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| Mendeliome v1.2429 | CDKL2 |
Sarah Milton gene: CDKL2 was added gene: CDKL2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CDKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDKL2 were set to PMID: 40088891 Phenotypes for gene: CDKL2 were set to Neurodevelopmental disorder, MONDO:0700092, CDKL2-related Mode of pathogenicity for gene: CDKL2 was set to Other Review for gene: CDKL2 was set to AMBER Added comment: CDKL2 encodes a cyclin dependent kinase of which there are CDKL1-5 in humans. (CDKL5 has been associated with a neurodevelopmental disorder previously.) Bereshneh et al describe 5 individuals with a neurodevelopmental disorder with de novo variants in CDKL2. 3 variants were missense, 1 was an in frame single amino acid deletion. 2 of the individuals described were monozygotic twins who were born at 30/40 and also had PVL on neuroimaging. Phenotype included GDD (5/5) - severity not described, speech impairment (5/5), motor impairment (4/5), epilepsy (3/5), ID (3/5), IUGR (3/5), poor growth postnatally (3/5), GI/feeding issues (3/5), tone abnormality (3/5) Missense variants were located in the kinase domain and dominant negative mechanism was postulated based on drosophilia studies. Functional studies in drosphilia showed variants seen in probands did not completely rescue a loss of function model, as well as this, overexpression of transcripts containing the variants resulted in a more severe phenotype suggesting dominant negative. Authors also noted the larger than expected number of LOF variants in gnomad for the disease to be caused by this mechanism. Sources: Literature Sources: Literature |
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| Mendeliome v1.2371 | MEG3 |
Zornitza Stark gene: MEG3 was added gene: MEG3 was added to Mendeliome. Sources: Literature SV/CNV, non-coding gene tags were added to gene: MEG3. Mode of inheritance for gene: MEG3 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) Publications for gene: MEG3 were set to 33010492; 33746039; 33067531; 38212313 Phenotypes for gene: MEG3 were set to Kagami-Ogata syndrome, MIM# 608149 Review for gene: MEG3 was set to GREEN Added comment: Small deletions of MAG3 reported in multiple patients as one of the mechanisms of disease. Sources: Literature |
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| Mendeliome v1.2276 | SEL1L | Zornitza Stark Phenotypes for gene: SEL1L were changed from Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067 to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinaemia, MIM# 621068; Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2275 | SEL1L | Zornitza Stark edited their review of gene: SEL1L: Added comment: Has been split into two conditions by OMIM -- uncertain that these are distinct and not part of a spectrum. Await further reports.; Changed phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinaemia, MIM# 621068, Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2263 | TRPM7 | Zornitza Stark edited their review of gene: TRPM7: Added comment: Protein expressed in the distal tubule, related to TRPM6. Postulated link with hypoMg with secondary hypoCa. PMID 35561741: two families reported with dominant inheritance. F1: three affected individuals with splicing variant; some supportive functional data. F2: single affected individual, de novo missense variant. PMID 35712613: de novo missense variant in an individual with hypoMg. PMID 39099563: three affected individuals with missense variants, all de novo. Probands had DD, two had seizures.; Changed rating: GREEN; Changed publications: 32503408, 31423533, 35561741, 35712613, 39099563; Changed phenotypes: Familial primary hypomagnesemia, MONDO:0018100, TRPM7-related, {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500, Cardiac arrhythmia, stillbirth | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2244 | DDX53 |
Chirag Patel gene: DDX53 was added gene: DDX53 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DDX53 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: DDX53 were set to PMID: 39706195 Phenotypes for gene: DDX53 were set to autism spectrum disorder MONDO:0005258 Review for gene: DDX53 was set to GREEN Added comment: The DDX53 gene is a single-exon RNA helicase which lies intronic to PTCHD1-AS (a multi-isoform long noncoding RNA (lncRNA) at the Xp22.11 locus. It is thought to play a role in RNA decay, RNA processing, ribosome biogenesis, and translation initiation. 9 affected males and 3 affected females from 9 unrelated families with ASD and rare, predicted damaging or loss-of-function variants in DDX53 (including a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS). A further 26 individuals with ASD were identified (from Autism Speaks MSSNG and Simons Foundation Autism Research Initiative) with 19 rare, damaging DDX53 variations (mostly maternally inherited). No functional evidence. Sources: Literature |
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| Mendeliome v1.2238 | RBFOX2 |
Jonathon Bradshaw changed review comment from: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs). - PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation. - PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492. - PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing. - PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS. - PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS. - 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data). - ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication). - ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease.; to: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs). - PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation. - PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492. - PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing. - PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS. - PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS. - 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data). - ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication). - ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease. |
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| Mendeliome v1.2134 | POU2AF1 | Bryony Thompson reviewed gene: POU2AF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35603192, 33571536; Phenotypes: Agammaglobulinemia MONDO:0015977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2024 | EPB41L3 |
Bryony Thompson gene: EPB41L3 was added gene: EPB41L3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EPB41L3 were set to 39292993 Phenotypes for gene: EPB41L3 were set to neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities MONDO:0030063 Review for gene: EPB41L3 was set to GREEN Added comment: 6 cases from 5 unrelated consanguineous families (2nd & 3rd degree) with homozygous LoF variants and a neurodevelopmental condition, including ID and seizures. Epb41l3 shRNA-mediated downregulation in mouse oligodendroglia demonstrated impaired oligodendrocyte function. Sources: Literature |
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| Mendeliome v1.1998 | MED16 |
