. Molecular characterization revealed that one of the break points was within the RUNX1T1 gene. Analysis of RUNX1T1 expression in human embryonic and fetal tissues suggests a role of RUNX1T1 in brain and heart development. PMID: 22644616 1 individual with mild ID and dysmorphism, and de novo deletion exons 3-7 in RUNX1T1. PMID: 31223340 1 individual with ID, anaemia, atrial septal defect, dysmorphism, and seizures. Found to have a 2.1 Mb deletion at 8q21.3q22.1 involving entire RUNX1T1 gene (and 2 adjacent genes - SLC26A7 and TRIQK), and a benign familial 4.3 Mb duplication at 1p22.1p21.3 (present in unaffected healthy brother). Sources: Literature |
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| Mendeliome v1.2150 | GARS | Zornitza Stark Phenotypes for gene: GARS were changed from 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 to Mitochondrial disease (MONDO:0044970), GARS1-related; 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 v1.2149 | GARS | Zornitza Stark edited their review of gene: GARS: Changed phenotypes: Mitochondrial disease (MONDO:0044970), GARS1-related, 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 v1.2113 | ME2 |
Bryony Thompson gene: ME2 was added gene: ME2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ME2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ME2 were set to 39401966 Phenotypes for gene: ME2 were set to inborn disorder of energy metabolism MONDO:0019243 Review for gene: ME2 was set to RED Added comment: A single individual with a homozygous frameshift variant from a consanguineous family. The phenotype included developmental delay, microcephaly, mild brain atrophy, peripheral hypotonia, subtle dysmorphic features, ectopic kidney, and mild lactate elevation. Deletion of yeast ortholog of the gene resulted in growth arrest (which could be rescued). Sources: Literature |
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| Mendeliome v1.2101 | UBTF | Zornitza Stark Phenotypes for gene: UBTF were changed from Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701 to Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701; Neurodevelopmental disorder, MONDO:0700092, UBTF-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2099 | UBTF |
Zornitza Stark edited their review of gene: UBTF: Added comment: PMID 39366741: 3 Chinese patients with global developmental delay, intellectual disability, social challenges and dysmorphism (wide forehead, sparse eyebrows, hypertelorism, narrow palpebral fissures, single-fold eyelids, flat nasal bridge, anteverted nares, a long philtrum and a thin upper lip), but no neuroregression (but aged 1.8yrs-4.8yrs). WES with SNV/CNV analysis showed: -nonsense variant c.1327C>T p. (Arg443Ter) - parental segregation not possible -de novo ~46 kb deletion at 17q21.31 containing 7 genes but UBTF as only OMIM Morbid gene -de novo ~106kb deletion at 17q21.31 containing 10 genes but UBTF as only relevant OMIM Morbid gene (other one was SLC4A1) Propose haploinsufficiency presents with different phenotype to CONDBA which is due to GOF variant. AMBER for this mechanism and phenotype.; Changed publications: 28777933, 29300972, 39366741; Changed phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672, MONDO:0044701, Neurodevelopmental disorder, MONDO:0700092, UBTF-related |
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| Mendeliome v1.2081 | LAMA3 | Ain Roesley Phenotypes for gene: LAMA3 were changed from Epidermolysis bullosa, generalized atrophic benign, MIM# 226650; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700 to Epidermolysis bullosa, junctional 2A, intermediate MIM#619783; Epidermolysis bullosa, junctional 2B, severe MIM#619784; Epidermolysis bullosa, junctional 2C, laryngoonychocutaneous MIM#245660 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2078 | LINC01578 |
Zornitza Stark gene: LINC01578 was added gene: LINC01578 was added to Mendeliome. Sources: Literature SV/CNV, new gene name tags were added to gene: LINC01578. Mode of inheritance for gene: LINC01578 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: LINC01578 were set to Neurodevelopmental disorder, MONDO:0700092, CHASERR-related Review for gene: LINC01578 was set to GREEN Added comment: CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Three unrelated children reported with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis, indicating bidirectional dosage sensitivity in human disease. Sources: Literature |
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| Mendeliome v1.2066 | BORCS8 | Zornitza Stark Phenotypes for gene: BORCS8 were changed from Neurodevelopmental disorder (MONDO#0700092), BORCS8-related to Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, MIM# 620987 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2065 | BORCS8 | Zornitza Stark reviewed gene: BORCS8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, MIM# 620987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2060 | BMP5 | Zornitza Stark Phenotypes for gene: BMP5 were changed from Skeletal dysostosis and atrioventricular septal defect, no OMIM# to Skeletal dysplasia, MONDO:0018230, BMP5-related; Skeletal dysostosis and atrioventricular septal defect, no OMIM# | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2048 | BMP5 |
Chirag Patel gene: BMP5 was added gene: BMP5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BMP5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BMP5 were set to Skeletal dysostosis and atrioventricular septal defect, no OMIM# Phenotypes for gene: BMP5 were set to Skeletal dysostosis and atrioventricular septal defect, no OMIM# Review for gene: BMP5 was set to RED Added comment: 1 patient with skeletal dysostosis, atrioventricular septal defect, hypermobility, laryngo-tracheo-bronchomalacia and dysmorphic features (malar hypoplasia, short palpebral fissures, short nose, low nasal bridge, anteverted nares, long philtrum, small ears with abnormally folded antihelix). Skeletal survey showed mild thoracolumbar scoliosis, four sacral segments, absent ossification of the inferior pubic rami, and patellar aplasia. Trio WGS identified compound heterozygous loss of function variants in BMP5 (c.88_89del, p.(Gly30Argfs*11) and c.1104+2del, p.(?). Abnormal splicing was proven on the suspected splice variant using maternal fibroblasts. BMP5 expression is confined to specific parts of the skeleton and cartilage in mice and is tightly regulated by different enhancers. Previous studies of chicken embryonic heart development showed BMP5 expression in the endoderm underlying the precardiac mesoderm, the myocardium of the atrioventricular canal and outflow tract regions. Other bone morphogenetic proteins are linked to several genetic skeletal disorders. Sources: Literature |
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| Mendeliome v1.2037 | FLVCR1 | Bryony Thompson edited their review of gene: FLVCR1: Added comment: A study with 30 patients from 23 unrelated families with biallelic ultra-rare missense and predicted loss-of-function variants in FLVCR1 with a novel FLVCR1-related phenotype characterised by severe developmental disorders with profound developmental delay, microcephaly, brain malformations, epilepsy, spasticity, and premature death. Optic disk atrophy, limb and digital malformations, and macrocytic anaemia can be present.; Changed publications: 21070897, 22279524, 21267618, 39306721; Changed phenotypes: posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177, neurodevelopmental disorder MONDO:0700092, FLVCR1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2028 | ZDHHC16 |
Ain Roesley gene: ZDHHC16 was added gene: ZDHHC16 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZDHHC16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZDHHC16 were set to 39313616 Phenotypes for gene: ZDHHC16 were set to neurodevelopmental disorder MONDO:0700092, ZDHHC16-related Review for gene: ZDHHC16 was set to AMBER gene: ZDHHC16 was marked as current diagnostic Added comment: 6 families including a pair of siblings Amber because 5 of the families had non specific phenotypes listed Abnormality of: the nervous system, metabolism/homeostasis, head/neck, immune system, the integument, the digestive system, the respiratory system, the endocrine system, Growth abnormality the skeletal system, the musculature, the eye Specific HPOs were provided for one individual (homoyzygous for a canonical splice) Abnormality of the face; Cerebellar hypoplasia; Developmental regression; Encephalopathy; Hyperreflexia; Hypertonia; Hypotonia; Inguinal hernia; Laryngomalacia; Microcephaly; Motor delay; Optic atrophy; Seizure; Spastic paraparesis; Spasticity; Talipes equinovarus; Umbilical hernia Sources: Literature |
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| Mendeliome v1.1992 | RFC4 |
Chirag Patel gene: RFC4 was added gene: RFC4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RFC4 were set to PMID: 39106866 Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder Review for gene: RFC4 was set to GREEN gene: RFC4 was marked as current diagnostic Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9). WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease. The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown. Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression. Sources: Literature |
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| Mendeliome v1.1983 | SPARCL1 |
Zornitza Stark gene: SPARCL1 was added gene: SPARCL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SPARCL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SPARCL1 were set to 39169229 Phenotypes for gene: SPARCL1 were set to Corneal dystrophy, MONDO:0018102 Review for gene: SPARCL1 was set to RED Added comment: 8 affected individuals with corneal dystrophy from 1 family (3 generations). Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue revealed mild stromal textural alterations with alcianophilic deposits. WGS from 4 affected individuals in family identified a novel heterozygous missense variant in exon 4 of SPARCL1 (c.334G > A; p.(Glu112Lys)) which segregated with disease. SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Immunohistochemistry showed the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium. Sources: Literature |
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| Mendeliome v1.1982 | NDUFA7 | Zornitza Stark Phenotypes for gene: NDUFA7 were changed from to Optic atrophy, MONDO:0003608, NDUFA7-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1980 | NDUFA7 | Zornitza Stark reviewed gene: NDUFA7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Optic atrophy, MONDO:0003608, NDUFA7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1980 | MED22 |
Mark Cleghorn gene: MED22 was added gene: MED22 was added to Mendeliome. Sources: Other Mode of inheritance for gene: MED22 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MED22 were set to complex neurodevelopmental disorder MONDO:0100038 Penetrance for gene: MED22 were set to unknown Review for gene: MED22 was set to AMBER Added comment: ESHG talk 2/6/24, unpublished Elisa Cali, UCL Recurrent homozygous MED22:c.397_399del (p.Glu133del) inframe variant in 8 individuals from 6 families w progressive NDD, microcepahly, cerebellar atrophy, dystonia, seizures Rare in gnomad v4.1 (9 het alleles, no homozygotes) Functional work on patient fibroblasts: quantity of protein comparable to controls, did not mentioned assays of protein function (?mechanism proposed) Drosophilia heterozygous model with equivalent of p.Glu133del variant: structural anomalies, less movements, all died prior to pupae stage Zebrafish: MED22 mutants less mobile, died prior to adulthood, reduced brain size Sources: Other |
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| Mendeliome v1.1978 | PLEC | Zornitza Stark Phenotypes for gene: PLEC were changed from ?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 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; Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1973 | TTL |
Mark Cleghorn gene: TTL was added gene: TTL was added to Mendeliome. Sources: Other Mode of inheritance for gene: TTL was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TTL were set to complex neurodevelopmental disorderMONDO:0100038 Added comment: TTL Valentina Serpieri, University of Pavia ESHG talk 1/6/24 FAM1 (Italy) 2 affected sisters born to consanguineous Pakistani parents GDD, spastic tetraparesis, optic atrophy, brain anomalies resembling tubulinopathies (dysplasia of corpus callosum, basal ganglia, brainstem) WES: homozygous TTL:c.1013G>A; p.Cys338Tyr in both affected sisters Via genematcher 5 more families (9 individuals) w similar phenotypes and biallelic variants in TTL FAM2 (Egypt): homozygous p.Arg46Pro FAM3 (Egypt): homozygous p.Arg46Pro FAM4 (Australia): homozygous p.Gln183Arg FAM5 (France): homozygous p.Trp147* FAM6 (Saudi Arabia): homozygous p.His243Tyr TTL KO mice: death soon after birth, no overt malformations, but defects in organisation of cerebral layers Functional work on patient fibroblasts FAM1 – reduced quantity of TTL protein compared to control on Western blot, decreased function of TTL protein (increase in detyrosinated tubulin) compared to controls – infer LoF as mechanism FAM3 – mentioned but no details FAM4– mentioned but no details Sources: Other |
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| Mendeliome v1.1969 | LRP1 | Zornitza Stark Phenotypes for gene: LRP1 were changed from to Developmental dysplasia of the hip 3, MIM# 620690; Keratosis pilaris atrophicans MIM#604093 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1893 | LDB3 | Bryony Thompson Added comment: Comment on mode of inheritance: AD missense variants in LDB3 that affect only short isoforms are associated with skeletal myopathies, while AR LoF variants cause paediatric cardiomyopathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1879 | FDXR | Zornitza Stark Phenotypes for gene: FDXR were changed from Auditory neuropathy and optic atrophy, MIM#617717 to Auditory neuropathy and optic atrophy, MIM#617717; Neurodevelopmental disorder with mitochondrial abnormalities, optic atrophy, and developmental regression, MIM# 620887 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1877 | FDXR | Zornitza Stark edited their review of gene: FDXR: Added comment: Multiple reports of individuals with extra-ocular features, including ID and regression.; Changed publications: 30250212, 28965846, 29040572, 33348459, 37046037, 37481223; Changed phenotypes: Auditory neuropathy and optic atrophy, MIM#617717, Neurodevelopmental disorder with mitochondrial abnormalities, optic atrophy, and developmental regression, MIM# 620887 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1840 | SUMF1 |
Achchuthan Shanmugasundram changed review comment from: PMID:38863195 reported three unrelated cases with biallelic SUMF1 variants and retinal dystrophy. One of them was a paediatric patient with an attenuated phenotype, while the other two are adult patients with non-syndromic retinal dystrophy.; to: PMID:38863195 reported three unrelated cases with biallelic SUMF1 variants and retinal dystrophy. One of them was a paediatric patient with an attenuated phenotype, while the other two are adult patients with non-syndromic retinal dystrophy. Retinal dystrophy is part of the multiple sulfatase deficiency phenotype (MIM #272200) typically associated with biallelic variants in SUMF1, and these cases show that presumed hypomorphic variants in SUMF1 may also be associated with non-syndromic retinal dystrophy. |
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| Mendeliome v1.1838 | RDH14 |
Zornitza Stark gene: RDH14 was added gene: RDH14 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RDH14 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RDH14 were set to 34848785 Phenotypes for gene: RDH14 were set to Neurodevelopmental disorder, MONDO:0700092, RDH14-related Review for gene: RDH14 was set to RED Added comment: Two related individuals with ID and cerebellar atrophy and homozygous LoF variant reported. Sources: Literature |
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| Mendeliome v1.1770 | ADAMTS18 |
Sangavi Sivagnanasundram gene: ADAMTS18 was added gene: ADAMTS18 was added to Mendeliome. Sources: Other Mode of inheritance for gene: ADAMTS18 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAMTS18 were set to https://search.clinicalgenome.org/CCID:004057 Phenotypes for gene: ADAMTS18 were set to microcornea-myopic chorioretinal atrophy (MONDO:0014195) Review for gene: ADAMTS18 was set to GREEN Added comment: Classified DEFINITIVE by ClinGen Retina GCEP on 02/03/20222 - https://search.clinicalgenome.org/CCID:004057 Sources: Other |
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| Mendeliome v1.1694 | SNF8 | Zornitza Stark Phenotypes for gene: SNF8 were changed from Developmental and epileptic encephalopathy 115, MIM#620783 to Developmental and epileptic encephalopathy 115, MIM#620783; Neurodevelopmental disorder plus optic atrophy, MIM# 620784 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1693 | SNF8 | Zornitza Stark edited their review of gene: SNF8: Added comment: Four individuals from 3 families with NDD plus OA, rather than DEE.; Changed phenotypes: Developmental and epileptic encephalopathy 115, MIM#620783, Neurodevelopmental disorder plus optic atrophy, MIM# 620784 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1680 | BANF1 | Zornitza Stark changed review comment from: Two Spanish families reported but likely founder effect. One additional family. Lipoatrophy reported.; to: Bi-allelic disease: Two Spanish families reported with progeria but likely founder effect. One additional family. Lipoatrophy reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1676 | YKT6 |
Zornitza Stark gene: YKT6 was added gene: YKT6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: YKT6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: YKT6 were set to 38522068 Phenotypes for gene: YKT6 were set to Syndromic disease, MONDO:0002254, YKT6-related Review for gene: YKT6 was set to AMBER Added comment: Two individuals homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] exhibited normal prenatal course followed by failure to thrive, developmental delay and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] exhibited neurodevelopmental disorders and optic atrophy. Supportive functional data in Drosophila. Amber rating due to homozygous missense variants and founder effect in two of the families. Sources: Literature |
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| Mendeliome v1.1624 | CRELD1 | Zornitza Stark Phenotypes for gene: CRELD1 were changed from Developmental and epileptic encephalopathy, MONDO:0100062, CRELD1-related; Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217 to Jeffries-Lakhani neurodevelopmental syndrome, MIM# 620771; Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1623 | CRELD1 | Zornitza Stark edited their review of gene: CRELD1: Changed phenotypes: Jeffries-Lakhani neurodevelopmental syndrome, MIM# 620771, Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1604 | CORIN | Zornitza Stark Phenotypes for gene: CORIN were changed from Preeclampsia/eclampsia 5 MIM#614595; ?Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734) to Preeclampsia/eclampsia 5 MIM#614595; Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1602 | CORIN | Zornitza Stark Phenotypes for gene: CORIN were changed from Preeclampsia/eclampsia 5 MIM#614595 to Preeclampsia/eclampsia 5 MIM#614595; ?Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1596 | MMS19 |
Paul De Fazio gene: MMS19 was added gene: MMS19 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MMS19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MMS19 were set to 38411040 Phenotypes for gene: MMS19 were set to Neuromuscular disease, MMS19-related (MONDO:0019056) Penetrance for gene: MMS19 were set to unknown Review for gene: MMS19 was set to RED gene: MMS19 was marked as current diagnostic Added comment: Single patient reported with postnatal microcephaly, bilateral cataracts, failure to thrive, progressive spastic tetraparesis, scoliosis, myoclonic epilepsy and precocious puberty. Cerebral MRI at age 4 years showed pontocerebellar atrophy and white matter abnormalities. Patient died age 13 after recurrent respiratory tract infections. A homozygous in-frame deletion p.(Glu213del) was identified. Cell line studies supported pathogenicity of the variant. A zebrafish knockout model also showed a detrimental effect of Mms19 deficincy. Sources: Literature |
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| Mendeliome v1.1589 | CORIN | Daniel Flanagan reviewed gene: CORIN: Rating: RED; Mode of pathogenicity: None; Publications: 37913506, 15637153; Phenotypes: ?Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1585 | SNF8 |
Chern Lim gene: SNF8 was added gene: SNF8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNF8 were set to 38423010 Phenotypes for gene: SNF8 were set to Neurodevelopmental disorder (MONDO:0700092), SNF8-related Review for gene: SNF8 was set to GREEN gene: SNF8 was marked as current diagnostic Added comment: PMID: 38423010 - Nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8. In total, three putative LoF variants and four missense variants were identified. - The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. - Functional studies using fibroblasts derived from patients and zebrafish model showed LoF is the disease mech. Sources: Literature |
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| Mendeliome v1.1583 | DIP2C |
Melanie Marty gene: DIP2C was added gene: DIP2C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DIP2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DIP2C were set to PMID: 38421105 Phenotypes for gene: DIP2C were set to Neurodevelopmental disorder (MONDO#0700092), DIP2C-related Review for gene: DIP2C was set to GREEN Added comment: PMID: 38421105 - Twenty three patients with het DIP2C variants (10 de novo). All patients had developmental delays affecting expressive language and speech, most had mild dev delay and ID. Four patients had seizures. Additional phenotypic findings were non-specific but recurrent anomalies did include a high anterior hair-line, prominent forehead, and a broad nasal tip. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects,and bicuspid aortic valve) Sources: Literature |
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| Mendeliome v1.1555 | ACO2 | Rylee Peters reviewed gene: ACO2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34056600; Phenotypes: Optic atrophy 9, MIM# 616289; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1485 | ATP6V0A1 | Elena Savva Phenotypes for gene: ATP6V0A1 were changed from Neurodevelopmental disorder MONDO:0700092, ATP6V0A1-associated to Developmental and epileptic encephalopathy 104 MIM#619970; Neurodevelopmental disorder with epilepsy and brain atrophy MIM#619971 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1457 | BORCS8 |
Lauren Rogers changed review comment from: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. Sources: Literature; to: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. 5/5 hypotonia, failure to thrive, global developmental delay, profound intellectual disability, muscle weakness and atrophy, dysmorphic features. 3/5 with microcephaly, 3/5 with seizures, 4/5 with spasticity, 3/5 with scoliosis, 4/4 with optic atrophy. HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. Sources: Literature |
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| Mendeliome v1.1402 | RNF213 | Seb Lunke edited their review of gene: RNF213: Changed phenotypes: Moyamoya disease, MONDO:0016820, pediatric arterial ischemic stroke, MONDO:0018585 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1402 | RNF213 | Seb Lunke reviewed gene: RNF213: Rating: GREEN; Mode of pathogenicity: None; Publications: 37924258; Phenotypes: Leigh syndrome, MONDO:0009723, pediatric arterial ischemic stroke, MONDO:0018585, Moyamoya disease, MONDO:0016820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1396 | TRAPPC4 | Zornitza Stark Phenotypes for gene: TRAPPC4 were changed from intellectual disability; epilepsy; spasticity; microcephaly to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, MIM# 618741 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1395 | TRAPPC4 | Zornitza Stark edited their review of gene: TRAPPC4: Changed phenotypes: Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, MIM# 618741 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1378 | MECR | Zornitza Stark Phenotypes for gene: MECR were changed from Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282; MONDO:0015003 to Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282; MONDO:0015003; Optic atrophy 16, MIM# 620629 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1377 | MECR | Zornitza Stark edited their review of gene: MECR: Changed phenotypes: Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282, MONDO:0015003, Optic atrophy 16, MIM# 620629 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1366 | MCAT | Zornitza Stark Phenotypes for gene: MCAT were changed from Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309 to Optic atrophy 15, MIM# 620583 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1364 | MCAT | Zornitza Stark edited their review of gene: MCAT: Changed phenotypes: Optic atrophy 15, MIM# 620583 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1343 | ELP1 | Ain Roesley Phenotypes for gene: ELP1 were changed from Dysautonomia, familial MIM#223900; paediatric medulloblastoma to Dysautonomia, familial MIM#223900; paediatric medulloblastoma; neurodevelopmental disorder, MONDO:0700092, ELP1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1330 | MIEF1 |
Lucy Spencer gene: MIEF1 was added gene: MIEF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MIEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MIEF1 were set to 33632269 Phenotypes for gene: MIEF1 were set to Optic atrophy 14 (MIM#620550) Review for gene: MIEF1 was set to AMBER Added comment: PMID: 33632269 Inherited optic neuropathies cohort from france with nothing found in OPA1, OPA3 and WFS1 or mtDNA. 2 individuals (55 and 47yo) found to have missense variant in MIEF1, p.Arg146Trp has 35 hets 0 homs in gnomad, p.Tyr240Asn is absent. Both have non-syndromic late onset inherited optic neuropathies characterized by initial loss of peripheral visual fields. Functional studies in HeLa cells- both missense localised to the mitochondria and formed oligomers similar to WT. MIEF1 normally regulates mitochondrial fission dynamics and causes an increase in mitochondrial fusion events, however both missense variants caused a significantly decreased mitochondrial fusion events. Sources: Literature |
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| Mendeliome v1.1323 | VRK1 | Zornitza Stark Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia to Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia; Neuronopathy, distal hereditary motor, autosomal recessive 10, MIM# 620542 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1322 | VRK1 | Zornitza Stark edited their review of gene: VRK1: Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia, Neuronopathy, distal hereditary motor, autosomal recessive 10, MIM# 620542 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1312 | DNAJB2 | Elena Savva Phenotypes for gene: DNAJB2 were changed from Spinal muscular atrophy, distal, autosomal recessive, 5, MIM# 614881; MONDO:0014866 to Neuronopathy, distal hereditary motor, autosomal recessive 5 (MIM#614881) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1279 | EPHX1 | Zornitza Stark Phenotypes for gene: EPHX1 were changed from Lipoatrophic diabetes to Hereditary lipodystrophy, MONDO:0020087, EPHX1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1245 | ATRX | Zornitza Stark Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome, MIM# 301040; Intellectual disability-hypotonic facies syndrome, X-linked, MIM# 309580 to ATR-X-related syndrome MONDO:0016980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1199 | ATRIP | Zornitza Stark Phenotypes for gene: ATRIP were changed from Seckel Syndrome to Seckel Syndrome, MONDO:0019342, ATRIP-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1133 | CRELD1 | Zornitza Stark Phenotypes for gene: CRELD1 were changed from Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217 to Developmental and epileptic encephalopathy, MONDO:0100062, CRELD1-related; Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1130 | CRELD1 | Zornitza Stark edited their review of gene: CRELD1: Added comment: Emerging association between bi-alleic variants in CRELD1 and DEE.; Changed rating: GREEN; Changed phenotypes: Developmental and epileptic encephalopathy, MONDO:0100062, CRELD1-related, Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1029 | TSPOAP1 | Zornitza Stark Phenotypes for gene: TSPOAP1 were changed from Dystonia, intellectual disability and cerebellar atrophy to Dystonia 22, MIM# 620453 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1026 | POPDC2 | Zornitza Stark Phenotypes for gene: POPDC2 were changed from Sinus node dysfunction to Sinoatrial node disorder, MONDO:0000469, POPDC2-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.989 | NAA60 |
Chirag Patel gene: NAA60 was added gene: NAA60 was added to Mendeliome. Sources: Other Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: NAA60 were set to Basal ganglia calcification Review for gene: NAA60 was set to GREEN gene: NAA60 was marked as current diagnostic Added comment: ESHG 2023: 10 individuals from 7 families with biallelic variants in NAA60 (missense and framshift). All with primary brain calcification - 4/10 childhood onset (DD, ID), 6/10 adult onset (cerebellar and pyramidal dysfunction, dystonia, parkinsonism, cognitive impairment, psychiatric manifestations). NAA60 catalyses N-terminal acetylation of transmembrane proteins and localises to Golgi apparatus. In vitro assay of variants showed reduced capacity of Nt acetylation. Fibroblast studies showed significantly reduced levels of phosphate importer (SLC20A2). Loss of function variants in SLC20A2 (~50% of PFBC cases) lead to increased extracellular phosphate (which is thought to lead to calcium deposits in brain). Sources: Other |
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| Mendeliome v1.987 | POPDC2 |
Chirag Patel gene: POPDC2 was added gene: POPDC2 was added to Mendeliome. Sources: Other Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POPDC2 were set to Sinus node dysfunction Review for gene: POPDC2 was set to GREEN gene: POPDC2 was marked as current diagnostic Added comment: ESHG 2023: 3 families with 7 affected with sinus node dysfunction (bradycardia) and AV block (2/7 HCM). 3 x HMZ variants found in POPDC2 (2 x missense, 1 x indel). Variants predicted to diminish cAMP binding of POPDC2, and shown to disrupt regulation of TREK1 channels (lowering of outward K+ current). POPDC2 is highly expressed in cardiac myocytes, sinoatrial node, and atrioventricular node. Knockdown in zebrafish leads to AV block, and knockout in mice leads to sinus node dysfunction. Sources: Other Sources: Other |
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| Mendeliome v1.961 | ARPC5 |
Paul De Fazio gene: ARPC5 was added gene: ARPC5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARPC5 were set to 37349293; 37382373 Phenotypes for gene: ARPC5 were set to Combined immunodeficiency, ARPC5-related MONDO:0015131 Review for gene: ARPC5 was set to GREEN gene: ARPC5 was marked as current diagnostic Added comment: 4 individuals from 3 families reported with homozygous LoF variants. All had recurrent and severe infections. Other developmental anomalies were present but seemed variable. PMID:37349293 reports 2 unrelated patients. Both had scoliosis. One had neurodevelopmental delay and brain atrophy. Patient 1 died at 15yo after a sudden episode of hemoptysis and hematochezia. Patient 2 died at 1yo because of progressive neurologic and respiratory disease; an autopsy was not performed. PMID:37382373 reports 2 patients from the same family. One had multiple congenital anomalies including a congenital heart defect (CHD) (patent foramen ovale), cleft palate, and hypoplastic corpus callosum. The sibling also had CHD (moderate pulmonary stenosis and atrial septal defect). Functional studies and a mouse model were supportive of the disease association. Sources: Literature |
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| Mendeliome v1.897 | ACBD6 |
Lucy Spencer gene: ACBD6 was added gene: ACBD6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACBD6 were set to 36457943; 21937992; 35446914 Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder (MONDO#0700092), ACBD6-related Review for gene: ACBD6 was set to GREEN Added comment: PMID: 36457943 2 siblings with a neurodevelopmental disorder: severely delayed development, obesity, pancytopenia, diabetes, liver cirrhosis, intravertebral disc herniation, mild brain atrophy. Consanguineous family both siblings found to have a homozygous frameshift. This paper also mentioned 3 other reported variants in 6 individuals (only 3 unrelated) all homozygous, 2 frameshift, 1 canonical splice. All reported to have a neurodevelopmental disorder, some with limited information but one family also has obesity, spasticity, and dysmorphism. PMIDs: 21937992, 35446914 Sources: Literature |
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| Mendeliome v1.836 | INTS11 |
Melanie Marty changed review comment from: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.; to: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. |
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| Mendeliome v1.834 | INTS11 | Melanie Marty reviewed gene: INTS11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37054711; Phenotypes: Global developmental delay, launguage delay, intellectual disability, impaired motor development, brain atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.819 | INTS11 |
Achchuthan Shanmugasundram gene: INTS11 was added gene: INTS11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INTS11 were set to 37054711 Review for gene: INTS11 was set to GREEN Added comment: Comment on gene rating: This gene should be rated GREEN in Intellectual disability panel as it has 10 unrelated cases and functional evidence in support of this association. PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy. Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Sources: Literature |
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| Mendeliome v1.789 | ACTC1 | Zornitza Stark reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 5 MIM#612794, Cardiomyopathy, dilated, 1R MIM#613424, Cardiomyopathy, hypertrophic, 11 MIM#612098, ACTC1 related distal arthrogryposis MONDO:0019942; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.776 | ACTC1 |
Lilian Downie gene: ACTC1 was added gene: ACTC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ACTC1 were set to PMID: 36945405 Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 MIM#612794; Cardiomyopathy, dilated, 1R MIM#613424; Cardiomyopathy, hypertrophic, 11 MIM#612098; ACTC1 related distal arthrogryposis MONDO:0019942 Review for gene: ACTC1 was set to GREEN Added comment: ClinGen definitive association with HCM, moderate for DCM 5 new families (8 individuals) with a distral arthrogryposis phenotype (PMID: 36945405) multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy facial features: microretrognathia, ptosis, downslanting palpebral fissures, low-set ears, and a long nasal bridge All missense variants Sources: Literature |
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| Mendeliome v1.757 | NPPA | Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.625 | NPTX1 |
Ain Roesley gene: NPTX1 was added gene: NPTX1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436 Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related Review for gene: NPTX1 was set to GREEN gene: NPTX1 was marked as current diagnostic Added comment: PMID:34788392 5 families with multigenerational segregations - late onset ataxia 4 families with p.(Gly389Arg) + 1x p.(Glu327Gly) functional studies done Note: case report of a family member published elsewhere (PMID:35288776) PMID:35285082 1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome p.(Arg143Leu) PMID:35560436 1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy p.(Gln370Arg) Sources: Literature |
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| Mendeliome v1.583 | OXGR1 |
Sarah Pantaleo gene: OXGR1 was added gene: OXGR1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OXGR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: OXGR1 were set to PMID:35671463 Phenotypes for gene: OXGR1 were set to Nephrolithiasis/nephrocalcinosis MONDO:0008171, OXGR1-related Penetrance for gene: OXGR1 were set to unknown Review for gene: OXGR1 was set to AMBER Added comment: Candidate disease gene for human calcium oxalate nephrolithiasis. Performed exome sequencing and directed sequencing of the OXGR1 locus in a worldwide nephrolithiasis/nephrocalcinosis (NL/NC) cohort, and putatively deleterious rare OXGR1 variants were functionally characterised. A heterozygous OXGR1 missense variant (c.371T>G; p.Leu124Arg) co-segregated with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals. Interrogation of the OXGR1 locus in 1,107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls. Four missense variants and one frameshift variant. Four of five NL/NC-associated missense variants revealed impaired AKG-dependent calcium ion uptake, demonstrating loss of function. Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. Six potentially deleterious variants were identified in six of 1,108 NL/NC families (0.54%). Limitations: only probands were able to be recruited for four of six families. In the future, it will be important to determine whether any of the affected family members share the identified OXGR1 variant. They also observe OXGR1 variants in 0.16% of ExAC subjects (selected on the basis of the absence of paediatric disease). Sources: Literature |
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| Mendeliome v1.572 | KMT2D | Zornitza Stark Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920; KMT2D-associated syndrome to Kabuki syndrome 1, MIM# 147920; Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.571 | KMT2D | Zornitza Stark edited their review of gene: KMT2D: Changed phenotypes: Kabuki syndrome 1, MIM# 147920, Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.437 | FOXI3 |
Paul De Fazio gene: FOXI3 was added gene: FOXI3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FOXI3 were set to 36260083 Phenotypes for gene: FOXI3 were set to Dysostosis with predominant craniofacial involvement (MONDO:0800085) Penetrance for gene: FOXI3 were set to Incomplete Review for gene: FOXI3 was set to GREEN gene: FOXI3 was marked as current diagnostic Added comment: Ten affected individuals from 4 families reported with monoallelic variants, 2 with missense variants affecting the nuclear localisation sequence and 2 with frameshift variants. The missense variants were associated with isolated microtia with aural atresia and affected subcellular localisation of the protein, while the frameshift variants were associated with microtia and mandubular hypoplasia, suggesting dosage sensitivity. Rated green but CAUTION for incomplete penetrance. 3 of the 4 families had unaffected carriers. Family 1 in particular had 25 genotyped individuals, of which 15 were carriers, of which 5 were affected. Sources: Literature |
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| Mendeliome v1.402 | HEATR3 | Zornitza Stark reviewed gene: HEATR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anaemia 21, MIM# 620072; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.382 | ADGRL1 | Zornitza Stark Phenotypes for gene: ADGRL1 were changed from Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092) to Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.381 | ADGRL1 | Zornitza Stark reviewed gene: ADGRL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.372 | LETM1 |
Ee Ming Wong gene: LETM1 was added gene: LETM1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LETM1 were set to 36055214 Phenotypes for gene: LETM1 were set to Mitochondrial disease MONDO#0044970, LETM1-related gene: LETM1 was marked as current diagnostic Added comment: -18 affected individuals from 11 unrelated families harbouring ultra-rare bi-allelic missense and loss-of-function LETM1 variants -Most of the affected individuals (14/18, 78%) had an infantile-onset disease manifestation, and 4/18 (22%) presented first symptoms between the ages of 1.5 and 2 years -Variant types included missense, frameshift, stop loss, in-frame deletion and splice defect -From biochemical and morphological studies, bi-allelic LETM1 variants are associated with defective mitochondrial K efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components Sources: Literature |
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| Mendeliome v1.366 | MED11 |
Ain Roesley gene: MED11 was added gene: MED11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED11 were set to 36001086 Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related Review for gene: MED11 was set to GREEN gene: MED11 was marked as current diagnostic Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*). Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes NO evidence of founder effect from haplotype analysis 7/7 cerebral dysgyria, cortical atrophy 5/7 limb contracture 4/7 epilepsy 3/7 families with IUGR 3/7 GDD 3/7 hearing loss 3/7 undescended testis 2/7 nystagmus 1/7 congenital cataract Sources: Literature |
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| Mendeliome v1.359 | MTSS1L |
Elena Savva gene: MTSS1L was added gene: MTSS1L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MTSS1L were set to PMID: 36067766 Phenotypes for gene: MTSS1L were set to Intellectual disability, MTSS2-related (MONDO#0001071) Review for gene: MTSS1L was set to GREEN Added comment: Alt gene name: MTSS2 Huang (2022): recurring de novo missense variant (p.R671W) causing syndromic intellectual disability in 5 unrelated individuals. - Individuals present with GDD, mild ID (5/5), nystagmus (3/5), optic atrophy (1/5), ptosis (2/5), sensorineural hearing loss (2/4), microcephaly or relative microcephaly (5/5), and shared mild facial dysmorphisms. - Overexpression supports a DN mechanism Sources: Literature |
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| Mendeliome v1.345 | DOHH | Zornitza Stark Phenotypes for gene: DOHH were changed from Neurodevelopmental disorder, DOHH-related (MONDO#0700092) to Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.344 | DOHH | Zornitza Stark reviewed gene: DOHH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
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| Mendeliome v1.342 | ATRX | Zornitza Stark Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome; Mental retardation-hypotonic facies syndrome, X-linked to Alpha-thalassemia/mental retardation syndrome, MIM# 301040; Intellectual disability-hypotonic facies syndrome, X-linked, MIM# 309580 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.310 | SLC31A1 |