Mark Cleghorn gene: MED16 was added gene: MED16 was added to Mendeliome. Sources: Other Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MED16 were set to complex neurodevelopmental disorder MONDO:0100038 Review for gene: MED16 was set to GREEN Added comment: Charlotte Guillouet, Imagine institute Paris ESHG presentation 4/6/24, unpublished MED16 is part of tail of ‘mediator complex’ Plays a role in enhancer/promotor regions Disruptive variants in other genes encoding proteins within this mediator complex (MED11/12/12/17/20, CDK8) are assoc w neurodevelopmental/neurodegenerative disorders Cases index family Sibs (M/F) to consanguineous parents w NDD/mod ID, tetralogy of Fallot or VSD, bilat deafness, micrognathia, malar hypoplasia, dental AbN, pre auricular tags, hypoplastic nails, brachydactly WES: biallelic MED16 p.Asp217Asn Via genematcher 16 families total, 22 individuals, homozygous or compound het rare MED16 variants Mixture of pLoF and missense variants Motor delay in 16/17 DD or ID in 17/17 Speech delay in 15/15 6/19 ToF 7/19 other septal/aortic defects 6/18 deafness 11/18 microretrognathia 6/17 cleft palate 8/19 preauricular tags 9/20 puffy eyelids 12/20 nasal dysplasia (most commonly short columella w bulbous nasal tip) 7/20 corpus callosum anomalies Not clear that functional work recapitulated phenotype as yet? Immunofluroescence on HeLa cells transfected with variants observed ?conclusion MED16 knockout mouse > growth delay, pre weaning lethality MED16 knockout zebrafish > reduced body length, early death, no obvious craniofacial phenotype Sources: Other |
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| Mendeliome v1.1733 | SUPT7L |
Chirag Patel gene: SUPT7L was added gene: SUPT7L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SUPT7L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SUPT7L were set to PMID: 38592547 Phenotypes for gene: SUPT7L were set to Lipodystrophy, MONDO:0006573 Review for gene: SUPT7L was set to RED Added comment: 1 case with generalised lipodystrophy, growth retardation, congenital cataracts, severe developmental delay and progeriod features. Trio WGS identified compound heterozygous variants in SUPT7L (missense causing abnormal splicing + frameshift). Variants validated with Sanger. SUPT7L encodes a component of the core structural module of the STAGA complex - a nuclear multifunctional protein complex that plays a role in various cellular processes (e.g. transcription factor binding, protein acetylation, splicing, and DNA damage control). Immunolabelling in fibroblasts from patient showed complete absence of SUPT7L protein. Transcriptome data from individual revealed downregulation of several gene sets associated with DNA replication, DNA repair, cell cycle, and transcription. Sources: Literature |
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| Mendeliome v1.1479 | SEC61A1 | Zornitza Stark Phenotypes for gene: SEC61A1 were changed from Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056; Hypogammaglobulinaemia; Neutropaenia to Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056; Immunodeficiency, common variable, 15, MIM# 620670; Neutropenia, severe congenital, 11, autosomal dominant, MIM# 620674 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1401 | SEL1L |
Sarah Pantaleo gene: SEL1L was added gene: SEL1L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEL1L were set to PMID: 37943610; PMID: 37943617 Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder, MONDO:0700092, SEL1L-related Penetrance for gene: SEL1L were set to Complete Added comment: Wang paper PMID: 37943610 SEL1L protein is involved in the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation. Report two biallelic missense variants in SEL1L in six children from three independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia and/or ataxia (termed ERAD-associated neurodevelopment disorder with onset in infancy (ENDI). The variants were hypomorphic and impaired ERAD function. Identified by WES. Parents heterozygous and asymptomatic. P.(Gly585Asp) in Patient 1, p.(Met528Arg) in Patients 2 and 3 (siblings). All variants cause substrate accumulation. The extent of substrate accumulation in knockin cells was modest compared to those in knockout cells, pointing to a hypomorphic nature. They also had a variant in HRD1. Weis paper PMID: 37943617 Third variant p.(Cys141Tyr), biallelic, causing premature death in five patients from a consanguineous family with early-onset neurodevelopmental disorders and agammaglobulinaemia due to severe SEL1L-HRD1 ERAD dysfunction. This variant appears to have a more severe outcome, exhibiting B cell depletion and agammaglobulinaemia, causing the most severe dysfunction among all of the variants described by this group so far. They postulate that functionality of SEL1L-HRD1 ERAD is inversely correlated with disease severity in humans. Their symptoms were dev delay, neurological disorder and agammaglobulinaemia in childhood. Along with severe axial hypotonia, short stature and microcephaly. “Not a complete loss-of-function variant”. Sources: Literature |
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| Mendeliome v1.1289 | CR2 | Zornitza Stark edited their review of gene: CR2: Added comment: PMID:28499783 reported two siblings from consanguineous parents, both with a homozygous frameshift variant in CR2 and with recurrent respiratory infections and hypogammaglobulinaemia.; Changed rating: GREEN; Changed publications: 22035880, 26325596, 28499783 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1254 | CFAP20 |
Sarah Pantaleo gene: CFAP20 was added gene: CFAP20 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CFAP20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CFAP20 were set to PMID:36329026 Phenotypes for gene: CFAP20 were set to Retinitis pigmentosa (MONDO:0019200) Review for gene: CFAP20 was set to GREEN Added comment: CFAP20 is a ciliopathy candidate. Demonstrate in zebrafish that cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development. Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy (retinitis pigments). Hence, CFAP20 functions within a structural./functional hub centred on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associaetd domains or macromolecular complexes. Describe 8 individuals from 4 independent families with damaging biallelic variants (homozygous or compound heterozygous) in CFAP20 that segregate with retinal dystrophy. All variants cluster to one side of the protein, with two of the residues directly contacting alpha-tubullin. Family 1 - consanguineous set of 3 siblings from Sudan, homozygous for CFAP20 c.305G>A; p.Arg102His (they also had a homozygous variant in DYNC1LI2 however CFAP20 was considered the better candidate. Family 2 - 3 siblings from Spain, 2 with retinal dystrophy, 1 genetically tested and has c.337C>T; p.(Arg113Trp) and c.397delC; p.(Gln133Serfs*5) Family 3 - single affected family member compound het for c.164+1G>A and c.457A>G; p.(Arg153Gly). Family 4 - 3 affected siblings with generalised retinopathy and variable neurological deficits with c.164+1G>A and c.257G>A; p.(Tyr86Cys) For all families, no individuals had signs of polycystic kidney disease; however, not all individuals had kidney imaging. Visual defecit phenotype presented between adolescence and adulthood (17-56 years old). Used HEK293T cell expression studies to demonstrate a statistically significant decline of mutated CFAP20 protein levels (with the exception of p.Arg102His). To test the specific variants, they used the C.elegans orthologues. Sources: Literature |
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| Mendeliome v1.1233 | CTNNBL1 | Zornitza Stark Phenotypes for gene: CTNNBL1 were changed from Primary Immunodeficiency; Autoimmune Cytopenias; Common variable immunodeficiency to Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, MIM# 619846 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1232 | CTNNBL1 | Zornitza Stark edited their review of gene: CTNNBL1: Changed phenotypes: Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, MIM# 619846 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1125 | STAT5B |
Zornitza Stark changed review comment from: Both bi-allelic and mono allelic (GoF) inheritance reported. AD GoF phenotype: increased IgE, growth failure, eczema but no immune defects compared to AR phenotype (modestly decreased T cells, reduced Tregs and function, hypergammaglobulinaemia, increased IgE).; to: Both bi-allelic and mono allelic (GoF) inheritance reported. AD GoF phenotype: increased IgE, growth failure, eczema but no immune defects compared to AR phenotype (modestly decreased T cells, reduced Tregs and function, hypergammaglobulinaemia, increased IgE). Somatic variants also reported. |
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| Mendeliome v1.1095 | PDGFD |
Zornitza Stark gene: PDGFD was added gene: PDGFD was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PDGFD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PDGFD were set to 33187088; 33971972 Phenotypes for gene: PDGFD were set to Pulmonary arterial hypertension MONDO:0015924, PDGFD-related Review for gene: PDGFD was set to RED Added comment: Rated as LIMITED by ClinGen. 10 unique variants (all missense) that have been reported in 10 probands in 2 publications (PMIDs: 33187088, 33971972) are included in this curation. 9 of these variants were observed in a cohort of 1647 idiopathic pulmonary arterial hypertension (IPAH) patients of European Ancestry as part of a case-control study. Variant aggregation analysis revealed a significant burden (p=0.0000172) of likely gene damaging PDGFD variants in the IPAH cohort as compared to a group of 18,819 European controls (PMID:33971972). Gelinas et al. also reported a missense PDGFD variant in a proband with IPAH (PMID:33187088). There is currently no functional evidence demonstrating a damaging effect of any of the reported PDGFD variants in humans. Sources: Expert list |
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| Mendeliome v1.1062 | STAT4 | Melanie Marty edited their review of gene: STAT4: Changed phenotypes: Disabling pansclerotic morphea, inflammatory disorder, poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, squamous-cell carcinoma | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1033 | MAP3K14 | Zornitza Stark Phenotypes for gene: MAP3K14 were changed from NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels to Immunodeficiency 112, MIM# 620449; NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1032 | MAP3K14 | Zornitza Stark edited their review of gene: MAP3K14: Changed phenotypes: Immunodeficiency 112, MIM# 620449, NIK deficiency, Poor T cell proliferation to antigen, Low B-cell numbers, Low NK number and function, recurrent bacterial/viral/ cryptosporidium infections, hypogammaglobulinaemia, decreased immunoglobulin levels | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.927 | NFATC1 |
Zornitza Stark gene: NFATC1 was added gene: NFATC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NFATC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NFATC1 were set to 37249233 Phenotypes for gene: NFATC1 were set to Inborn error of immunity, MONDO:0003778, NFATC1-related; Combined Immune deficiency Review for gene: NFATC1 was set to AMBER Added comment: 3 individuals from a multigenerational consanguineous pedigree with early-onset sinopulmonary infections and bronchiectasis, recurrent viral (warts) and bacterial (folliculitis and abscesses) skin infections, hypogammaglobulinemia, lower CD4+/CD8+ T-cell ratio and lower recent thymic emigrants compared with the age-matched controls. Lymphocyte proliferation responses to PHA and CD3/CD28 stimulations were defective. Single pedigree with supportive functional studies. Sources: Literature |
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| Mendeliome v1.694 | HMGB1 | Ain Roesley Phenotypes for gene: HMGB1 were changed from Mirror image foot polydactyly; Neurodevelopmental disorder MONDO:0700092, HMGB1-related to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Neurodevelopmental disorder MONDO:0700092, HMGB1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.651 | RRAGD | Zornitza Stark Phenotypes for gene: RRAGD were changed from Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.649 | RRAGD |
Hazel Phillimore changed review comment from: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature; to: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature |
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| Mendeliome v1.649 | RRAGD |
Hazel Phillimore gene: RRAGD was added gene: RRAGD was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RRAGD were set to PMID: 34607910 Phenotypes for gene: RRAGD were set to Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis Review for gene: RRAGD was set to GREEN Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature |
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| Mendeliome v1.611 | ZNF668 | Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.554 | SETD2 |
Zornitza Stark edited their review of gene: SETD2: Added comment: PMID 32710489: 12 unrelated patients, ranging from 1 month to 12 years of age, with a multisystemic neurodevelopmental disorder associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740W). Key clinical features: severely impaired global development apparent from infancy, feeding difficulties with failure to thrive, small head circumference, and dysmorphic facial features. Affected individuals have impaired intellectual development and hypotonia; they do not achieve walking or meaningful speech. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and possibly endocrine. Further 3 unrelated patients identified with mild to moderately impaired intellectual development associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740Q). These are distinct clinically from Luscan-Lumish syndrome, which is characterised by overgrowth.; Changed publications: 29681085, 32710489; Changed phenotypes: Luscan-Lumish syndrome, MIM#616831, Rabin-Pappas syndrome,MIM# 620155, Intellectual developmental disorder, autosomal dominant 70, MIM# 620157 |
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| Mendeliome v1.547 | IL2RB |
Zornitza Stark changed review comment from: Five families reported. Sources: Expert list; to: Five families reported. Affected individuals present in infancy with features of both abnormal activation of certain immune signaling pathways, resulting in lymphoid proliferation, dermatitis, enteropathy, and hypergammaglobulinemia, as well as features of immunodeficiency, such as recurrent infections and increased susceptibility to viral infections, especially CMV. Laboratory studies show increased NK cells that show impaired differentiation, as well as abnormal T cell populations or responses. Some patients may die in childhood; hematopoietic bone marrow transplantation is curative. Sources: Expert list |
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| Mendeliome v1.538 | CHUK | Zornitza Stark edited their review of gene: CHUK: Added comment: PMID 34533979: single individual reported with homozygous missense variant in this gene and recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine. Supportive functional data.; Changed publications: 25691407, 20961246, 10195895, 10195896, 29523099, 28513979, 34533979 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.535 | LIG1 | Zornitza Stark Phenotypes for gene: LIG1 were changed from Combined immunodeficiency; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis to Immunodeficiency 96, MIM# 619774; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.463 | IRF2BP2 | Zornitza Stark edited their review of gene: IRF2BP2: Added comment: Reports of additional patients: 4yo with chronic diarrhea, severe eczema, anemia, failure to thrive, fevers, short stature, recurrent infections, cataracts, hypodontia, hypotrichosis alopecia, hypogammaglobulinemia. The 33-year-old male presented with recurrent respiratory infections since childhood, colitis and RA beginning at age 25 years.; Changed rating: GREEN; Changed publications: 27016798, 32048120, 36193988, 33864888; Changed phenotypes: Immunodeficiency, common variable, 14, MIM# 617765 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.346 | TRAF3 | Zornitza Stark edited their review of gene: TRAF3: Added comment: PMID 35960817: Nine individuals from five unrelated families with childhood-onset immune diseases and recurrent infections. All patients had suffered recurrent ear and sinopulmonary infections, including pneumonias from encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenza, resulting in early-onset bronchiectasis in several individuals; Changed rating: GREEN; Changed publications: 20832341, 35960817; Changed phenotypes: Autoinflammatory syndrome, TRAF3-related, MONDO:0019751, hypergammaglobulinemia, lymphadenopathy, splenomegaly, Sjögren’s syndrome, {?Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 5}, MIM# 614849 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.247 | ZMYND8 |