Daniel Flanagan gene: SLC31A1 was added gene: SLC31A1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC31A1 were set to PMID: 35913762 Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) Review for gene: SLC31A1 was set to RED Added comment: SLC31A1 is also referred to as CTR1. Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality. Sources: Expert list |
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| Mendeliome v1.306 | NBAS | Zornitza Stark Phenotypes for gene: NBAS were changed from Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800; Infantile liver failure syndrome 2, MIM# 616483 to Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800; Infantile liver failure syndrome 2, MIM# 616483; Haemophagocytic lymphohistiocytosis (HLH), MONDO:0015541 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.304 | NBAS | Zornitza Stark edited their review of gene: NBAS: Added comment: PMID 35902954 - Biallelic NBAS variants identifed in three HLH patients who harbored no pathogenic variants in any of the known HLH genes. Functionally, impaired NK-cell cytotoxicity and degranulation were revealed in both NBAS biallelic variant patients and in an NBAS-defcient NK-cell line. Knockdown of NBAS in an NK-cell line (IMC-1) using short hairpin RNA (shRNA) resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus.; Changed publications: 31761904, 35902954; Changed phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800, Infantile liver failure syndrome 2, MIM# 616483, Haemophagocytic lymphohistiocytosis (HLH), MONDO:0015541 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.271 | REEP1 | Zornitza Stark Phenotypes for gene: REEP1 were changed from Neuronopathy, distal hereditary motor, type VB MIM#614751; Spastic paraplegia 31, autosomal dominant MIM#610250; Charcot-Marie-Tooth; severe congenital distal SMA with diaphragmatic paralysis; congenital axonal neuropathy and diaphragmatic palsy to Spinal muscular atrophy, distal, autosomal recessive, 6, MIM#620011; Neuronopathy, distal hereditary motor, type VB MIM#614751; Spastic paraplegia 31, autosomal dominant MIM#610250 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.270 | REEP1 | Zornitza Stark reviewed gene: REEP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy, distal, autosomal recessive, 6, MIM#620011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.252 | FOCAD |
Zornitza Stark gene: FOCAD was added gene: FOCAD was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: FOCAD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FOCAD were set to 35864190 Phenotypes for gene: FOCAD were set to Liver disease, severe congenital, MIM# 619991 Review for gene: FOCAD was set to GREEN Added comment: Moreno Traspas et al 2022 reported 14 children from ten unrelated families with syndromic form of pediatric liver cirrhosis. Genome/exome sequencing analysis reveled biallelic variants in the FOCAD gene. Most of the mutations were nonsense, frameshift, or splice site alterations, predicted to result in a loss of function, but there were also 3 missense variants at highly conserved residues. Western blot analysis of dermal fibroblasts derived from 2 patients showed near absent FOCAD expression in cellular extracts. There were also decreased levels of the SKIC2 protein, suggesting that FOCAD may contribute to the stability of RNA helicase (OMIM: 619991). Sources: Expert Review |
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| Mendeliome v1.227 | BICD2 | Zornitza Stark Phenotypes for gene: BICD2 were changed from Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM# 615290; MONDO:0014121; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, MIM# 618291 to Neurodevelopmental disorder (MONDO#0700092), BICD2-related; 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 v1.212 | KIF15 |
Krithika Murali gene: KIF15 was added gene: KIF15 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KIF15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIF15 were set to 28150392 Phenotypes for gene: KIF15 were set to ?Braddock-Carey syndrome 2 - MIM#619981 Review for gene: KIF15 was set to GREEN Added comment: PMID 28150392 Sleiman et al 2017 report one individual with homozygous R501* variant (NMD-predicted) from a consanguineous family. The child had thrombocytopenia, PRS, microcephaly -3SD by age 6, dysmorphic facies, bilateral external auditory canal atresia and deafness, microphthalmia, clinodactyly, short stature. Variant absent from gnomAD. Parents confirmed to be carriers and unaffected siblings were carriers/homozygous wild-type. No other SNVs reported in ClinVar. Variant is absent from gnomAD. Authors note phenotypic similarities with Braddock-Carey syndrome (21q22 contiguous deletion also involving RUNX1). Sources: Literature |
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| Mendeliome v1.195 | TAF8 | Zornitza Stark Phenotypes for gene: TAF8 were changed from Neurodevelopmental disorder, MONDO:0700092, TAF8-related to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, MIM# 619972 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.194 | TAF8 | Zornitza Stark edited their review of gene: TAF8: Changed phenotypes: Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, MIM# 619972 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.190 | EIF2B1 | Zornitza Stark Phenotypes for gene: EIF2B1 were changed from leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; Neonatal diabetes mellitus, MONDO:0016391, EIF2B1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.96 | NEK8 | Zornitza Stark edited their review of gene: NEK8: Added comment: ESHG 2022: 12 families with paediatric renal cystic disease (enlarged kidneys, kidney cysts, ESKF <20yrs) -3 recurrent HTZ variants in NEK8 kinase domain (Arg45Trp, Ile150Met, Lys157Gln) -suspected dominant negative effect -patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8 (Note carriers of AR-NEK8 disease do not show renal manifestations, as variants are LOF); Changed phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415, MONDO:0014174, Familial renal cystic disease MONDO:0019741, NEK8-related, dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.68 | PRDM13 | Zornitza Stark Phenotypes for gene: PRDM13 were changed from Chorioretinal atrophy, progressive bifocal, MIM# 600790; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761 to Chorioretinal atrophy, progressive bifocal, MIM# 600790; Pontocerebellar hypoplasia, type 17, MIM# 619909; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 61976 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.66 | PRDM13 | Zornitza Stark edited their review of gene: PRDM13: Added comment: Note only single family reported with Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 61976 -- this likely lies on the same spectrum as Pontocerebellar hypoplasia, type 17, MIM# 619909 rather than being a distinct disorder.; Changed publications: 30710461, 34730112; Changed phenotypes: Retinal dystrophy, Chorioretinal atrophy, progressive bifocal, MIM# 600790, Pontocerebellar hypoplasia, type 17, MIM# 619909, Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 61976; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.39 | HEATR3 | Zornitza Stark Phenotypes for gene: HEATR3 were changed from Diamond Blackfan anaemia, MONDO:0015253, HEATR3 related to Diamond Blackfan anaemia, MONDO:0015253, HEATR3 related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.38 | HEATR3 | Zornitza Stark Marked gene: HEATR3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.38 | HEATR3 | Zornitza Stark Gene: heatr3 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.38 | HEATR3 | Zornitza Stark Phenotypes for gene: HEATR3 were changed from DiMONDO:0015253 to Diamond Blackfan anaemia, MONDO:0015253, HEATR3 related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.37 | HEATR3 | Zornitza Stark Phenotypes for gene: HEATR3 were changed from Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability to DiMONDO:0015253 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.36 | HEATR3 | Zornitza Stark Classified gene: HEATR3 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.36 | HEATR3 | Zornitza Stark Gene: heatr3 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.34 | HEATR3 |
Chern Lim gene: HEATR3 was added gene: HEATR3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HEATR3 were set to PMID: 35213692 Phenotypes for gene: HEATR3 were set to Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability Review for gene: HEATR3 was set to GREEN gene: HEATR3 was marked as current diagnostic Added comment: PMID: 35213692: - 4 unrelated individuals with biallelic HEATR3 variants (missense and splice site variants), exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability. - Functional analysis showed HEATR3 variants destabilised the protein, resulting in a reduction of nuclear uL18 and impaired ribosome biogenesis. Sources: Literature |
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| Mendeliome v1.33 | PRDM13 | Zornitza Stark Phenotypes for gene: PRDM13 were changed from Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790; intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770 to Chorioretinal atrophy, progressive bifocal, MIM# 600790; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.20 | GJA5 | Zornitza Stark reviewed gene: GJA5: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial fibrillation, familial, 11, OMIM# 614049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.14 | MYO9A | Zornitza Stark edited their review of gene: MYO9A: Added comment: This gene-disease association has been reviewed as part of GenCC discordance resolution: note at least two of the variants reported have homozygotes with gnomad, which would be out of keeping for a severe paediatric disorder.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14797 | DNM1L | Zornitza Stark Phenotypes for gene: DNM1L were changed from to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388 (AD, AR); Optic atrophy 5 - MIM#610708 (AD) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14654 | GJA5 | Zornitza Stark Phenotypes for gene: GJA5 were changed from to Atrial fibrillation, familial, 11, OMIM# 614049 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14647 | GJA5 |
Chirag Patel commented on gene: GJA5: Gollob et al. (2006) presented evidence that tissue-specific mutations in the GJA5 gene may predispose the atria to fibrillation. They identified a heterozygous missense mutation in blood and cardiac tissue in patient with AF. They also found 3 heterozygous missense mutations in cardiac tissue only in 3 other patients, indicating a somatic source of the genetic defects Yang et al. (2010) identified a heterozygous nonsense mutationin a 64-year-old female patient who was diagnosed with paroxysmal AF at 32 years of age. The mutation was detected in 6 additional affected family members, but was not found in 6 unaffected family members or in 200 ethnically matched controls. Yang et al. (2010) identified 3 heterozygous missense mutations in 3 probands with AF. The mutations segregated with disease in all 3 families and were not found in 200 ethnically matched controls. Sun et al. (2013) identified a heterozygous missense mutation in a 42-year-old woman who had been diagnosed with AF at age 40 years. The mutation was also detected in her father, who had been diagnosed with lone AF at 41 years of age, but it was not found in unaffected family members, in 200 controls, or in the dbSNP database. Functional analysis demonstrated that the I75F mutant is unable to form functional gap junction channels and also impairs coupling when expressed with wildtype CX40 or CX43. |
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| Mendeliome v0.14647 | GJA5 | Chirag Patel reviewed gene: GJA5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16790700, 20818502, 20650941, 23348765; Phenotypes: Atrial fibrillation, familial, 11, OMIM# 614049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14422 | MATR3 | Zornitza Stark Marked gene: MATR3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14422 | MATR3 | Zornitza Stark Gene: matr3 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14422 | MATR3 | Zornitza Stark Phenotypes for gene: MATR3 were changed from to Amyotrophic lateral sclerosis 21, MIM# 606070; Distal myopathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14421 | MATR3 | Zornitza Stark Publications for gene: MATR3 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14420 | MATR3 | Zornitza Stark Mode of inheritance for gene: MATR3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14419 | MATR3 | Zornitza Stark reviewed gene: MATR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19344878, 24686783, 35205163, 34659085, 34173818, 26493020; Phenotypes: Amyotrophic lateral sclerosis 21, MIM# 606070, Distal myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14291 | DNM1L | Krithika Murali reviewed gene: DNM1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388 (AD, AR), Optic atrophy 5 - MIM#610708 (AD); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13890 | AR | Elena Savva Phenotypes for gene: AR were changed from to Hypospadias 1, X-linked MIM#30063; Androgen insensitivity MIM#300068; Androgen insensitivity, partial, with or without breast cancer MIM#312300; Spinal and bulbar muscular atrophy of Kennedy MIM#313200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13888 | AR | Elena Savva reviewed gene: AR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22334387; Phenotypes: Hypospadias 1, X-linked MIM#30063, Androgen insensitivity MIM#300068, Androgen insensitivity, partial, with or without breast cancer MIM#312300, Spinal and bulbar muscular atrophy of Kennedy MIM#313200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13788 | PRDM13 | Zornitza Stark Phenotypes for gene: PRDM13 were changed from Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790; intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770 to Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790; intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13784 | DROSHA |
Lucy Spencer gene: DROSHA was added gene: DROSHA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DROSHA were set to 35405010 Phenotypes for gene: DROSHA were set to Neurodevelopmental disorder (MONDO#0700092), DROSHA-related Review for gene: DROSHA was set to AMBER Added comment: 2 individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly, and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. Both variants are missense, absent from gnomad. Both individuals noted to have Rett-like features. Functional studies in patient fibroblasts showed one of the missense altered the expression of mature miRNA. Fruit fly models with homozygous LOF variants die during larval stages. introduction of the missense seen in the patients was able to partially rescue this phenotype suggesting LOF is not the mechanism. Sources: Literature |
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| Mendeliome v0.13727 | CRB1 | Ain Roesley Phenotypes for gene: CRB1 were changed from to Leber congenital amaurosis 8 MIM#613835; Pigmented paravenous chorioretinal atrophy MIM#172870; Retinitis pigmentosa-12 MIM#600105 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13725 | CRB1 | Ain Roesley reviewed gene: CRB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30285347, 32922261, 31884620, 15459956; Phenotypes: Leber congenital amaurosis 8 MIM#613835, Pigmented paravenous chorioretinal atrophy MIM#172870, Retinitis pigmentosa-12 MIM#600105; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13637 | HK1 |
Zornitza Stark changed review comment from: HMSNR is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy. Founder variant in the Roma, -3818-195G-C, AltT2 EXON in 5'UTR identified in multiple families. Note gene is associated with other phenotypes.; to: Bi-allelic variants and neuropathy: HMSNR is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy. Founder variant in the Roma, -3818-195G-C, AltT2 EXON in 5'UTR identified in multiple families. Note gene is associated with other phenotypes. |
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| Mendeliome v0.13613 | RRAS |
Belinda Chong changed review comment from: Catts et al (2021) identified a 7-year-old boy with a history of craniosynostosis, congenital heart defect, and mild dysmorphic features who was incidentally found to have pediatric MDS with monosomy 7 in the context of previously unrecognized germline RRAS mutation. A heterozygous c.116_118dup (NM_006270.5) variant resulting in p.G39dup was identified and excluded in an unaffected sibling, and both parents. Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen (reviewed 27/04/2018).; to: Catts et al (2021) identified a 7-year-old boy with a history of craniosynostosis, congenital heart defect, and mild dysmorphic features who was incidentally found to have pediatric MDS with monosomy 7 in the context of previously unrecognized germline RRAS mutation. A heterozygous c.116_118dup (NM_006270.5) variant resulting in p.G39dup was identified and excluded in an unaffected sibling, and both parents. Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen (reviewed 27/04/2018). |
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| Mendeliome v0.13153 | PIDD1 | Zornitza Stark Phenotypes for gene: PIDD1 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum to Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13152 | PIDD1 | Zornitza Stark edited their review of gene: PIDD1: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12937 | PTPN14 | Zornitza Stark Phenotypes for gene: PTPN14 were changed from to Choanal atresia and lymphoedema, MIM# 613611 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12934 | PTPN14 | Zornitza Stark reviewed gene: PTPN14: Rating: GREEN; Mode of pathogenicity: None; Publications: 20826270; Phenotypes: Choanal atresia and lymphoedema, MIM# 613611; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12922 | PTRH2 |
Zornitza Stark commented on gene: PTRH2: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-1 (IMNEPD1) is an autosomal recessive multisystemic disorder with variable expressivity. The core features usually include global developmental delay with impaired intellectual development and speech delay, ataxia, sensorineural hearing loss, and pancreatic insufficiency. Additional features may include peripheral neuropathy, postnatal microcephaly, dysmorphic facial features, and cerebellar atrophy. More than 5 unrelated families reported. The Q85P missense variant is reported in several families, likely founder effect. |
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| Mendeliome v0.12792 | EXOC7 | Bryony Thompson Phenotypes for gene: EXOC7 were changed from brain atrophy; seizures; developmental delay; microcephaly to Neurodevelopmental disorder with seizures and brain atrophy MIM#619072; brain atrophy; seizures; developmental delay; microcephaly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12759 | TTC19 |
Zornitza Stark edited their review of gene: TTC19: Added comment: Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life. The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances. At least 4 unrelated families reported.; Changed publications: 21278747, 23532514, 24368687, 24397319 |