Zornitza Stark gene: ZMYND8 was added gene: ZMYND8 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZMYND8 were set to 35916866; 32530565 Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures Review for gene: ZMYND8 was set to GREEN Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565). Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11). As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression. The protein is broadly expressed in brain and shows highest expression in early development. Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain). Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning. Sources: Expert Review |
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| Mendeliome v1.245 | PAX5 | Zornitza Stark Phenotypes for gene: PAX5 were changed from Neurodevelopmental disorder MONDO:0700092, PAX5-related to Neurodevelopmental disorder MONDO:0700092, PAX5-related; Hypogammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.242 | PAX5 | Zornitza Stark reviewed gene: PAX5: Rating: AMBER; Mode of pathogenicity: None; Publications: 35947077; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PAX5-related, Hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.185 | IKZF1 | Zornitza Stark Phenotypes for gene: IKZF1 were changed from Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset to Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset; Immune dysregulation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.183 | IKZF1 | Zornitza Stark edited their review of gene: IKZF1: Added comment: PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation.; Changed publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317, 35333544; Changed phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset, Immune dysregulation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.180 | IKZF2 | Zornitza Stark edited their review of gene: IKZF2: Added comment: Iranian male with homozygous missense variant with recurrent infection, hypogammaglobulinaemia. Extends inheritance to AR. Supportive functional data.; Changed publications: 34920454, 34826259; Changed phenotypes: Immunodeficiency, MONDO:0021094, IKZF2-related, Immune dysregulation; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.126 | WNK3 |
Lucy Spencer gene: WNK3 was added gene: WNK3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WNK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: WNK3 were set to 35678782 Phenotypes for gene: WNK3 were set to Neurodevelopmental disorder, WNK3-related (MONDO#0700092) Added comment: 6 maternally inherited hemizygous variants, 3 missense, 2 canonical splice, and a nonsense. Seen in 14 individuals from 6 families, all 14 are male who inherited hemizygous variants from their unaffected heterozygous mothers. The variants cosegregated with disease in 3 families with multiple affected individuals. All 14 patients have ID, 11 have speech delay, 10 have facial abnormalities, 5 have seizures, 6 with microcephaly and 7 with anomalies in brain imaging. Sources: Literature |
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| Mendeliome v1.111 | TNFSF13 |
Zornitza Stark gene: TNFSF13 was added gene: TNFSF13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TNFSF13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TNFSF13 were set to 32298700 Phenotypes for gene: TNFSF13 were set to Hypogammaglobulinaemia, MONDO:0015977, TNSF13-related Review for gene: TNFSF13 was set to RED Added comment: Single individual, consanguineous parents. Sources: Literature |
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| Mendeliome v1.110 | POU2AF1 |
Zornitza Stark gene: POU2AF1 was added gene: POU2AF1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: POU2AF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POU2AF1 were set to 33571536 Phenotypes for gene: POU2AF1 were set to Agammaglobulinaemia, MONDO:0015977, POU2AF1-related Review for gene: POU2AF1 was set to RED Added comment: Single individual from consanguineous parents lacking immunoglobulins despite normal total B-cell numbers. Sources: Expert Review |
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| Mendeliome v1.65 | RBFOX2 |
Chern Lim changed review comment from: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. Same cohort later included in PMID: 32368696, listed 4 de novo variants in this gene, in patients with left ventricular outflow tract obstruction (LVOTO) or conotruncal defects (CTDs). - PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492. - PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing. - PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS. - PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.; to: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs). - PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492. - PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing. - PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS. - PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS. |
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| Mendeliome v1.45 | PTPN13 |
Ain Roesley gene: PTPN13 was added gene: PTPN13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPN13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPN13 were set to 35643866 Phenotypes for gene: PTPN13 were set to bone marrow failure syndrome MONDO#0000159, PTPN13-related Review for gene: PTPN13 was set to AMBER gene: PTPN13 was marked as current diagnostic Added comment: 2 families Family A: 3 affecteds only 2 sequenced. Hom for a missense 3/3 Anaemia, 1x thrombocytopaenia, 1x severe neutropaenia, bone marrow with pure red cell aplasia noted that the sibling who wasn't sequenced had normal bone marrow morphology Family B: Chet for a missense and inframe del of 1 amino acid Persistent hypogammaglobulinemia after transplant (at least 14 months after) with normal blood counts and Pre-B ALL with MLL rearrangement In vitro studies of individual variants were LoF, including defective erythroid and megakaryocytic differentiation, consistent with anaemia and thrombocytopaenia reported in family A Sources: Literature |
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| Mendeliome v1.15 | IKBKG |
Zornitza Stark edited their review of gene: IKBKG: Added comment: X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature. 6 unrelated boys and a girl reported. All variants resulted in absence of the domain encoded by exon 5 (NEMOdelEx5). Note variants in this gene are associated with immunodeficiency +/- ectodermal features and with IP.; Changed phenotypes: Ectodermal dysplasia and immunodeficiency 1, MIM# 300291, Immunodeficiency 33 , MIM#300636, Incontinentia pigmenti, MIM# 308300, Autoinflammatory disease, systemic, X-linked, MIM# 301081 |
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| Mendeliome v0.14482 | ATP1A1 | Elena Savva Phenotypes for gene: ATP1A1 were changed from Charcot-Marie-Tooth disease, axonal, type 2DD MIM#618036; Hypomagnesemia, seizures, and mental retardation 2 MIM#618314 to Charcot-Marie-Tooth disease, axonal, type 2DD MIM#618036; Hypomagnesemia, seizures, and mental retardation 2 MIM#618314 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14476 | ATP1A1 | Elena Savva Phenotypes for gene: ATP1A1 were changed from to Charcot-Marie-Tooth disease, axonal, type 2DD MIM#618036; Hypomagnesemia, seizures, and mental retardation 2 MIM#618314 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14442 | OAS1 | Zornitza Stark Phenotypes for gene: OAS1 were changed from Autoinflammatory immunodeficiency; infantile-onset pulmonary alveolar proteinosis; hypogammaglobulinaemia to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14441 | OAS1 | Zornitza Stark edited their review of gene: OAS1: Changed phenotypes: Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14413 | MAGT1 | Zornitza Stark Marked gene: MAGT1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14413 | MAGT1 | Zornitza Stark Gene: magt1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14413 | MAGT1 | Zornitza Stark Phenotypes for gene: MAGT1 were changed from to Congenital disorder of glycosylation, type Icc (MIM# 301031); Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14412 | MAGT1 | Zornitza Stark Publications for gene: MAGT1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14411 | MAGT1 | Zornitza Stark Mode of inheritance for gene: MAGT1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14410 | MAGT1 | Zornitza Stark reviewed gene: MAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31036665, 31714901; Phenotypes: Congenital disorder of glycosylation, type Icc (MIM# 301031), Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14410 | MAGI2 | Zornitza Stark Marked gene: MAGI2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14410 | MAGI2 | Zornitza Stark Gene: magi2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14410 | MAGI2 | Zornitza Stark Phenotypes for gene: MAGI2 were changed from to Nephrotic syndrome, type 15, MIM# 617609 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14409 | MAGI2 | Zornitza Stark Publications for gene: MAGI2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14408 | MAGI2 | Zornitza Stark Mode of inheritance for gene: MAGI2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14407 | MAGI2 | Zornitza Stark reviewed gene: MAGI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27932480, 25108225, 25271328, 31171376, 31010479; Phenotypes: Nephrotic syndrome, type 15, MIM# 617609; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14379 | RBFOX2 |
Chern Lim edited their review of gene: RBFOX2: Added comment: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. Same cohort later included in PMID: 32368696, listed 4 de novo variants in this gene, in patients with left ventricular outflow tract obstruction (LVOTO) or conotruncal defects (CTDs). - PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492. - PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing. - PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS. - PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.; Changed publications: PMID: 26785492, 27670201, 27485310, 25205790, 35137168, 26785492 |
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| Mendeliome v0.14345 | RBFOX2 |
Chern Lim gene: RBFOX2 was added gene: RBFOX2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RBFOX2 were set to PMID: 26785492; 27670201; 27485310; 25205790; 35137168 Phenotypes for gene: RBFOX2 were set to Hypoplastic left heart syndrome (HLHS) Review for gene: RBFOX2 was set to AMBER gene: RBFOX2 was marked as current diagnostic Added comment: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. - PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492. - PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing. - PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS. - PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS. Sources: Literature |
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| Mendeliome v0.14328 | MAGED2 | Zornitza Stark Marked gene: MAGED2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14328 | MAGED2 | Zornitza Stark Gene: maged2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14328 | MAGED2 | Zornitza Stark Phenotypes for gene: MAGED2 were changed from to Bartter syndrome, type 5, antenatal, transient, MIM# 300971 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14327 | MAGED2 | Zornitza Stark Publications for gene: MAGED2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14326 | MAGED2 | Zornitza Stark Mode of inheritance for gene: MAGED2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14325 | MAGED2 | Zornitza Stark reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27120771; Phenotypes: Bartter syndrome, type 5, antenatal, transient, MIM# 300971; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14244 | FXYD2 | Bryony Thompson Phenotypes for gene: FXYD2 were changed from to Renal hypomagnesemia 2 MONDO:0007937 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14239 | FXYD2 | Bryony Thompson reviewed gene: FXYD2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 17980699, 12763862, 18448590, 11062458, 25765846, 27014088; Phenotypes: Renal hypomagnesemia 2 MONDO:0007937; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14185 | FBP2 |
Zornitza Stark gene: FBP2 was added gene: FBP2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: FBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBP2 were set to 33977262 Phenotypes for gene: FBP2 were set to Leukodystrophy, childhood-onset, remitting, MIM# 619864 Review for gene: FBP2 was set to AMBER Added comment: 8 individuals from 3 generations in a single family reported with a variant in this gene. The children presented with episode of regression and leukodystrophy in early childhood, from which they made a slow recovery. The adults had a broad range of neurobehavioural phenotypes but also had leukodystrophy on imaging. Some functional data presented (in vitro). Sources: Expert list |
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| Mendeliome v0.13843 | DARS2 | Zornitza Stark changed review comment from: Slowly progressive disorder with variable age of onset, multiple families reported.; to: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (Scheper et al., 2007). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.13539 | BTK | Zornitza Stark Phenotypes for gene: BTK were changed from to Agammaglobulinaemia, X-linked 1, MIM# 300755; Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13536 | BTK |
Zornitza Stark commented on gene: BTK: Well established gene-disease association with agammaglobulinaemia, >100 families reported. At least 3 families reported with GH deficiency plus agammaglobulinaemia. |
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| Mendeliome v0.13536 | BTK | Zornitza Stark reviewed gene: BTK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8013627, 7849697; Phenotypes: Agammaglobulinaemia, X-linked 1, MIM# 300755, Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13384 | CNNM2 | Ain Roesley Phenotypes for gene: CNNM2 were changed from to Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13382 | CNNM2 | Ain Roesley reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34604137, 35170241; Phenotypes: Hypomagnesemia 6, renal MIM#613882, Hypomagnesemia, seizures, and mental retardation MIM#616418; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13357 | CLDN19 | Zornitza Stark Phenotypes for gene: CLDN19 were changed from Hypomagnesemia 5, renal, with ocular involvement, MIM#248190 to Hypomagnesaemia 5, renal, with ocular involvement, MIM#248190 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13326 | CLDN19 | Ain Roesley Phenotypes for gene: CLDN19 were changed from to Hypomagnesemia 5, renal, with ocular involvement, MIM#248190 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13324 | CLDN19 | Ain Roesley reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033971, 22422540, 