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| Mendeliome v0.12686 | LIG3 | Zornitza Stark Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy to Mitochondrial DNA depletion syndrome 20 (MNGIE type), MIM# 619780 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12612 | SPG7 | Zornitza Stark Phenotypes for gene: SPG7 were changed from Spastic paraplegia 7, autosomal recessive, MIM# 607259 to Spastic paraplegia 7, autosomal recessive, MIM# 607259; Autosomal dominant optic atrophy, MONDO:0020250 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12610 | SPG7 | Zornitza Stark edited their review of gene: SPG7: Changed publications: 9635427, 9635427, 16534102, 18799786, 22571692, 34500365, 33598982, 32548275; Changed phenotypes: Spastic paraplegia 7, autosomal recessive, MIM# 607259, Autosomal dominant optic atrophy, MONDO:0020250; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12604 | RTN4IP1 | Zornitza Stark Phenotypes for gene: RTN4IP1 were changed from to Optic atrophy 10 with or without ataxia, mental retardation, and seizures, MIM#616732 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12573 | RTN4IP1 | Belinda Chong reviewed gene: RTN4IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26593267, 31077085; Phenotypes: Optic atrophy 10 with or without ataxia, mental retardation, and seizures, MIM#616732; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12366 | TLL1 | Zornitza Stark Phenotypes for gene: TLL1 were changed from Atrial septal defect to Atrial septal defect 6, MIM# 613087 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12365 | TLL1 | Zornitza Stark reviewed gene: TLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 6, MIM# 613087; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12339 | EIF2B4 | Zornitza Stark Phenotypes for gene: EIF2B4 were changed from leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; primary ovarian failure to Leukoencephalopathy with vanishing white matter, MIM# 603896; leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; primary ovarian failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12323 | EIF2B5 | Bryony Thompson Phenotypes for gene: EIF2B5 were changed from to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; primary ovarian failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12314 | EIF2B4 | Bryony Thompson Phenotypes for gene: EIF2B4 were changed from to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; primary ovarian failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12307 | EIF2B3 | Bryony Thompson Phenotypes for gene: EIF2B3 were changed from to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12301 | EIF2B1 | Bryony Thompson Phenotypes for gene: EIF2B1 were changed from to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12298 | EIF2B1 | Bryony Thompson reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11835386, 26285592, 15776425, 18263758, 25843247, 25761052, 30014503; Phenotypes: leukoencephalopathy with vanishing white matter MONDO:0011380, ataxia, spasticity, optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12265 | SMN2 | Zornitza Stark Phenotypes for gene: SMN2 were changed from to {Spinal muscular atrophy, type III, modifier of} 253400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12262 | SMN2 | Zornitza Stark reviewed gene: SMN2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: {Spinal muscular atrophy, type III, modifier of} 253400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12214 | OAT | Zornitza Stark Phenotypes for gene: OAT were changed from to Gyrate atrophy of choroid and retina with or without ornithinemia - MIM#258870 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12183 | OAT | Krithika Murali reviewed gene: OAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 1618792, 2220818, 3339136, 3417397, 2916581, 1737786, 33463379; Phenotypes: Gyrate atrophy of choroid and retina with or without ornithinemia - MIM#258870; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12172 | NKX2-5 | Zornitza Stark Phenotypes for gene: NKX2-5 were changed from to Atrial septal defect 7, with or without AV conduction defects, MIM# 108900; Ventricular septal defect 3 (MIM#614432); Tetralogy of Fallot (MIM#187500) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12107 | CACNA2D2 | Ain Roesley Phenotypes for gene: CACNA2D2 were changed from Cerebellar atrophy with seizures and variable developmental delay MIM#618501 to Cerebellar atrophy with seizures and variable developmental delay MIM#618501 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12105 | CACNA2D2 | Ain Roesley Phenotypes for gene: CACNA2D2 were changed from Cerebellar atrophy with seizures and variable developmental delay MIM#618501 to Cerebellar atrophy with seizures and variable developmental delay MIM#618501 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12104 | CACNA2D2 | Ain Roesley Phenotypes for gene: CACNA2D2 were changed from to Cerebellar atrophy with seizures and variable developmental delay MIM#618501 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12101 | CACNA2D2 | Ain Roesley edited their review of gene: CACNA2D2: Changed publications: 23339110, 24358150, 30410802, 29997391, 31402629, 11487633, 11756448, 4177347, 14660671, 15331424; Changed phenotypes: Cerebellar atrophy with seizures and variable developmental delay MIM#618501 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12100 | CACNA2D2 | Ain Roesley reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: Cerebellar atrophy with seizures and variable developmental delay MIM#618501; Phenotypes: 23339110, 24358150, 30410802, 29997391, 31402629, 11487633, 11756448, 4177347, 14660671, 15331424; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11977 | TEAD1 | Zornitza Stark Phenotypes for gene: TEAD1 were changed from to Sveinsson chorioretinal atrophy, MIM# 108985 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11975 | TEAD1 |
Zornitza Stark changed review comment from: Sveinsson chorioretinal atrophy (SCRA) is characterized by bilateral, well-defined, tongue-shaped strips of atrophic retina and choroid that extend from the optic nerve into the peripheral ocular fundus. The lesions may be evident at birth and usually progress at a variable rate, sometimes leading to central visual loss. Separate small distinct circular atrophic lesions are observed in the peripheral ocular fundus in some patients. Congenital anterior polar cataracts are found in approximately 25% of affected individuals. The vast majority of reported cases were of Icelandic origin but the characteristic clinical picture of SCRA is also described in patients of non-Icelandic descent. The variant reported in the Icelanding population is (c.1261T>C, p.Tyr421His), another variant at same position c.1261T>A, p.Tyr421Asn also reported in non-Icelandic family. Functional data supports gene-disease association.; to: Sveinsson chorioretinal atrophy (SCRA) is characterized by bilateral, well-defined, tongue-shaped strips of atrophic retina and choroid that extend from the optic nerve into the peripheral ocular fundus. The lesions may be evident at birth and usually progress at a variable rate, sometimes leading to central visual loss. Separate small distinct circular atrophic lesions are observed in the peripheral ocular fundus in some patients. Congenital anterior polar cataracts are found in approximately 25% of affected individuals. The vast majority of reported cases were of Icelandic origin but the characteristic clinical picture of SCRA is also described in patients of non-Icelandic descent. The variant reported in the Icelanding population is (c.1261T>C, p.Tyr421His), another variant at same position c.1261T>A, p.Tyr421Asn also reported in non-Icelandic family. A de novo nonsense variant has also been reported in a case with Aicardi syndrome with infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. |
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| Mendeliome v0.11973 | TEAD1 | Zornitza Stark reviewed gene: TEAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15016762, 33864784, 17689488, 30903741; Phenotypes: Sveinsson chorioretinal atrophy, MIM# 108985; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11958 | TBX20 | Zornitza Stark Phenotypes for gene: TBX20 were changed from to Atrial septal defect 4, MIM# 611363 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11955 | TBX20 | Zornitza Stark reviewed gene: TBX20: Rating: GREEN; Mode of pathogenicity: None; Publications: 17668378, 19762328, 33585493, 29089047; Phenotypes: Atrial septal defect 4, MIM# 611363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11764 | TXNRD2 |
Zornitza Stark changed review comment from: Further cases reported in this large cohort of paediatric primary adrenal insufficiency.; to: Further cases reported in this large cohort of paediatric primary adrenal insufficiency. Evidence for association with DCM is limited, considering pop frequency of variants reported. |
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| Mendeliome v0.11342 | KCNA5 | Zornitza Stark Phenotypes for gene: KCNA5 were changed from to Atrial fibrillation, familial, 7, MIM# 612240 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11339 | KCNA5 | Zornitza Stark reviewed gene: KCNA5: Rating: ; Mode of pathogenicity: None; Publications: 16772329, 19343045, 23264583; Phenotypes: Atrial fibrillation, familial, 7, MIM# 612240; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11335 | KCNE5 | Zornitza Stark Phenotypes for gene: KCNE5 were changed from to Atrial fibrillation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11331 | KCNE5 | Zornitza Stark reviewed gene: KCNE5: Rating: RED; Mode of pathogenicity: None; Publications: 18313602, 16054468, 30289750; Phenotypes: Atrial fibrillation; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11323 | KCNMA1 | Zornitza Stark Phenotypes for gene: KCNMA1 were changed from to Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM# 609446; Cerebellar atrophy, developmental delay, and seizures, MIM# 617643; Liang-Wang syndrome, MIM# 618729 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11320 | KCNMA1 | Zornitza Stark reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15937479, 26195193, 27567911, 29545233, 31427379, 31152168; Phenotypes: Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM# 609446, Cerebellar atrophy, developmental delay, and seizures, MIM# 617643, Liang-Wang syndrome, MIM# 618729; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11076 | PPP2R3C |
Zornitza Stark gene: PPP2R3C was added gene: PPP2R3C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PPP2R3C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPP2R3C were set to 30893644; 34714774; 34750818 Phenotypes for gene: PPP2R3C were set to Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, OMIM # 618419 Review for gene: PPP2R3C was set to GREEN Added comment: Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy (GDRM) is characterized by 46,XY complete gonadal dysgenesis in association with extragonadal anomalies, low birth weight, typical facial gestalt, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. 11 unrelated families with syndromic complete gonadal dysgenesis. 9 families had 46,XY females with complete gonadal dysgenesis, but 2 families had 46,XX patients with hypergonadotropic hypogonadism, nonvisualized gonads, primary amenorrhea, and absence of secondary sexual characteristics. Variants segregated with disease in each family and were not found in ethnically matched controls or in public variant databases. The heterozygous fathers exhibited morphologic abnormalities of spermatozoa and reduced fertility. Sources: Literature |
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| Mendeliome v0.10950 | BAG5 |
Zornitza Stark gene: BAG5 was added gene: BAG5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BAG5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BAG5 were set to 35044787 Phenotypes for gene: BAG5 were set to Cardiomyopathy, dilated, 2F, MIM# 619747 Review for gene: BAG5 was set to GREEN Added comment: 5 individuals from four unrelated families reported. All had early-onset disease, with the diagnosis being made in the second decade of life in 4 patients (families 1, 3, and 4) and at age 34 in 1 (family 2). Refractory ventricular arrhythmias (tachycardia or fibrillation), severely reduced left ventricular ejection fractions, elevated left ventricular diastolic dimensions, and elevated brain natriuretic peptide (BNP) levels reported. All developed severe heart failure requiring placement of a left ventricular assist device for circulatory support, and at least 1 underwent cardiac transplantation. Sources: Literature |
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| Mendeliome v0.10917 | HYAL2 | Krithika Murali reviewed gene: HYAL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34906488, 28081210, 23172227, 26515055; Phenotypes: Cleft lip and palate, cor triatriatum, congenital cardiac malformations; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10793 | CHP1 |
Zornitza Stark gene: CHP1 was added gene: CHP1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CHP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHP1 were set to 29379881; 32787936 Phenotypes for gene: CHP1 were set to Spastic ataxia 9, autosomal recessive, MIM #618438 Review for gene: CHP1 was set to GREEN Added comment: 2 different consanguineous families with 2 affected siblings with ataxia (1 paediatric onset, 1 adult onset). 3 of the patients had cerebellar atrophy. WES identified homozygous variants in CHP1 gene in both families (K19del and Arg91Cys), which segregated with the disorder in the family. Decreased CHP1 protein on IHC of cerebellar tissue in family with Arg91Cys variant. In vitro functional expression studies in HEK293 cells showed that the K19del mutation resulted in decreased protein expression, with normal levels of transcript, suggesting defects in protein stability. The mutant protein formed massive protein aggregates in transfected neuronal cell bodies and neurite-like projections, whereas the wildtype protein showed a more uniform distribution. The mutant protein altered CHP1 association into functional complexes and impaired membrane localization of the Na+/H+ transporter NHE1. The findings indicated that the CHP1 mutation likely causes ataxia in an NHE1-dependent manner, resembling the mechanism observed in the Chp1 vacillator mutant mouse. Sources: Expert Review |
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| Mendeliome v0.10567 | PRDM13 | Zornitza Stark Phenotypes for gene: PRDM13 were changed from Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790 to Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790; intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10333 | CITED2 | Zornitza Stark Phenotypes for gene: CITED2 were changed from to Atrial septal defect 8 - MIM#614433; Ventricular septal defect 2 - MIM#614431 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10321 | CITED2 | Krithika Murali reviewed gene: CITED2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33706167, 33439552, 31515672, 29536580; Phenotypes: Atrial septal defect 8 - MIM#614433, Ventricular septal defect 2 - MIM#614431; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10212 | GATA4 | Zornitza Stark Phenotypes for gene: GATA4 were changed from to Atrial septal defect 2 MIM#607941; Atrioventricular septal defect 4 MIM#614430; Ventricular septal defect 1 MIM#614429 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10204 | GATA4 | Ain Roesley reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12845333, 18055909, 15689439, 33413087, 30455927; Phenotypes: Atrial septal defect 2 MIM#607941, Atrioventricular septal defect 4 MIM#614430, Ventricular septal defect 1 MIM#614429; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10181 | ADCY5 |
Zornitza Stark edited their review of gene: ADCY5: Added comment: Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD) is an autosomal recessive complex neurologic disorder characterized by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. Five individuals from 2 families reported. Autosomal recessive hyperkinetic movement disorder with dyskinesia, myoclonus, chorea, and dystonia-2 (HYDMCD2) is characterized by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. The severity is variable; some patients have orofacial dyskinesia, resulting in speech difficulties, or develop neuropsychiatric features, including anxiety and social withdrawal. Cardiomyopathy has rarely been described and may be a manifestation of the disorder. Eight individuals from 2 families reported.; Changed publications: 22782511, 24700542, 33051786, 32647899, 33704598, 34631954, 28971144, 30975617; Changed phenotypes: Dyskinesia, familial, with facial myokymia, MIM# 606703, MONDO:0011707, Hyperkinetic movement disorder with dyskinesia, myoclonus, chorea, and dystonia-2 (HYDMCD2), MIM#619647, Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD), MIM#619651; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.10100 | MSH5 |
Bryony Thompson changed review comment from: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature; to: 4 unrelated male azoospermia cases with 3 different homozygous frameshift/missense variants. A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.10100 | MSH5 |
Bryony Thompson changed review comment from: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature; to: 4 unrelated male azoospermia cases with 3 different homozygous frameshift/missense variants. A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.10019 | FOXR1 |
Paul De Fazio changed review comment from: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnornmalities, and dysmorphic features. In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation). A mouse knockout has comparable phenotypes, and a severe survival deficit. Rated amber (1 patient, functional evidence, mouse model). Sources: Literature; to: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnormalities, and dysmorphic features. A variant in ATP1A3 was considered to have contributed to the final phenotype. In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation). A mouse knockout has comparable phenotypes, and a severe survival deficit. Rated amber (1 patient, functional evidence, mouse model). Sources: Literature |
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| Mendeliome v0.10017 | FOXR1 |
Paul De Fazio gene: FOXR1 was added gene: FOXR1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FOXR1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FOXR1 were set to 34723967 Phenotypes for gene: FOXR1 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay Review for gene: FOXR1 was set to AMBER gene: FOXR1 was marked as current diagnostic Added comment: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnornmalities, and dysmorphic features. In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation). A mouse knockout has comparable phenotypes, and a severe survival deficit. Rated amber (1 patient, functional evidence, mouse model). Sources: Literature |
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| Mendeliome v0.9921 | ACO2 | Zornitza Stark Phenotypes for gene: ACO2 were changed from to Infantile cerebellar-retinal degeneration, MIM#614559; Optic atrophy 9, MIM# 616289 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9918 | ACO2 | Zornitza Stark edited their review of gene: ACO2: Changed phenotypes: Infantile cerebellar-retinal degeneration, MIM#614559, Optic atrophy 9, MIM# 616289 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9807 | KCNJ2 | Zornitza Stark Phenotypes for gene: KCNJ2 were changed from to Andersen syndrome MIM#170390; Atrial fibrillation, familial, 9 MIM#613980; Short QT syndrome 3 MIM#609622 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9779 | KCNJ2 | Ain Roesley reviewed gene: KCNJ2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Andersen syndrome MIM#170390, Atrial fibrillation, familial, 9 MIM#613980, Short QT syndrome 3 MIM#609622; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9694 | BRAT1 | Zornitza Stark Phenotypes for gene: BRAT1 were changed from to Neurodevelopmental disorder with cerebellar atrophy and with or without seizures, MIM#618056; Rigidity and multifocal seizure syndrome, lethal neonatal, MIM# 614498 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9691 | BRAT1 |
Zornitza Stark changed review comment from: At least 4 individuals reported from unrelated families and bi-allelic variants in this gene. Sources: Expert list; to: Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL) to neurodevelopmental disorder and cerebellar atrophy with or without seizures (NEDCAS), without obvious genotype-phenotype associations. Multiple families reported with each. |
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| Mendeliome v0.9691 | BRAT1 | Zornitza Stark edited their review of gene: BRAT1: Changed publications: 26483087, 26494257, 27282546, 22279524, 23035047, 25319849, 25500575, 34747546; Changed phenotypes: Neurodevelopmental disorder with cerebellar atrophy and with or without seizures, MIM#618056, Rigidity and multifocal seizure syndrome, lethal neonatal, MIM# 614498 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9661 | HR | Zornitza Stark Phenotypes for gene: HR were changed from to Alopecia universalis MIM#203655; Atrichia with papular lesions MIM#209500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9638 | HR | Ain Roesley reviewed gene: HR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alopecia universalis MIM#203655, Atrichia with papular lesions MIM#209500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9616 | MYH10 |
Krithika Murali gene: MYH10 was added gene: MYH10 was added to Mendeliome. Sources: Expert list,Literature Mode of inheritance for gene: MYH10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYH10 were set to 24825879; 24901346; 25356899; 22495309; 25003005 Phenotypes for gene: MYH10 were set to Microcephaly; Intellectual Disability Review for gene: MYH10 was set to GREEN Added comment: De novo variants were identified in 5 unrelated individuals with moderate-severe ID and developmental delay. Other reported phenotypic features include microcephaly (4/5), IUGR/failure to thrive (4/5), cerebral atrophy (3/5), hydrocephalus (2/5), congenital bilateral hip dysplasia (2/5), cerebellar atrophy (1/5), congenital diaphragmatic hernia (1/5), cranial nerve palsy (1/5), nystagmus (1/5), dysplastic kidney (1/5). Defects in heart development, body wall closure and other birth defects noted in mouse models. Sources: Expert list, Literature |
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| Mendeliome v0.9537 | ACTC1 |
Krithika Murali gene: ACTC1 was added gene: ACTC1 was added to Mendeliome. Sources: Expert list,Literature Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ACTC1 were set to 26061005; 17947298; 31430208; 18403758; 30384889 Phenotypes for gene: ACTC1 were set to Atrial septal defect 5, MIM# 612794; Cardiomyopathy, dilated, 1R - MIM# 613424; Cardiomyopathy, hypertrophic, 11 - #612098 Review for gene: ACTC1 was set to GREEN Added comment: Four families reported with congenital heart disease and variants in this gene. Note gene is also associated with cardiomyopathies, including paediatric-onset dilated and hypertrophic cardiomyopathy. Sources: Expert list, Literature |
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| Mendeliome v0.9467 | ACTC1 |
Krithika Murali gene: ACTC1 was added gene: ACTC1 was added to Mendeliome. Sources: Literature,Expert list Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ACTC1 were set to 17947298; 31430208 Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 - MIM# 612794; Cardiomyopathy, dilated, 1R - MIM# 613424; Cardiomyopathy, hypertrophic, 11 - #612098; Left ventricular noncompaction 4 - #613424 Review for gene: ACTC1 was set to GREEN Added comment: Three families reported with congenital heart disease and variants in this gene. Gene is also associated with cardiomyopathies, including paediatric onset. Sources: Literature, Expert list |
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| Mendeliome v0.9370 | GABRD | Zornitza Stark edited their review of gene: GABRD: Added comment: 10 individuals with 7 unique variants reported in individuals with neurodevelopmental disorders and epilepsy. Six of the variants were demonstrated to be GoF, and those individuals with neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. In contrast, the one individual carrying a loss-of-function variant had normal intelligence, no seizure history but has a diagnosis of autism spectrum disorder and suffering from elevated internalizing psychiatric symptoms.; Changed rating: GREEN; Changed publications: 15115768, 34633442; Changed phenotypes: Intellectual disability, Epilepsy, Susceptibility to epilepsy, MIM#613060 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9297 | ATP11A |
Elena Savva gene: ATP11A was added gene: ATP11A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATP11A were set to PMID: 34403372 Phenotypes for gene: ATP11A were set to Neurological disorder Mode of pathogenicity for gene: ATP11A was set to Other Review for gene: ATP11A was set to AMBER Added comment: PMID: 34403372: - Single de novo missense variant reported in a patient with developmental delay and neurological deterioration. - Patient MRI showed severe cerebral atrophy, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. Axonal neuropathy suggested. - K/I heterozygous mice died perinatally. - Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc. gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets. Sources: Literature |
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| Mendeliome v0.9253 | OPA1 | Zornitza Stark Phenotypes for gene: OPA1 were changed from Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type)MIM# 6168963; Behr syndrome MIM#210000, AR; Optic atrophy 1, MIM#165500; Optic atrophy plus syndrome, MIM# 125250 to Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type)MIM# 616896; Behr syndrome MIM#210000, AR; Optic atrophy 1, MIM#165500; Optic atrophy plus syndrome, MIM# 125250 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9203 | B9D1 |
Bryony Thompson changed review comment from: hNow N PMID: 34338422 - compound het missense and frameshift variant in a proband with anal atresia with vestibular fistula, ventricular septal defect, and right renal agenesis (VACTERL cohort) PMID: 21763481 - B9d1 -/- mouse displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction.; to: 3 unrelated cases with a syndromic phenotype and a supporting null mouse model PMID: 34338422 - compound het missense and frameshift variant in a proband with anal atresia with vestibular fistula, ventricular septal defect, and right renal agenesis (VACTERL cohort) PMID: 24886560 - 2 Joubert syndrome cases PMID: 21763481 - B9d1 -/- mouse displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction. |
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| Mendeliome v0.9203 | CARMIL2 | Zornitza Stark Phenotypes for gene: CARMIL2 were changed from to Immunodeficiency 58, MIM# 618131; Early onset paediatric inflammatory bowel disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9200 | CARMIL2 | Zornitza Stark reviewed gene: CARMIL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29479355, 28112205, 27896283, 33723309; Phenotypes: Immunodeficiency 58, MIM# 618131, Early onset paediatric inflammatory bowel disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9186 | AMPD2 | Zornitza Stark edited their review of gene: AMPD2: Added comment: Well established gene-disease association. Clinical features include severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination.; Changed rating: GREEN; Changed publications: 23911318, 27066553 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9112 | TF | Zornitza Stark Phenotypes for gene: TF were changed from to Atransferrinaemia MIM# 209300; iron overload; hypochromic anaemia; low serum transferrin; Hemosiderosis of the heart and/or liver; Congestive heart failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9109 | TF | Danielle Ariti reviewed gene: TF: Rating: GREEN; Mode of pathogenicity: None; Publications: 11110675, 3472216; Phenotypes: Atransferrinaemia MIM# 209300, iron overload, hypochromic anaemia, low serum transferrin, Hemosiderosis of the heart and/or liver, Congestive heart failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9101 | UMPS |
Zornitza Stark edited their review of gene: UMPS: Added comment: 20 unrelated patients have been reported with biallelic missense variants; one mouse model Orotic aciduria is characterised by megaloblastic anaemia and orotic acid crystalluria, frequently associated with a degree of physical and intellectual disability. Other features include, congenital malformations (Atrial/ Ventricular septal defect) and immunodeficiencies (T-cell dysfunction, failure to thrive, recurrent infections). Haematology features - Megaloblastic anaemia - Low to normal reticulocyte count - Anisocytosis - Poikilocytosis - Hypochromia; Changed publications: 9042911, 33489760; Changed phenotypes: Orotic aciduria, MIM# 258900 |
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| Mendeliome v0.9098 | TPI1 |
Zornitza Stark changed review comment from: More than 10 unrelated families reported; bi-allelic (missense, nonsense, frameshift) variants; Common p.Glu104Asp variant in Northern European population Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterised by early childhood onset congenital hemolytic anaemia, and progressive neuromuscular dysfunction. Many patients die from respiratory failure in childhood. The neurological features are variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Other features include intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells and increased susceptibility to infections.; to: More than 10 unrelated families reported; bi-allelic (missense, nonsense, frameshift) variants; Common p.Glu104Asp variant in Northern European population Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterised by early childhood onset congenital haemolytic anaemia, and progressive neuromuscular dysfunction. Many patients die from respiratory failure in childhood. The neurological features are variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Other features include intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells and increased susceptibility to infections. |
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| Mendeliome v0.9098 | TPI1 |
Zornitza Stark edited their review of gene: TPI1: Added comment: More than 10 unrelated families reported; bi-allelic (missense, nonsense, frameshift) variants; Common p.Glu104Asp variant in Northern European population Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterised by early childhood onset congenital hemolytic anaemia, and progressive neuromuscular dysfunction. Many patients die from respiratory failure in childhood. The neurological features are variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Other features include intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells and increased susceptibility to infections.; Changed publications: 9338582, 32873690, 8503454; Changed phenotypes: Haemolytic anaemia due to triosephosphate isomerase deficiency, MIM# 615512 |
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| Mendeliome v0.9098 | YARS2 | Zornitza Stark Phenotypes for gene: YARS2 were changed from to Myopathy, lactic acidosis, and sideroblastic anaemia 2 MIM# 613561; sideroblastic anaemia; muscle atrophy; myopathy; lactic acidosis; Hypertrophic cardiomyopathy; Hepatomegaly; Decreased cytochrome C oxidase activity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9095 | YARS2 | Zornitza Stark reviewed gene: YARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24430573, 24344687; Phenotypes: Myopathy, lactic acidosis, and sideroblastic anaemia 2 MIM# 613561, sideroblastic anaemia, muscle atrophy, myopathy, lactic acidosis, Hypertrophic cardiomyopathy, Hepatomegaly, Decreased cytochrome C oxidase activity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9075 | LRP1 | Elena Savva reviewed gene: LRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26142438, 33776059; Phenotypes: ?Keratosis pilaris atrophicans MIM#604093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9021 | CHRM1 |
Bryony Thompson gene: CHRM1 was added gene: CHRM1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218 Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability; autism Review for gene: CHRM1 was set to AMBER Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways. PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu) PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction. Sources: Literature |
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| Mendeliome v0.9009 | SHOX2 |
Zornitza Stark gene: SHOX2 was added gene: SHOX2 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: SHOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SHOX2 were set to 30443179 Phenotypes for gene: SHOX2 were set to Sinus Node Dysfunction; Atrial Fibrillation Review for gene: SHOX2 was set to RED Added comment: Single family reported with LoF in this gene and AF. Sources: Expert Review |
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| Mendeliome v0.8984 | PNPLA6 |
Zornitza Stark changed review comment from: Ataxia is part of the phenotype. Sources: Expert list; to: Variants in this gene are associated with multiple phenotypes. Oliver-McFarlane syndrome is a rare congenital disorder characterized by trichomegaly, severe chorioretinal atrophy and multiple pituitary hormone deficiencies, including growth hormone. At least 10 families reported. Laurence-Moon syndrome has a clinical presentation similar to that of Oliver-McFarlane syndrome, including chorioretinopathy and pituitary dysfunction, but with childhood onset of ataxia, peripheral neuropathy, and spastic paraplegia and without trichomegaly. Single family reported. |
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| Mendeliome v0.8910 | EPHX1 | Zornitza Stark Phenotypes for gene: EPHX1 were changed from to Lipoatrophic diabetes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8906 | EPHX1 | Zornitza Stark reviewed gene: EPHX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34342583; Phenotypes: Lipoatrophic diabetes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8879 | ATR | Zornitza Stark Marked gene: ATR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8879 | ATR | Zornitza Stark Gene: atr has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8879 | ATR | Zornitza Stark Phenotypes for gene: ATR were changed from to Seckel syndrome 1, MIM# 210600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8878 | ATR | Zornitza Stark Publications for gene: ATR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8877 | ATR | Zornitza Stark Mode of inheritance for gene: ATR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8876 | ATR | Zornitza Stark reviewed gene: ATR: Rating: GREEN; Mode of pathogenicity: None; Publications: 12640452, 19620979, 30199583, 23111928; Phenotypes: Seckel syndrome 1, MIM# 210600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8838 | PGRMC1 | Bryony Thompson Phenotypes for gene: PGRMC1 were changed from Premature ovarian failure to Premature ovarian failure; Isolated paediatric cataract | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8835 | PGRMC1 | Bryony Thompson reviewed gene: PGRMC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33867527, 23783460; Phenotypes: Isolated paediatric cataract; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8834 | RNF220 |
Zornitza Stark gene: RNF220 was added gene: RNF220 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF220 were set to 33964137; 10881263 Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum Review for gene: RNF220 was set to GREEN Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal. Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9). The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263). Extensive segregation analyses were carried out including several affected and unaffected members. RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc : *RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS) *The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions. *Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome. *Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2). *RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1. *Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt. *Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies. Sources: Literature |
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| Mendeliome v0.8833 | NBAS | Zornitza Stark Phenotypes for gene: NBAS were changed from to Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800; Infantile liver failure syndrome 2, MIM# 616483 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8830 | NBAS | Zornitza Stark reviewed gene: NBAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31761904; Phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800, Infantile liver failure syndrome 2, MIM# 616483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8829 | ARF3 |
Zornitza Stark gene: ARF3 was added gene: ARF3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARF3 were set to 34346499 Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system Review for gene: ARF3 was set to AMBER Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality. Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu. Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both. ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively. Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons. There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185). In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val). This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia. Evidence to support the effect of each variant include: Arg99Leu: Had identical Golgi localization to that of wt Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF) In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF). In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu) Asp67Val: Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant) Displayed decreased protein stability In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF) In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye. There is no associated phenotype in OMIM, G2P or SysID. Sources: Literature |
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| Mendeliome v0.8741 | TCF7L2 |
Zornitza Stark changed review comment from: 2 reviews Konstantinos Varvagiannis (Other) I don't know Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants. Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11). One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury. TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts. Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development. Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1]. The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA). No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism. There are no variant or other studies performed, nor any animal models discussed. In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs). Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm. There is no other associated phenotype (notably NDD) in OMIM. G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF). SysID includes this gene within the autism candidate genes and current primary ID genes.; to: Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants. Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11). One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury. TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts. Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development. Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1]. The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA). No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism. There are no variant or other studies performed, nor any animal models discussed. In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs). Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm. There is no other associated phenotype (notably NDD) in OMIM. G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF). SysID includes this gene within the autism candidate genes and current primary ID genes. |
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| Mendeliome v0.8736 | PIDD1 |
Zornitza Stark gene: PIDD1 was added gene: PIDD1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010 Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum Review for gene: PIDD1 was set to GREEN Added comment: There is enough evidence to include this gene in the current panel with green rating. Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested. The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families]. Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants. Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder. PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage. There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation. Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants. Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26 Evidence so far provided includes: - Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern. - Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability. - Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp] - Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain. - Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD. Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects. There is currently no associated phenotype in OMIM. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes. Sources: Expert Review |
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| Mendeliome v0.8608 | VRK1 | Zornitza Stark Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A, MIM# 607596; SMA to Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8606 | VRK1 |
Zornitza Stark changed review comment from: Complex phenotype with mixed peripheral and central neurological features. Two families reported where PCH was prominent and accompanied by ataxia. At least three families also reported where peripheral neuropathy dominated the clinical picture without PCH/ataxia.; to: Complex phenotype with mixed peripheral and central neurological features. Two families reported where PCH was prominent and accompanied by ataxia. At least three families also reported where peripheral neuropathy dominated the clinical picture without PCH/ataxia. Further delineation of phenotype 2021: PMID 34169149: expanding spectrum of neurologic disorders associated with VRK1. Two Hispanic individuals, one homozygous (R321C: VUS and LP/P in ClinVar) and one cHet (R321C+V236M, latter P and more recently VUS in ClinVar), with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy WITHOUT pontocerebellar atrophy. No hom in gnomAD and both have been reported in cHet individuals with other features: R321C in association with adult-onset amyotrophic lateral sclerosis and V236M with rapidly progressive sensorimotor polyneuropathy and microcephaly. Authors suggest PMID 26583493 and 31837156 have similar reports. PMID 26583493 reports a 32yo Hispanic individual, cHet H119R+R321C, with early-onset amyotrophic lateral sclerosis, 5 years progressive weakness. PMID 31837156 reports two patients with adult-onset length-dependent motor neuropathy from unrelated consanguineous families of Moroccan Jewish descent, both hom for R387H. |
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| Mendeliome v0.8606 | VRK1 | Zornitza Stark edited their review of gene: VRK1: Changed publications: 19646678, 21937992, 25609612, 24126608, 27281532, 34169149, 26583493; Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 v0.8569 | SGO1 | Zornitza Stark Phenotypes for gene: SGO1 were changed from to Chronic atrial and intestinal dysrhythmia, MIM# 616201 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8565 | SGO1 | Zornitza Stark reviewed gene: SGO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25282101; Phenotypes: Chronic atrial and intestinal dysrhythmia, MIM# 616201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8511 | CAMK4 |
Zornitza Stark gene: CAMK4 was added gene: CAMK4 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350 Phenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus Review for gene: CAMK4 was set to GREEN Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant. Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms. CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018). The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below]. Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function. Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported. Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below). Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function. Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID. --- The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy. Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one. Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein. Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect. To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV. Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect. ---- Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20]. ---- Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*). Sources: Expert Review |