27530400]; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM#248190; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13324 | CLDN16 | Ain Roesley Phenotypes for gene: CLDN16 were changed from to Hypomagnesemia 3, renal MIM#248250; amelogenesis imperfecta MONDO#0019507, CLDN16-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13323 | CLDN16 | Ain Roesley reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 26426912, 16501001, 10878661, 32869508; Phenotypes: Hypomagnesemia 3, renal MIM#248250, amelogenesis imperfecta MONDO#0019507, CLDN16-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13159 | CD79B | Zornitza Stark Phenotypes for gene: CD79B were changed from Agammaglobulinemia 6 MIM#612692 to Agammaglobulinaemia 6, MIM#612692 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13022 | CD79B | Ain Roesley Phenotypes for gene: CD79B were changed from to Agammaglobulinemia 6 MIM#612692 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13020 | CD79B | Ain Roesley reviewed gene: CD79B: Rating: GREEN; Mode of pathogenicity: None; Publications: 17709424, 17675462, 33733381, 24722855; Phenotypes: Agammaglobulinemia 6 MIM#612692; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12932 | TCF3 | Zornitza Stark Phenotypes for gene: TCF3 were changed from Agammaglobulinaemia 8, autosomal dominant, MIM# 616941 to Agammaglobulinaemia 8, autosomal dominant, MIM# 616941; Agammaglobulinaemia 8B, autosomal recessive, MIM# 619824 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12931 | TCF3 | Zornitza Stark edited their review of gene: TCF3: Changed phenotypes: Agammaglobulinaemia 8, autosomal dominant, MIM# 616941, Agammaglobulinaemia 8B, autosomal recessive, MIM# 619824 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12884 | CD79A | Zornitza Stark Phenotypes for gene: CD79A were changed from Agammaglobulinemia 3 MIM#613501 to Agammaglobulinaemia 3 MIM#613501 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12855 | CD79A | Ain Roesley Phenotypes for gene: CD79A were changed from to Agammaglobulinemia 3 MIM#613501 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12853 | CD79A | Ain Roesley reviewed gene: CD79A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29335801, 31696364, 24481606, 10525050, 11920841; Phenotypes: Agammaglobulinemia 3 MIM#613501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12691 | TMEM106B |
Zornitza Stark changed review comment from: Cerebellar signs including ataxia prominent.; to: Hypomyelinating leukodystrophy-16 is an autosomal dominant neurologic disorder characterized by onset of hypotonia, nystagmus, and mildly delayed motor development in infancy. Affected individuals have motor disabilities, including ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. Brain imaging typically shows hypomyelination, leukodystrophy, and thin corpus callosum. At least 5 unrelated individuals reported. |
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| Mendeliome v0.11795 | SUZ12 | Zornitza Stark Phenotypes for gene: SUZ12 were changed from to Imagawa-Matsumoto syndrome, MIM# 618786 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11792 | SUZ12 | Zornitza Stark reviewed gene: SUZ12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31736240, 28229514; Phenotypes: Imagawa-Matsumoto syndrome, MIM# 618786; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11520 | IGLL1 | Zornitza Stark Phenotypes for gene: IGLL1 were changed from to Agammaglobulinaemia 2, MIM# 613500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11517 | IGLL1 | Zornitza Stark reviewed gene: IGLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9419212, 25502423, 27576013; Phenotypes: Agammaglobulinaemia 2, MIM# 613500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11286 | KIF5A |
Zornitza Stark edited their review of gene: KIF5A: Added comment: Neonatal intractable myoclonus is a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants have intermittent apnea, abnormal eye movements, pallor of the optic nerve, and lack of developmental progress. Brain imaging shows a progressive leukoencephalopathy. At least 3 unrelated individuals with de novo LoF variants. SPG10/CMT: variants are generally in the motor domain.; Changed publications: 30057544, 29892902, 28902413, 26403765, 25695920, 25008398, 27463701, 27414745; Changed phenotypes: Neuropathy, Spastic paraplegia 10, autosomal dominant, MIM# 604187, Myoclonus, intractable, neonatal, MIM# 617235 |
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| Mendeliome v0.10870 | HMGB1 | Zornitza Stark Phenotypes for gene: HMGB1 were changed from Mirror image foot polydactyly; Developmental delay and microcephaly, no OMIM # to Mirror image foot polydactyly; Neurodevelopmental disorder MONDO:0700092, HMGB1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10791 | FNIP1 | Zornitza Stark Phenotypes for gene: FNIP1 were changed from Hypertrophic Cardiomyopathy; Primary Immunodeficiency; Agammaglobulinemia; Neutropenia to Immunodeficiency 93 and hypertrophic cardiomyopathy, MIM# 619705 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10789 | SPI1 | Zornitza Stark Phenotypes for gene: SPI1 were changed from Agammaglobulinaemia to Agammaglobulinaemia 10, autosomal dominant, MIM# 619707 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10788 | SPI1 | Zornitza Stark edited their review of gene: SPI1: Changed phenotypes: Agammaglobulinaemia 10, autosomal dominant, MIM# 619707 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10758 | IKZF2 |
Zornitza Stark gene: IKZF2 was added gene: IKZF2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: IKZF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IKZF2 were set to 34920454 Phenotypes for gene: IKZF2 were set to Immune dysregulation Review for gene: IKZF2 was set to GREEN Added comment: Six individuals with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated haemophagocytic lymphohistiocytosis reported with variants in this gene. Patients exhibited hypogammaglobulinaemia, decreased number of T-follicular helper and NK-cells. Sources: Literature |
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| Mendeliome v0.10674 | PITX1 | Zornitza Stark Phenotypes for gene: PITX1 were changed from to Brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520; Clubfoot, MONDO:0007342; Liebenberg syndrome, OMIM:186550; Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly, OMIM:119800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10671 | PITX1 | Zornitza Stark reviewed gene: PITX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21775501, 22258522, 18950742; Phenotypes: Brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520, Clubfoot, MONDO:0007342, Liebenberg syndrome, OMIM:186550, Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly, OMIM:119800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10618 | SLC39A7 | Zornitza Stark Phenotypes for gene: SLC39A7 were changed from Antibody deficiency; early onset infections; blistering dermatosis; failure to thrive; thrombocytopaenia to Agammaglobulinaemia 9, autosomal recessive, MIM# 619693; Antibody deficiency; early onset infections; blistering dermatosis; failure to thrive; thrombocytopaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10617 | SLC39A7 | Zornitza Stark edited their review of gene: SLC39A7: Changed phenotypes: Agammaglobulinemia 9, autosomal recessive, MIM# 619693, Antibody deficiency, early onset infections, blistering dermatosis, failure to thrive, thrombocytopaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10552 | CRACR2A |