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| Mendeliome v0.8379 | 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 v0.8367 | 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 v0.8326 | TMEM126A | Zornitza Stark Phenotypes for gene: TMEM126A were changed from to Optic atrophy 7, MIM# 612989; MONDO:0013069; Syndromic auditory neuropathy spectrum disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8323 | TMEM126A | Zornitza Stark reviewed gene: TMEM126A: Rating: GREEN; Mode of pathogenicity: None; Publications: 19327736, 20405026, 22815638, 33879611, 31119195, 30961538; Phenotypes: Optic atrophy 7, MIM# 612989, MONDO:0013069, Syndromic auditory neuropathy spectrum disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 |
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| 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. |
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| 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 |
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| Mendeliome v0.8273 | HEATR5B | Seb Lunke Phenotypes for gene: HEATR5B were changed from pontocerebellar hypoplasia to pontocerebellar hypoplasia; intellectual disability; seizures | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8269 | HEATR5B | Seb Lunke Marked gene: HEATR5B as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8269 | HEATR5B | Seb Lunke Gene: heatr5b has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8269 | HEATR5B | Seb Lunke Classified gene: HEATR5B as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8269 | HEATR5B | Seb Lunke Gene: heatr5b has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| Mendeliome v0.8201 | HEATR5B |
Teresa Zhao gene: HEATR5B was added gene: HEATR5B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HEATR5B were set to PMID: 33824466 Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia Review for gene: HEATR5B was set to AMBER Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay. Two homozygous splice variants were reported ((c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. Homozygous knockout mice were not viable. *NOTE: gene (and alias) not found in OMIM Sources: Literature |
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| Mendeliome v0.7944 | 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 |
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| 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 |
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| Mendeliome v0.7885 | UBTF | Zornitza Stark Phenotypes for gene: UBTF were changed from to Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7882 | UBTF | Zornitza Stark reviewed gene: UBTF: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777933, 29300972; Phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672, MONDO:0044701; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 v0.7696 | 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 v0.7675 | 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 v0.7615 | 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 v0.7561 | 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. |
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| 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." |
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| 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 v0.7412 | MECR | Zornitza Stark Phenotypes for gene: MECR were changed from to Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282; MONDO:0015003 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7409 | MECR | Zornitza Stark reviewed gene: MECR: Rating: GREEN; Mode of pathogenicity: None; Publications: 27817865, 33401012, 31137067, 31070877; Phenotypes: Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282, MONDO:0015003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 v0.7217 | 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 v0.7180 | MAPKAPK5 |
Zornitza Stark gene: MAPKAPK5 was added gene: MAPKAPK5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAPKAPK5 were set to 3344202 Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic Review for gene: MAPKAPK5 was set to GREEN Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization. Sources: Literature |
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| Mendeliome v0.7175 | 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 v0.7121 | 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 |
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| Mendeliome v0.7118 | SLC45A1 | Zornitza Stark Phenotypes for gene: SLC45A1 were changed from to Intellectual developmental disorder with neuropsychiatric features, MIM# 617532 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7114 | SLC45A1 | Zornitza Stark reviewed gene: SLC45A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28434495; Phenotypes: Intellectual developmental disorder with neuropsychiatric features, MIM# 617532; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7084 | FBN2 |
Zornitza Stark edited their review of gene: FBN2: Added comment: The association between mono-allelic variants in FBN2 and CCA is well established. Recent report of bi-allelic variants, Kloth (2021): biallelic FBN2 variants (PTC/missense) in a teenager with severe CCA, including cardiac defects, mild scoliosis and muscular involvement. Carrier parents both "healthy/unaffected". Phenotype matches mouse K/O. Authors performed a lit review and identified an additional 2 homozygous patients (both missense variants) with - fetal akinesia, brain ischemia and neonatal death - severe muscle weakness with bilateral clubfeet, a pronounced gait disturbance, recurrent patellar dislocations, flexion contractures, camptodactyly, widespread striae and an unusual myofibrillar disorganization, variation in fiber size and atrophic fibers in muscle biopsy. Evidence for association with Macular degeneration, early-onset MIM#616118 is limited. One family reported, plus some rare variants reported in cohort studies. The familial variant p.Glu1144Lys is present in 11 hets in gnomad and has benign in silicos. The second variant reported in the paper, p.Met1247Thr is present in >20 hets.; Changed rating: GREEN; Changed publications: 33571691; Changed phenotypes: Contractural arachnodactyly, congenital MIM#121050, Macular degeneration, early-onset MIM#616118; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.7001 | 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 v0.6908 | 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 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 v0.6901 | 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 v0.6356 | 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 v0.6353 | LAMA3 | Zornitza Stark Phenotypes for gene: LAMA3 were changed from to Epidermolysis bullosa, generalized atrophic benign, MIM# 226650; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6350 | LAMA3 | Zornitza Stark reviewed gene: LAMA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 7633458, 8530087, 11810295, 10366601; Phenotypes: Epidermolysis bullosa, generalized atrophic benign, MIM# 226650, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6207 | WBP11 |
Eleanor Williams gene: WBP11 was added gene: WBP11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WBP11 were set to 33276377 Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems Review for gene: WBP11 was set to GREEN Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies. Sources: Literature |
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| Mendeliome v0.6162 | 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 |
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| Mendeliome v0.6153 | PRDM13 | Zornitza Stark Phenotypes for gene: PRDM13 were changed from Retinal dystrophy to Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6152 | PRDM13 | Zornitza Stark edited their review of gene: PRDM13: Changed phenotypes: Retinal dystrophy, Chorioretinal atrophy, progressive bifocal, MIM# 600790 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.6012 | 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 |
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| 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 | 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 v0.5671 | 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 v0.5665 | 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 v0.5644 | MSH5 |
Bryony Thompson gene: MSH5 was added gene: MSH5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MSH5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MSH5 were set to 28175301; 9916805; 24970489 Phenotypes for gene: MSH5 were set to Premature ovarian failure 13 MIM#617442 Review for gene: MSH5 was set to AMBER Added comment: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.5579 | 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 |
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| Mendeliome v0.5567 | VPS4A |
Kristin Rigbye changed review comment from: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." Sources: Literature; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." |
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| Mendeliome v0.5567 | VPS4A |
Elena Savva changed review comment from: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." |
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| Mendeliome v0.5567 | VPS4A | Elena Savva Added comment: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5558 | VPS4A |
Kristin Rigbye gene: VPS4A was added gene: VPS4A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS4A were set to PMID: 33186543; 33186545 Phenotypes for gene: VPS4A were set to Neurodevelopmental disorder Review for gene: VPS4A was set to GREEN Added comment: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life." Sources: Literature |
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| Mendeliome v0.5553 | MINPP1 |
Zornitza Stark gene: MINPP1 was added gene: MINPP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MINPP1 were set to 33257696 Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia Review for gene: MINPP1 was set to GREEN Added comment: 8 individuals from 6 unrelated families reported with bi-allelic LOF variants. All presented with almost complete absence of motor and cognitive development, progressive or congenital microcephaly, spastic tetraplegia or dystonia, and vision impairments. For most, the first symptoms included neonatal severe axial hypotonia and epilepsy that started during the first months or years of life. Prenatal symptoms of microcephaly associated with increased thalami echogenicity were detected in one, while the seven other individuals presented with progressive microcephaly. Some exhibited rapidly progressive phenotype and the affected children died in their infancy or middle-childhood. Strikingly, all the affected children had a unique brain MRI showing a mild to severe PCH, fluid-filled posterior fossa, with dilated lateral ventricles. In addition, severe atrophy at the level of the basal ganglia or thalami often associated with typical T2 hypersignal were identified in all the patients MRI. Supportive functional data showing accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. Sources: Literature |
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| Mendeliome v0.5514 | NPPA | Zornitza Stark Phenotypes for gene: NPPA were changed from to Atrial fibrillation, familial, 6, (MIM#612201) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5511 | NPPA | Zornitza Stark reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 18614783, 20064500, 31034774, 31077706; Phenotypes: Atrial fibrillation, familial, 6, (MIM#612201); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.5483 | 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 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 v0.5474 | 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 v0.5439 | HOXA4 | Zornitza Stark Phenotypes for gene: HOXA4 were changed from to Microtia-Atresia; CAKUT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5431 | HOXA4 | Naomi Baker reviewed gene: HOXA4: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 33193662; Phenotypes: Microtia-Atresia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.5319 | 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 v0.5272 | 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 v0.5269 | 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 v0.5235 | 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 v0.5216 | 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 v0.5139 | CTNNA3 |
Bryony Thompson gene: CTNNA3 was added gene: CTNNA3 was added to Mendeliome. Sources: ClinGen Mode of inheritance for gene: CTNNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CTNNA3 were set to 23136403; 21254927; 22421363; 30415094; 31539150 Phenotypes for gene: CTNNA3 were set to Arrhythmogenic right ventricular cardiomyopathy; Arrhythmogenic right ventricular dysplasia, familial, 13 MIM#615616 Review for gene: CTNNA3 was set to AMBER Added comment: Gene is classified as Limited by the ClinGen ARVC GCEP (Classification - 08/06/2019). PMID: 23136403 - an assumed de novo missense (V94D) was identified in an Italian proband with arrhythmogenic right ventricular dysplasia. An inframe deletion (Leu765del) was identified in a proband with arrhythmogenic right ventricular dysplasia, and was also present in the proband's asymptomatic father and paternal aunt, who had mild right ventricular dilation on echocardiography and increased trabeculations in the right ventricular apex on MRI, respectively, as well as in the aunt's asymptomatic son. There was supporting in vitro functional assay evidence for both variants. PMID: 21254927 - a missense variant was found in one of 55 Danish ARVD patients, but was found 37 times in 276,338 (1 homozygous) reference alleles in gnomAD making it less likely as a causal variant. PMID: 22421363 - null mice exhibit progressive dilated cardiomyopathy, gap junction remodelling, and increased sensitivity to ventricular arrhythmia following acute ischaemia, but not spontaneous ARVC. Additional publications identified - PMID: 30415094 - a VUS identified in a sudden unexpected death case with slight LV hypertrophy. PMID: 31539150 - 2 VUS and a nonsense variant identified in 3 probands with atrial fibrillation, with the nonsense variant segregating in an affected first-degree relative. Sources: ClinGen |
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| Mendeliome v0.5102 | PRKACB |
Konstantinos Varvagiannis gene: PRKACB was added gene: PRKACB was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKACB were set to 33058759 Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability Penetrance for gene: PRKACB were set to unknown Mode of pathogenicity for gene: PRKACB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: PRKACB was set to GREEN Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants. The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD. Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors. Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID. As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes. WES was carried out in all. PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD). PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo. Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt). By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals. As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284). Sources: Literature |
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| Mendeliome v0.5102 | PRKACA |
Konstantinos Varvagiannis gene: PRKACA was added gene: PRKACA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKACA were set to 33058759; 31130284 Phenotypes for gene: PRKACA were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability Penetrance for gene: PRKACA were set to unknown Mode of pathogenicity for gene: PRKACA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: PRKACA was set to GREEN Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants. The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD. Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors. Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID. As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes. WES was carried out in all. PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD). PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo. Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt). By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals. As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284). Sources: Literature |
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| Mendeliome v0.5069 | PTCD3 | Zornitza Stark Phenotypes for gene: PTCD3 were changed from Intellectual disability; optic atrophy; Leigh-like syndrome to Combined oxidative phosphorylation deficiency-51, MIM#619057; Intellectual disability; optic atrophy; Leigh-like syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5068 | PTCD3 | Zornitza Stark edited their review of gene: PTCD3: Changed phenotypes: Combined oxidative phosphorylation deficiency-51, MIM#619057, Intellectual disability, optic atrophy, Leigh-like syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.4976 | 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 v0.4973 | 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 v0.4872 | 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 |
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| 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 |
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| Mendeliome v0.4860 | VPS16 |
Zornitza Stark gene: VPS16 was added gene: VPS16 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS16 were set to 32808683 Phenotypes for gene: VPS16 were set to Dystonia Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood. Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals. Sources: Literature |
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| Mendeliome v0.4820 | 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 v0.4808 | 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 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 | SMN1 | Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: Spinal muscular atrophy; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 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 v0.4557 | 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 v0.4551 | 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 v0.4520 | SLC12A2 |
Zornitza Stark edited their review of gene: SLC12A2: Added comment: Monoallelic : DD/ID was a feature in >= 6 individuals with monoallelic de novo SLC12A2. An individual with an exon 22 truncating variant was reported to have normal milestones and cognitive function. Exon 21 variants have been described in individuals with rather isolated hearing impairment (possibly some associated motor delay, but normal cognition). Hearing impairment was also reported in 2/6 patients with variants in other exons (1 missense / 1 frameshift). Biallelic : DD/ID was reported in at least 3 individuals in literature. Hearing impairment has been reported on 2 occasions (although this was not probably evaluated in all subjects). --- Monoallelic SLC12A2 mutations : ► Individuals with de novo mutations and developmental disorder were first identified by the DDD study (2017 - PMID: 28135719). 