Dean Phelan gene: CRACR2A was added gene: CRACR2A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CRACR2A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRACR2A were set to PMID:34908525 Phenotypes for gene: CRACR2A were set to Late onset combined immunodeficiency Review for gene: CRACR2A was set to AMBER Added comment: PMID:34908525 - one patient compound het (missense and PTC) with late onset combined immunodeficiency (current chest infections, panhypogammaglobulinemia and CD4+T cell lymphopenia). Functional studies showed defective JNK phosphorylation, defective SOCE and impaired cytokine production. Further search did not identify any additional publications. Sources: Literature |
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| Mendeliome v0.10044 | ECM1 |
Zornitza Stark changed review comment from: PMID: 11929856 - Hamada et al 2002 - looked at 6 different unrelated consanguineous families (from Saudi Arabia, Kuwait, Pakistan, The Netherlands, UK, and a group of South African families with a probable common ancestor) with a clinical diagnosis of Lipoid proteinosis (LP)/Urbach–Wiethe disease. They performed a genome-wide linkage analysis and identified a region and then looked at the expression of candidate genes in fibroblasts from patients compared to controls. ECM1 was found to have lower expression levels. 6 homozygous deletion variants were identified in the patients. In one family they established that the parents were heterozygous for the variant. PMID: 28720532 - Afifi et al 2017 - studied 12 patients from 10 unrelated consanguineous Egyptian families with a clinical diagnosis of lipoid proteinosis. The patients reported progressive hoarseness of voice and easily damaged skin by minor trauma or friction. Homozygous ECM1 variants were detected in affected members in all families: 1 family had a missense variant, 5 families had splice site variants and 4 families had indels predicted to cause frameshifts. Parents were found to be heterozygous for the variants. PMID: 33159951 - Zhu et al 2021 - a novel homozygous three-nucleotide duplication (c.506_508dupCTG) in ECM in two siblings affected with LP from a consanguineous Chinese family.; to: Lipoid proteinosis of Urbach and Wiethe is a rare autosomal recessive disorder typified by generalized thickening of skin, mucosae, and certain viscera. Classic features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. The disorder is clinically heterogeneous, with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurologic abnormalities such as temporal lobe epilepsy. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane PMID: 11929856 - Hamada et al 2002 - looked at 6 different unrelated consanguineous families (from Saudi Arabia, Kuwait, Pakistan, The Netherlands, UK, and a group of South African families with a probable common ancestor) with a clinical diagnosis of Lipoid proteinosis (LP)/Urbach–Wiethe disease. They performed a genome-wide linkage analysis and identified a region and then looked at the expression of candidate genes in fibroblasts from patients compared to controls. ECM1 was found to have lower expression levels. 6 homozygous deletion variants were identified in the patients. In one family they established that the parents were heterozygous for the variant. PMID: 28720532 - Afifi et al 2017 - studied 12 patients from 10 unrelated consanguineous Egyptian families with a clinical diagnosis of lipoid proteinosis. The patients reported progressive hoarseness of voice and easily damaged skin by minor trauma or friction. Homozygous ECM1 variants were detected in affected members in all families: 1 family had a missense variant, 5 families had splice site variants and 4 families had indels predicted to cause frameshifts. Parents were found to be heterozygous for the variants. PMID: 33159951 - Zhu et al 2021 - a novel homozygous three-nucleotide duplication (c.506_508dupCTG) in ECM in two siblings affected with LP from a consanguineous Chinese family. |
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| Mendeliome v0.10041 | SMPX | Zornitza Stark edited their review of gene: SMPX: Added comment: PMID 33974137: Four different missense variants were identified in ten patients from nine families in five different countries. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. Clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.; Changed publications: 21549342, 21549336, 21893181, 22911656, 28542515, 33974137; Changed phenotypes: Deafness, X-linked 4, MIM# 300066, Distal myopathy, adult-onset | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9387 | MAGEL2 | Zornitza Stark Marked gene: MAGEL2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9387 | MAGEL2 | Zornitza Stark Gene: magel2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9387 | MAGEL2 | Zornitza Stark Phenotypes for gene: MAGEL2 were changed from to Schaaf-Yang syndrome, MIM# 615547 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9386 | MAGEL2 | Zornitza Stark Publications for gene: MAGEL2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9385 | MAGEL2 | Zornitza Stark Mode of inheritance for gene: MAGEL2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9384 | MAGEL2 | Zornitza Stark reviewed gene: MAGEL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24076603, 31397880, 29599419, 30302899; Phenotypes: Schaaf-Yang syndrome, MIM# 615547; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9328 | UNC13B |
Zornitza Stark gene: UNC13B was added gene: UNC13B was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: UNC13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: UNC13B were set to 33876820 Phenotypes for gene: UNC13B were set to Epilepsy Review for gene: UNC13B was set to RED Added comment: No OMIM human disease association. Gene encodes a presynaptic protein Munc13-2 highly expressed in the brain (predominantly cerebral cortex). Variant interpretation data in human epilepsy cohort somewhat conflicting and restricted to a single study. Conflicting data esp regarding MOI, and evidence for pathogenicity of several of the variants is limited. Wang et al, Brain, 2021 - trio-based whole-exome sequencing identified UNC13B in 12 individuals affected by partial epilepsy and/or febrile seizures from 8 unrelated families. Identified: x1 de novo nonsense variant, absent in gnomad, damaging in silicos x1 de novo splice site, absent in gnomad, damaging in silicos x1 splice site variant present in unaffected mother (low frequency in gnomad) x2 compound het in one individual - more severe phenotype postulated (x1 variant present in contro cohortl, the other variant present in low frequency in gnomad) x1 missense variant - in Han Chinese major depressive disorders study, not in gnomad x1 missense variant - highly conserved residue, not in gnomad x2 other missense variant - highly conserved residue, low frequency in gnomad Latter 4 missense variants cosegregated with affected individuals in the families In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila De novo UNC13B variants previously reported in bipolar disorder and autism spectrum disorder Sources: Expert Review |
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| Mendeliome v0.9207 | CDKN1C | Zornitza Stark Phenotypes for gene: CDKN1C were changed from to Beckwith-Wiedemann syndrome, MIM# 130650; IMAGe syndrome, MIM# 614732; Silver-Russell syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9204 | CDKN1C | Zornitza Stark reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 10424811, 8841187, 22205991, 20503313, 19843502, 15372379, 23511928, 30794780, 33076988, 31976094, 31497289; Phenotypes: Beckwith-Wiedemann syndrome, MIM# 130650, IMAGe syndrome, MIM# 614732, Silver-Russell syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9169 | HMGB1 | Zornitza Stark Phenotypes for gene: HMGB1 were changed from Mirror image foot polydactyly to Mirror image foot polydactyly; Developmental delay and microcephaly, no OMIM # | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9104 | MAGEL2 | Anna Le Fevre reviewed gene: MAGEL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33820833, 24076603, 31397880, 29599419, 30302899; Phenotypes: Schaaf-Yang syndrome, Chitayat-Hall Syndrome, Arthrogryposis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9082 | UBE2U |