5 of them have been reported in detail by McNeill et al (below). ► McNeill et al (2020 - PMID: 32658972) report on 6 individuals with neurodevelopmental disorder due to de novo SLC12A2 mutation. All presented DD or ID ranging from mild to severe. ASD was reported in 3/6. Sensorineural hearing loss was a feature in 2/6 with the remaining having normal formal evaluations. Brain, cardiac and/or additional malformations were reported in a single individual. Following non-diagnostic prior work-up (CMA, FMR1 or other investigations) trio exome sequencing revealed missense (4/6) or truncating variants (2/6). Three additional individuals (incl. a father and his son) with missense variants in exon 21 (NM_001046.3 / p.Glu979Lys and p.Glu980Lys) presented with bilateral sensorineural hearing loss. Speech and/or motor delay reported in these cases were attributed to the hearing impairment/vestibular arreflexia (cognitive abilities not tested). SLC12A2 encodes sodium-potassium-chloride transporter 1 (also NKCC1). The GTEx project has identified 8 isoforms. In brain both exon 21-containing/deleted isoforms are expressed (cited Morita et al 2014 - PMID: 24695712). As the authors discuss, RNA-seq of the developing mouse cochlea suggests that the exon 21 containing isoform is the single transcript expressed. Evidence from RNA-seq data (BrainSpan project) and literature suggests that the significant amounts of exon 21 lacking isoforms in fetal brain compensate for the deleterious effects of exon 21 variants and explain the lack of NDD in relevant patients. Slc12a2 (NKCC1) null mouse model has demonstrated that the transporter plays a role in accumulation of the potassium rich endolymph in the inner ear, with NKCC1 absence causing sensorineural deafness and imbalance. Slc12a2 display cochlear malformations, loss of hair cells and hearing impairment (cited Delpire et al 1999 - PMID: 10369265). The brain phenotype has not been studied extensively, although loss of Slc12a2 has been shown to inhibit neurogenesis (cited: Magalhães and Rivera et al. - PMID: 27582690). Slc12a2 null zebrafish display a collapse of the otic vesicle and reduced endolymph (Abbas and Whitfield, 2009 - PMID: 19633174) relevant to the human hearing disorder. In vitro assessment of NKCC1 ion transporter function in Xenopus laevis, supported the deleterious effect of the identified variants (significant reduction in K+ influx). Using available single cell RNA-seq data the authors further demonstrated that SLC12A2 expressing cells display transcriptomic profiles reflective of active neurogenesis. ► Delpire et al (2016 - PMID: 27900370 - not reviewed in detail) described a 13 y.o. girl harboring a de novo 11-bp deletion in SLC12A2 exon 22. This individual reached developmental milestones on time and had a NORMAL cognitive function. Hearing was seemingly normal. Features included orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency and multiorgan failure incl. gut and bladder. Exome in the proband, parents and 3 unaffected sibs suggested SLC12A2 as the only candidate for her phenotype. Functional analyses in Xenopus laevis oocytes suggested that a non functional transporter was expressed and trafficked to the membrane as the wt. Detection of the truncated protein at higher molecular sizes suggested either enhanced dimerization or misfolded aggregate. There was no dominant-negative effect of mutant NKCC1. In patient fibroblasts a reduced total and NKCC1-mediated K+ influx. ► Mutai et al (2020 - PMID: 32294086) report on several individuals from 4 families, harboring variants within exon 21 or - in one case - at it's 3' splice-site (leading to skipping oe this exon at the mRNA level). All subjects were investigated for severe/profound hearing loss (in line with the role of exon 21-included isoforms in cochlea. The variant segregated with hearing impairment in 3 generations of a family while in all other subjects the variant had occured as de novo event. Despite motor delays (e.g. the subject from fam2 could not hold head or sit at the age of 10m / the proband in Fam3 was able to hold his head and walk at 6 and 20 m respectively) behavior and cognition were commented to be within normal range. ----- Biallelic SLC12A2 mutations: ► Anazi et al (2017 - PMID: 29288388) briefly reported on a 3 y.o. boy (17DG0776) with central hypotonia, neonatal respiratory distress, failure to thrive, global DD and microcephaly and a skeletal survey suggestive of osteopenia. After non-diagnostic prior investigations (CMA revealing a 1p duplication classified as VUS, extensive metabolic workup), WES revealed a homozygous SLC12A2 splicing variant [NM_001046.2:c.2617-2A>G]. ► Macnamara et al (2019 - PMID: 30740830) described a 5.5 y.o. male with sensorineural hearing loss, profound delays in all developmental areas among several other features (choanal atresia, failure to thrive, respiratory problems, absent sweat and tear production or salivation, GI abnormalities). Genetic testing for several disorders considered (cystic fibrosis, spinal muscular atrophy, sequencing and del/dup analysis of mtDNA) was normal. CMA revealed paternal uniparental isodisomy for chr. 5 and WGS a homozygous 22kb deletion in SLC12A2. This was followed by confirmation of homozygosity in the proband, heterozygosity of the unaffected father, delineation of breakpoints (chr5:127441491-127471419). mRNA studies in patient fibroblasts confirmed deletion of ex2-7, splicing of ex1 directly to ex8 and introduction of a premature stop codon in ex9. qRT-PCR confirmed that mRNA is likely subjected to NMD (expression ~80% of control). Western blot confirmed absence of the protein in the patient's fibroblasts. Again mouse models are thought to recapitulate the hearing defect but also the deficient saliva production (cited Evans et al 2000 - PMID: 10831596). Again the authors speculate a role of SLC12A2 in brain development based on evidence from murine models (migration, dendritic growth, increse in neuron density through regulation of GABAergic signalling (Young et al 2012 - PMID: 23015452). Hypotheses are also made on a regulatory relationship between NKCC1 and CFTR based on mRNA data from the ko mouse model. ► Stödberg et al (2020 - PMID: 32754646) reported 2 sibs with a complex neurodevelopmental disorder due to compound heterozygosity for a frameshift SLC12A2 variant and a splicing one (NM_001046:c.1431delT and c.2006-1G>A). Both presented hypotonia, neonatal S. aureus parotitis and respiratory problems (incl. apneas). While the older sib died at the age of 22 days, the younger one had persistent respiratory issues incl. a dry respiratory mucosa motivating metabolic, immunology investigations and testing for CF. She displayed microcephaly (OFC -2.5 SD, H was also -3.5SD), severe intellectual disability. MRI was suggestive of white matter and basal ganglia abnormalities. Other features incl. hearing impairment, and lack of tears,saliva and sweat, constipation and intestinal malrotation. There was facial dysmorphism. The variants were the only retained following WGS of the 2 affected sisters, parents and an unaffected brother. The splicing variant was shown to result in skipping of exon 13, while the indel in NMD. Again the authors discuss that the deficient saliva production, impaired hearing and GI problems are recapitulated in the mouse model (several refs provided).; Changed rating: GREEN; Changed publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Changed phenotypes: Kilquist syndrome, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.4497 | NEMF |
Zornitza Stark gene: NEMF was added gene: NEMF was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NEMF was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEMF were set to 32934225 Phenotypes for gene: NEMF were set to Intellectual disability; neuropathy Review for gene: NEMF was set to GREEN Added comment: 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 |
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| Mendeliome v0.4392 | SLC25A46 |
Zornitza Stark changed review comment from: Age of onset is variable, but childhood onset described. Ataxia is a feature.; 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. At least 10 unrelated families reported, supportive functional data. |
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| Mendeliome v0.4389 | MAPK8IP3 | Zornitza Stark edited their review of gene: MAPK8IP3: Added comment: 18 unrelated individuals reported with de novo variants and a neurodevelopmental disorder characterised by global developmental delay, variably impaired intellectual development, and poor or absent speech. Additional features may include hypotonia, spasticity, or ataxia. About half have abnormal findings on brain imaging, including cerebral or cerebellar atrophy, loss of white matter volume, thin corpus callosum, and perisylvian polymicrogyria. Seizures are not a prominent finding, and nonspecific dysmorphic facial features are described.; Changed publications: 30612693, 30945334 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4380 | KCNA2 | Zornitza Stark commented on gene: KCNA2: Review of 23 affected individuals in PMID 29050392: some variants are LoF and others GoF, and some genotype-phenotype correlations made. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalised and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4355 | SOS1 | Zornitza Stark edited their review of gene: SOS1: Added comment: Over 50 individuals reported with SOS1 variants and a Noonan syndrome phenotype. Pulmonic stenosis tends to be more frequent compared to those with PTPN11 mutations, and atrial septal defect is relatively rare. Ectodermal features including keratosis pilaris and curly hair are significantly more prevalent compared with the general Noonan population. Height below the third percentile and learning disability are observed in fewer individuals compared with Noonan syndrome in general. In contrast, macrocephaly is overrepresented among those with SOS1 mutations.; Changed rating: GREEN; 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; Changed publications: 17143285, 17143282, 28884940, 17586837; Changed phenotypes: Noonan syndrome 4, MIM# 610733; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4309 | SREBF1 | Zornitza Stark Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4308 | SREBF1 | Zornitza Stark reviewed gene: SREBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4275 | EXOSC5 |
Arina Puzriakova changed review comment from: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXCOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient. Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively. A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5. - PMID: 29302074 (2019) - Three sibs with a homozygous EXCOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.; to: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient. Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively. A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5. - PMID: 29302074 (2019) - Three sibs with a homozygous EXOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken. |
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| Mendeliome v0.4269 | NR2F1 | Zornitza Stark Phenotypes for gene: NR2F1 were changed from to Bosch-Boonstra-Schaaf optic atrophy syndrome, MIM# 615722 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4266 | NR2F1 | Zornitza Stark reviewed gene: NR2F1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32275123; Phenotypes: Bosch-Boonstra-Schaaf optic atrophy syndrome, MIM# 615722; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4262 | KMT2D | Zornitza Stark edited their review of gene: KMT2D: Added comment: Four further individuals with KMT2D-associated neurodevelopmental syndrome reported. Features include: athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. Two of the four individuals had severe interstitial lung disease.; Changed publications: 31949313, 32083401 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4231 | SSBP1 | Zornitza Stark Phenotypes for gene: SSBP1 were changed from Optic atrophy with or without extraocular phenotypes to Optic atrophy with or without extraocular phenotypes; Optic atrophy-13 with retinal and foveal abnormalities, MIM#165510 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4230 | SSBP1 | Zornitza Stark reviewed gene: SSBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Optic atrophy-13 with retinal and foveal abnormalities, MIM#165510; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4229 | FDXR | Zornitza Stark Phenotypes for gene: FDXR were changed from to Auditory neuropathy and optic atrophy, MIM#617717 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4220 | TRAPPC6B | Zornitza Stark Phenotypes for gene: TRAPPC6B were changed from to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4217 | TRAPPC6B | Zornitza Stark reviewed gene: TRAPPC6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28626029, 28397838, 31687267; Phenotypes: Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4217 | TRAPPC12 | Zornitza Stark Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4214 | TRAPPC12 | Zornitza Stark reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837, 28777934; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4145 | PCYT2 | Zornitza Stark Phenotypes for gene: PCYT2 were changed from to Spastic paraplegia 82, autosomal recessive 618770; global developmental delay; regression; spastic parapesis or tetraparesis; epilepsy; progressive cerebral and cerebellar atrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4097 | CHCHD10 | Zornitza Stark Phenotypes for gene: CHCHD10 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 615911; Spinal muscular atrophy, Jokela type 615048; Myopathy, isolated mitochondrial, autosomal dominant 616209 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4093 | CHCHD10 | Zornitza Stark reviewed gene: CHCHD10: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24934289, 25428574, 25193783, 32042922, 31690696, 30877432, 30874923; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 615911, Spinal muscular atrophy, Jokela type 615048, Myopathy, isolated mitochondrial, autosomal dominant 616209; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4035 | ATRIP | Zornitza Stark Marked gene: ATRIP as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4035 | ATRIP | Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4035 | ATRIP | Zornitza Stark Classified gene: ATRIP as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4035 | ATRIP | Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4034 | ATRIP |
Ain Roesley gene: ATRIP was added gene: ATRIP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATRIP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATRIP were set to 23144622 Phenotypes for gene: ATRIP were set to Seckel Syndrome Penetrance for gene: ATRIP were set to unknown Review for gene: ATRIP was set to RED Added comment: PMID: 23144622; - 1x proband from a consanguineous family - progressive severe microcephaly (-9 to -10SD) - cHet for a nonsense and a splice Sources: Literature |
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| Mendeliome v0.3866 | AFG3L2 | Zornitza Stark Phenotypes for gene: AFG3L2 were changed from to Spastic ataxia 5, autosomal recessive (MIM#614487); Spinocerebellar ataxia 28 (MIM#610246); Optic atrophy 12, MIM# 618977 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3863 | AFG3L2 | Zornitza Stark reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29181157, 26539208, 30252181, 30389403, 32219868, 32600459, 32548275; Phenotypes: Spastic ataxia 5, autosomal recessive (MIM#614487), Spinocerebellar ataxia 28 (MIM#610246), Optic atrophy 12, MIM# 618977; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3834 | TAF1C |
Zornitza Stark gene: TAF1C was added gene: TAF1C was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TAF1C were set to 32779182 Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology Review for gene: TAF1C was set to AMBER Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants. Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual). Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1). The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele. TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit. RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs). A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data). The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual). Sources: Expert list |
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| Mendeliome v0.3657 | MORC2 | Dean Phelan reviewed gene: MORC2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 32693025; Phenotypes: Spinal muscular atrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3242 | SREBF1 |
Paul De Fazio gene: SREBF1 was added gene: SREBF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SREBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SREBF1 were set to 32497488 Phenotypes for gene: SREBF1 were set to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome Review for gene: SREBF1 was set to GREEN gene: SREBF1 was marked as current diagnostic Added comment: 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. 3 different msisense variants identified affecting the same region (residues 527, 528, and 530). Functional studies support impaired function (impaired nuclear translocation of the transcriptionally active form of SREBP1 resulting in lower expression of the SREBP1 variants). Increased keratinocyte apoptosis was observed in patient scalp samples. Sources: Literature |
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| Mendeliome v0.3231 | ADPRHL2 |
Zornitza Stark changed review comment from: Ataxia is part of the phenotype. Sources: Expert list; to: 14 families reported, onset is in the first years of life following normal early development. Patients have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy. Sources: Expert list |
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| Mendeliome v0.3230 | GPR161 |
Zornitza Stark gene: GPR161 was added gene: GPR161 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GPR161 were set to 31609649 Phenotypes for gene: GPR161 were set to Predisposition to paediatric medulloblastoma Review for gene: GPR161 was set to GREEN Added comment: 6 unrelated individuals reported with germline variants, 5 with truncating, one missense. Somatic second hit in tumour tissue. Sources: Literature |
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| Mendeliome v0.3202 | CAPZA2 |
Eleanor Williams gene: CAPZA2 was added gene: CAPZA2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CAPZA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CAPZA2 were set to 32338762 Phenotypes for gene: CAPZA2 were set to intellectual disability Review for gene: CAPZA2 was set to AMBER Added comment: PMID: 32338762 - Huang et al 2020 - report 2 unrelated families (Chinese and European) in which a de novo heterozygous variant has been identified in CAPZA2 in paediatric probands that present with global motor development delay, speech delay, intellectual disability, hypotonia. One proband had seizures at 7 months but these were controlled with medication and did not repeat. The other proband at age one had an atypical febrile seizure that was controlled without medication. Functional studies in Drosophila suggest that these variants are mild loss of function mutations but that they can act as dominant negative variants in actin polymerization in bristles. Sources: Literature |
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| Mendeliome v0.3196 | EXOC7 |
Zornitza Stark gene: EXOC7 was added gene: EXOC7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOC7 were set to 32103185 Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly Review for gene: EXOC7 was set to GREEN Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration. Sources: Literature |
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| Mendeliome v0.3181 | GATA6 | Zornitza Stark Phenotypes for gene: GATA6 were changed from to Pancreatic agenesis and congenital heart defects, 600001; Atrial septal defect 9, 614475; Atrioventricular septal defect 5, 614474; Tetralogy of Fallot, 187500; Persistent truncus arteriosus, 217095 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3177 | GATA6 | Elena Savva reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:20581743, 19666519; Phenotypes: Pancreatic agenesis and congenital heart defects, 600001, Atrial septal defect 9, 614475, Atrioventricular septal defect 5, 614474, Tetralogy of Fallot, 187500, Persistent truncus arteriosus, 217095; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3174 | TSHZ1 | Zornitza Stark changed review comment from: Two individuals reported with LoF variants, both with a phenotype of congenital aural atresia and hyposmia (PMID: 22152683). Temporal and spatial expression of Tshz1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). Tsh2 null mouse model showed a middle ear malformation, and neonatal lethality. A conditional nervous system-specific Tshz1 knock out mouse model demonstrated hyposmia (PMIDs: 24487590; 17586487).; to: Two individuals reported with LoF variants, both with a phenotype of congenital aural atresia and hyposmia (PMID: 22152683). Temporal and spatial expression of Tshz1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). Tsh2 null mouse model showed a middle ear malformation, and neonatal lethality. A conditional nervous system-specific Tshz1 knock out mouse model demonstrated hyposmia (PMIDs: 24487590; 17586487). Also note original report contains four individuals with deletions of this gene, further supporting gene-disease association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3173 | TSHZ1 | Zornitza Stark Phenotypes for gene: TSHZ1 were changed from to Aural atresia, congenital, MIM# 607842; Hyposmia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3170 | TSHZ1 | Zornitza Stark reviewed gene: TSHZ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15834955, 22152683, 17586487, 24487590; Phenotypes: Aural atresia, congenital, MIM# 607842, Hyposmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3150 | GOLGA2 |
Elena Savva gene: GOLGA2 was added gene: GOLGA2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: GOLGA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501 Phenotypes for gene: GOLGA2 were set to Nueromuscular disorder Review for gene: GOLGA2 was set to GREEN Added comment: PMID: 30237576 - One 11 year old patient with a homozygous PTC. Patient had global dev delay, microcephaly, distal muscle weakness with joint contractures and elevated CK levels. Muscle biopsy showed dystrophin changes. MRI at 2 years old showed brain atrophy with thin corpus callosum and hypomyelination. No seizures or regression. PMID: 26742501 - One infant with a homozygous PTC. Patient had dev delay, seizures, microcephaly and muscular dystrophy. Zebrafish null model recapitulates the human phenotype with microcephaly and skeletal muscle disorganization. Summary: 2 patients + animal model Sources: Expert list |
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| Mendeliome v0.3086 | ARL6IP1 |
Bryony Thompson gene: ARL6IP1 was added gene: ARL6IP1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ARL6IP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARL6IP1 were set to 24482476; 31272422; 30980493; 28471035 Phenotypes for gene: ARL6IP1 were set to Spastic paraplegia 61, autosomal recessive MIM#615685 Review for gene: ARL6IP1 was set to GREEN gene: ARL6IP1 was marked as current diagnostic Added comment: At least 4 families reported with paediatric onset complicated spastic paraplegia and neuropathy. Supporting zebrafish model. Sources: Expert list |
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| Mendeliome v0.2981 | TLL1 | Zornitza Stark Phenotypes for gene: TLL1 were changed from to Atrial septal defect | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2978 | TLL1 | Dean Phelan reviewed gene: TLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18830233, 30538173, 27418595, 31570783; Phenotypes: Atrial septal defect; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2912 | ELP1 | Zornitza Stark Phenotypes for gene: ELP1 were changed from to Dysautonomia, familial MIM#223900; paediatric medulloblastoma | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2909 | ELP1 | Bryony Thompson reviewed gene: ELP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11179008, 32296180; Phenotypes: Dysautonomia, familial MIM#223900, paediatric medulloblastoma; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2825 | PDXK | Zornitza Stark reviewed gene: PDXK: Rating: AMBER; Mode of pathogenicity: None; Publications: 31187503; Phenotypes: Axonal polyneuropathy, optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2825 | PDXK |
Russell Gear gene: PDXK was added gene: PDXK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PDXK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDXK were set to (PMID: 31187503) Phenotypes for gene: PDXK were set to Axonal polyneuropathy; optic atrophy Review for gene: PDXK was set to RED Added comment: Currently two unrelated families with axonal polyneuropathy and optic atrophy described in the same paper, with bi-allelic PDXK pathogenic variants. Functional work in the same paper includes work on patient derived fibroblasts, measurement of an axonal damage biomarker (NFL protein), and response to PLP supplementation treatment. Need one further unrelated family to upgrade to green? Sources: Literature |
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| Mendeliome v0.2636 | VPS51 |
Zornitza Stark gene: VPS51 was added gene: VPS51 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS51 were set to 30624672; 31207318 Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606 Review for gene: VPS51 was set to AMBER Added comment: Two families reported with bi-allelic variants in this gene and global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable. Sources: Expert list |
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| Mendeliome v0.2604 | KIAA1161 | Zornitza Stark Phenotypes for gene: KIAA1161 were changed from Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317 to Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2602 | KIAA1161 | Hazel Phillimore reviewed gene: KIAA1161: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29910000, 31009047; Phenotypes: Basal ganglia calcification, idiopathic, 7, autosomal recessive (OMIM #618317), primary familial brain calcifications (PFBC), ataxia, dysarthria, cerebellar atrophy, akinetic-hypertonic syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2602 | CACNB4 | Zornitza Stark edited their review of gene: CACNB4: Added comment: PMID 32176688: A homozygous missense variant (Leu126Pro) reported in two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy. Some functional data.; Changed publications: 10762541, 9628818, 27003325, 32176688; Changed phenotypes: Episodic ataxia, type 5, MIM#613855, Intellectual disability, Epilepsy, Movement disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2588 | KLC2 |
Zornitza Stark gene: KLC2 was added gene: KLC2 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: KLC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KLC2 were set to 26385635 Phenotypes for gene: KLC2 were set to Spastic paraplegia, optic atrophy, and neuropathy MIM#609541 Review for gene: KLC2 was set to GREEN Added comment: In 73 Brazilian patients and 2 sibs of Egyptian descent with SPOAN, a homozygous 216-bp deletion in the noncoding upstream region of the KLC2 gene was identified. Only reported cause of condition is the upstream large deletion, which is not detected by whole-exome sequencing. Sources: Expert Review |
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| Mendeliome v0.2549 | GAD1 | Zornitza Stark changed review comment from: Single family reported with bi-allelic variants. Association studies linking with neuropsychiatric issues.; to: Single family reported with bi-allelic variants and CP phenotype. Association studies linking with neuropsychiatric issues. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2466 | SIGMAR1 | Zornitza Stark Phenotypes for gene: SIGMAR1 were changed from to Amyotrophic lateral sclerosis 16, juvenile 614373; ?Spinal muscular atrophy, distal, autosomal recessive, 2 605726; distal hereditary motor neuropathy of Jerash type (HMNJ) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2452 | SEC31A | Zornitza Stark Phenotypes for gene: SEC31A were changed from congenital neurodevelopmental syndrome; spastic paraplegia; multiple contractures; profound developmental delay; epilepsy; failure to thrive to Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MIM# 618651; congenital neurodevelopmental syndrome; spastic paraplegia; multiple contractures; profound developmental delay; epilepsy; failure to thrive | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2440 | AGTPBP1 | Kristin Rigbye reviewed gene: AGTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30420557; Phenotypes: Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy, Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2392 | SIGMAR1 | Michelle Torres reviewed gene: SIGMAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31511340; Phenotypes: ?Amyotrophic lateral sclerosis 16, juvenile 614373, ?Spinal muscular atrophy, distal, autosomal recessive, 2 605726, distal hereditary motor neuropathy of Jerash type (HMNJ); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2389 | ASCC1 | Zornitza Stark Phenotypes for gene: ASCC1 were changed from to Spinal muscular atrophy with congenital bone fractures 2, MIM#616867 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2378 | SEC31A |
Hazel Phillimore gene: SEC31A was added gene: SEC31A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEC31A were set to PMID: 30464055 Phenotypes for gene: SEC31A were set to congenital neurodevelopmental syndrome; spastic paraplegia; multiple contractures; profound developmental delay; epilepsy; failure to thrive Review for gene: SEC31A was set to AMBER Added comment: Frameshift. c.2776_2777, TA duplication, causing predicted p.A927fs*61 truncation and predicted NMD in 2 affected siblings in consanguineous Bedouin family with severe congenital neurological syndrome with spastic paraplegia, multiple contractures, profound developmental delay and convulsions. Failure to thrive. Lethal by age 4 years. Also had hearing defect, bilateral congenital cataract, horizontal nystagmus, with flat retina and optic atrophy. Supporting functional assays from knockout drosophila. Sources: Literature |
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| Mendeliome v0.2378 | SLC44A1 |
Sebastian Lunke gene: SLC44A1 was added gene: SLC44A1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC44A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC44A1 were set to 31855247 Phenotypes for gene: SLC44A1 were set to progressive ataxia; tremor; cognitive decline; dysphagia; optic atrophy; dysarthria Review for gene: SLC44A1 was set to GREEN Added comment: Four affected individuals from three families with homozygous frameshift variants. Functional evidence points to impaired choline transporter function yet unchanged membrane phosphatidylcholine content. Choline treatments may be beneficial. Sources: Literature |
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| Mendeliome v0.2365 | FUS |
Elena Savva gene: FUS was added gene: FUS was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FUS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FUS were set to PMID: 32281455; 20668259; 20385912 Phenotypes for gene: FUS were set to Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia 608030; Essential tremor, hereditary, 4 614782 Mode of pathogenicity for gene: FUS was set to Other Review for gene: FUS was set to GREEN Added comment: PMID: 32281455 - Reports a case of Pediatric Amyotrophic Lateral Sclerosis. Reviews and shows multiple other reports of ALS casued by FUS PMID: 20668259 - additional reports of ALS PMID: 20385912 - postulated that disruption of this region may disrupt subcellular distribution of FUS, in turn affecting transcription and RNA processing and conferring a toxic gain of function. Sources: Literature |
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| Mendeliome v0.2365 | ELOVL1 | Hazel Phillimore changed review comment from: De novo in 2 unrelated patients. Decrease in ELOVL1 enzyme activity. The same 2 patients are in PMIDs: 30487246 and 29496980 but with different clinical findings. Deafness and optic atrophy are the additional features.; to: De novo missense (S165F) in 2 unrelated patients. Decrease in ELOVL1 enzyme activity. The same 2 patients are in PMIDs: 30487246 and 29496980 but with different clinical findings. Deafness and optic atrophy are the additional features. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2365 | ELOVL1 | Hazel Phillimore reviewed gene: ELOVL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30487246, 29496980; Phenotypes: ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness, optic atrophy, nystagmus; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2361 | ASCC1 | Sarah Pantaleo reviewed gene: ASCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30327447, 12077347, 26924529, 31880396, 26503956; Phenotypes: Arthrogryposis, congenital bone fractures, spinal muscular atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2256 | MED17 | Zornitza Stark Phenotypes for gene: MED17 were changed from to Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM#613668 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2225 | SHANK2 | Zornitza Stark Added comment: Comment when marking as ready: Reports of CNVs, LoF variants, and missense variants in this gene, generally ascertained in autism cohorts. Some de novo and others inherited from parents with a range of neuropsychiatric phenotypes. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2198 | TBCD | Zornitza Stark Phenotypes for gene: TBCD were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, MIM#617193 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2189 | VARS | Zornitza Stark Phenotypes for gene: VARS were changed from to Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy; OMIM #617802 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1888 | PIGK |
Zornitza Stark gene: PIGK was added gene: PIGK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PIGK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGK were set to 32220290 Phenotypes for gene: PIGK were set to Intellectual disability; seizures; cerebellar atrophy Review for gene: PIGK was set to GREEN Added comment: 12 individuals from 9 unrelated families reported. Sources: Literature |
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| Mendeliome v0.1865 | DYNC1H1 | Zornitza Stark Phenotypes for gene: DYNC1H1 were changed from to Charcot-Marie-Tooth disease, axonal, type 20; Mental retardation, autosomal dominant 13; Spinal muscular atrophy, lower extremity-predominant 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1845 | AGTPBP1 |
Zornitza Stark gene: AGTPBP1 was added gene: AGTPBP1 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: AGTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGTPBP1 were set to 30420557 Phenotypes for gene: AGTPBP1 were set to Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276 Review for gene: AGTPBP1 was set to GREEN Added comment: Thirteen individuals with bi-allelic variants in this gene, complex neurological phenotype of dev delay/ID, cerebellar atrophy and neuropathy, severe progressive course in six. Sources: NHS GMS |
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| Mendeliome v0.1842 | DYNC1H1 | Elena Savva reviewed gene: DYNC1H1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 25512093, 28196890; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 20, Mental retardation, autosomal dominant 13, Spinal muscular atrophy, lower extremity-predominant 1; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1820 | QARS | Zornitza Stark Phenotypes for gene: QARS were changed from to Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, MIM# 615760 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1816 | QARS | Zornitza Stark reviewed gene: QARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28620870, 25471517, 25432320, 25041233, 24656866, 32042906; Phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, MIM# 615760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1815 | PTCD3 |
Zornitza Stark gene: PTCD3 was added gene: PTCD3 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: PTCD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTCD3 were set to 30607703; 19427859 Phenotypes for gene: PTCD3 were set to Intellectual disability; optic atrophy; Leigh-like syndrome Review for gene: PTCD3 was set to AMBER Added comment: One compound heterozygote case and functional assays. Essential subunit of oxidative phosphorylation (OXPHOS) complexes. Sources: NHS GMS |
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| Mendeliome v0.1773 | SSBP1 |
Bryony Thompson gene: SSBP1 was added gene: SSBP1 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: SSBP1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SSBP1 were set to 31298765; 31479473; 31550237; 31550240 Phenotypes for gene: SSBP1 were set to Optic atrophy with or without extraocular phenotypes Review for gene: SSBP1 was set to GREEN Added comment: At least 9 dominant families/cases and 1 recessive with optic atrophy with/without additional clinical features, including retinal macular dystrophy, sensorineural deafness, mitochondrial myopathy, and kidney failure. Supporting evidence in functional assays and zebrafish model. Sources: NHS GMS |
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| Mendeliome v0.1769 | YME1L1 |
Zornitza Stark gene: YME1L1 was added gene: YME1L1 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: YME1L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: YME1L1 were set to 30544562; 27495975 Phenotypes for gene: YME1L1 were set to Optic atrophy 11, MIM#617302 Review for gene: YME1L1 was set to AMBER Added comment: One consanguineous family with a homozygous variant and functional assays. YME1L leads to mitochondrial fragmentation and severely disorganized and attenuated cristae architecture in in vitro functional assays. Sources: NHS GMS |
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| Mendeliome v0.1588 | VARS | Zornitza Stark reviewed gene: VARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30755616, 30755602, 26539891, 29691655, 30275004; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, OMIM #617802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1438 | MYL1 |
Bryony Thompson gene: MYL1 was added gene: MYL1 was added to Mendeliome. Sources: NHS GMS Mode of inheritance for gene: MYL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYL1 were set to 30215711 Phenotypes for gene: MYL1 were set to Myopathy, congenital, with fast-twitch (type II) fiber atrophy MIM#618414 Review for gene: MYL1 was set to AMBER Added comment: Two probands with congenital myopathy and a zebrafish model. Probably need one more family to push it over the line. Sources: NHS GMS |
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| Mendeliome v0.1435 | TBCE | Zornitza Stark Phenotypes for gene: TBCE were changed from to Encephalopathy, progressive, with amyotrophy and optic atrophy; Hypoparathyroidism-retardation-dysmorphism syndrome; Kenny-Caffey syndrome, type 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1415 | TBCE | Elena Savva reviewed gene: TBCE: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27666369; Phenotypes: Encephalopathy, progressive, with amyotrophy and optic atrophy, Hypoparathyroidism-retardation-dysmorphism syndrome, Kenny-Caffey syndrome, type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1359 | ATRX | Zornitza Stark Marked gene: ATRX as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1359 | ATRX | Zornitza Stark Gene: atrx has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1359 | ATRX | Zornitza Stark Phenotypes for gene: ATRX were changed from to Alpha-thalassemia/mental retardation syndrome; Mental retardation-hypotonic facies syndrome, X-linked | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1358 | ATRX | Zornitza Stark Mode of inheritance for gene: ATRX 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 v0.1357 | ATRX | Elena Savva reviewed gene: ATRX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alpha-thalassemia myelodysplasia syndrome, somatic, Alpha-thalassemia/mental retardation syndrome, Mental retardation-hypotonic facies syndrome, X-linked; 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 v0.1292 | 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 v0.1239 | OPA1 | Zornitza Stark Phenotypes for gene: OPA1 were changed from to Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type)MIM# 6168963; Behr syndrome MIM#210000, AR; Optic atrophy 1, MIM#165500; Optic atrophy plus syndrome, MIM# 125250 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1220 | OPA1 | Ee Ming Wong reviewed gene: OPA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30165240; Phenotypes: 1. ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) 6168963, 2. {Glaucoma, normal tension, susceptibility to} 6066573, 3. Behr syndrome 210000 AR, 4. Optic atrophy 1 165500 AD, 5. Optic atrophy plus syndrome 125250 AD; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1167 | EMC1 | Zornitza Stark Phenotypes for gene: EMC1 were changed from to Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM# 616875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1164 | EMC1 | Zornitza Stark reviewed gene: EMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26942288, 29271071; Phenotypes: Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM# 616875; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.854 | ICE1 |
Alison Yeung gene: ICE1 was added gene: ICE1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ICE1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ICE1 were set to PMID: 31130284 Phenotypes for gene: ICE1 were set to Intellectual disability, cerebral atrophy Review for gene: ICE1 was set to AMBER Added comment: Two unrelated families reported, no functional data Sources: Literature |
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| Mendeliome v0.660 | AIMP2 |
Zornitza Stark gene: AIMP2 was added gene: AIMP2 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: AIMP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AIMP2 were set to 29215095 Phenotypes for gene: AIMP2 were set to Leukodystrophy, hypomyelinating, 17 618006 Review for gene: AIMP2 was set to RED Added comment: Two apparently unrelated consanguineous families, however same homozygous variant identified in both. Affected individuals had early-onset multifocal seizures, spasticity, poor overall growth, and microcephaly (up to -10 SD). Brain imaging showed multiple abnormalities, including cerebral and cerebellar atrophy, thin corpus callosum, abnormal signals in the basal ganglia, and features suggesting hypo- or demyelination Sources: Expert list |
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| Mendeliome v0.343 | CSNK1E |
Zornitza Stark gene: CSNK1E was added gene: CSNK1E was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: CSNK1E was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CSNK1E were set to 30488659 Phenotypes for gene: CSNK1E were set to Epileptic encephalopathy Review for gene: CSNK1E was set to RED Added comment: De novo splicing variant reported but in conjunction with STXBP1 variants; authors postulate it may contribute to susceptibility. Also reports linking variants in this gene to psychiatric disorders. Sources: Literature |
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| Mendeliome v0.324 | TANC2 |
Zornitza Stark gene: TANC2 was added gene: TANC2 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: TANC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TANC2 were set to 31616000 Phenotypes for gene: TANC2 were set to Intellectual disability; autism; epilepsy; dysmorphism Review for gene: TANC2 was set to GREEN Added comment: 19 families with potentially disruptive heterozygous TANC2 variants, including 16 likely gene-disrupting mutations and three intragenic microdeletions. Patients presented with autism, intellectual disability, delayed language and motor development, epilepsy, facial dysmorphism, with complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. No functional evidence of specific variants, but they show TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, and shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes. Sources: Literature |
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| Mendeliome v0.206 | OXR1 |
Zornitza Stark gene: OXR1 was added gene: OXR1 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OXR1 were set to 31785787 Phenotypes for gene: OXR1 were set to Intellectual disability; seizures; cerebellar atrophy Review for gene: OXR1 was set to GREEN Added comment: Five individuals from three families. Sources: Literature |
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| Mendeliome v0.0 | MATR3 |
Zornitza Stark gene: MATR3 was added gene: MATR3 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MATR3 was set to Unknown |
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| Mendeliome v0.0 | ATRX |
Zornitza Stark gene: ATRX was added gene: ATRX was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ATRX was set to Unknown |
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| Mendeliome v0.0 | ATR |
Zornitza Stark gene: ATR was added gene: ATR was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ATR was set to Unknown |
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