Ee Ming Wong changed review comment from: - one missense UBE2U variant identified in one family with four other affected individuals (includes proband) - in silico analyses predicts the UBE2U variant to be damaging - no functional - another STUM missense variant identified in the same family predicted to be benign - additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome Sources: Literature; to: - one missense UBE2U variant identified in one family with five affected individuals (includes proband) - in silico analyses predicts the UBE2U variant to be damaging - no functional - another STUM missense variant identified in the same family predicted to be benign - additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome Sources: Literature |
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| Mendeliome v0.9075 | UBE2U |
Ee Ming Wong gene: UBE2U was added gene: UBE2U was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UBE2U were set to PMID: 33776059 Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay Penetrance for gene: UBE2U were set to Complete Review for gene: UBE2U was set to RED gene: UBE2U was marked as current diagnostic Added comment: - one missense UBE2U variant identified in one family with four other affected individuals (includes proband) - in silico analyses predicts the UBE2U variant to be damaging - no functional - another STUM missense variant identified in the same family predicted to be benign - additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome Sources: Literature |
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| Mendeliome v0.9068 | ZNF668 |
Paul De Fazio changed review comment from: 5 individuals from 3 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature; to: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature |
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| Mendeliome v0.9067 | ZNF668 |
Paul De Fazio changed review comment from: 5 individuals from 3 consanguineous families reported with different truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature; to: 5 individuals from 3 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature |
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| Mendeliome v0.9067 | ZNF668 |
Paul De Fazio gene: ZNF668 was added gene: ZNF668 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF668 were set to 34313816; 26633546 Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism Review for gene: ZNF668 was set to GREEN gene: ZNF668 was marked as current diagnostic Added comment: 5 individuals from 3 consanguineous families reported with different truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Literature |
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| Mendeliome v0.9026 | TOM1 |
Zornitza Stark gene: TOM1 was added gene: TOM1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TOM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TOM1 were set to 31263572 Phenotypes for gene: TOM1 were set to Immunodeficiency 85 and autoimmunity, MIM# 619510 Review for gene: TOM1 was set to RED Added comment: Parent and child reported with onset of atopic eczema and recurrent respiratory infections in the first decade of life; autoimmune enteropathy with vomiting, diarrhoea, and poor overall growth. More variable features included autoimmune oligoarthritis, interstitial pneumonitis, and EBV viremia. Laboratory studies showed hypogammaglobulinaemia and abnormal T-cell function, consistent with a combined immunodeficiency. Missense variant in TOM1, with limited functional data. Sources: Expert list |
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| Mendeliome v0.8939 | RAC2 | Zornitza Stark Phenotypes for gene: RAC2 were changed from to Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis MIM# 608203; Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinaemia MIM# 618987; Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8935 | RAC2 | Danielle Ariti reviewed gene: RAC2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 21167572, 10758162, 10072071, 25512081, 32542921, 31919089; Phenotypes: Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis MIM# 608203, Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinaemia MIM# 618987, Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8848 | TCN2 |
Zornitza Stark changed review comment from: Well established gene-disease association. 26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models Homologous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation. Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia. Sources: Expert list; to: Well established gene-disease association. 26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models Homozygous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation. Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia. Sources: Expert list |
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| Mendeliome v0.8847 | TCN2 |
Zornitza Stark changed review comment from: Well established gene-disease association. Sources: Expert list; to: Well established gene-disease association. 26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models Homologous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation. Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia. Sources: Expert list |
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| Mendeliome v0.8815 | BLNK | Zornitza Stark Phenotypes for gene: BLNK were changed from to Agammaglobulinaemia 4, MIM# 613502 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8812 | BLNK | Zornitza Stark reviewed gene: BLNK: Rating: GREEN; Mode of pathogenicity: None; Publications: 10583958, 32194234, 25893637; Phenotypes: Agammaglobulinaemia 4, MIM# 613502; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8807 | VPS50 |
Zornitza Stark gene: VPS50 was added gene: VPS50 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to 34037727 Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum Review for gene: VPS50 was set to AMBER Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes. Sources: Literature |
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| Mendeliome v0.8773 | SP110 | Zornitza Stark Phenotypes for gene: SP110 were changed from to Hepatic veno-occlusive disease with immunodeficiency MIM#235550; Hepatic veno-occlusive disease; susceptibility to Pneumocystis jirovecii pneumonia; cytomegalovirus; thrombocytopaenia; hepatosplenomegaly; cerebrospinal leukodystrophy; memory T/B cell deficiency; low Ig levels; absent tissue plasma cells; absent lymph node germinal centers; hypogammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8767 | SP110 | Danielle Ariti reviewed gene: SP110: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301448, 31721003; Phenotypes: Hepatic veno-occlusive disease with immunodeficiency MIM#235550, Hepatic veno-occlusive disease, susceptibility to Pneumocystis jirovecii pneumonia, cytomegalovirus, thrombocytopaenia, hepatosplenomegaly, cerebrospinal leukodystrophy, memory T/B cell deficiency, low Ig levels, absent tissue plasma cells, absent lymph node germinal centers, hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.8722 | RFXAP | Zornitza Stark Phenotypes for gene: RFXAP were changed from to Bare lymphocyte syndrome, type II, complementation group D MIM# 209920; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8719 | RFXANK | Zornitza Stark Phenotypes for gene: RFXANK were changed from to MHC class II deficiency, complementation group B MIM# 209920; Bare Lymphocyte Syndrome, type II, complementation group B; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8713 | RFXANK | Danielle Ariti reviewed gene: RFXANK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12618906; Phenotypes: MHC class II deficiency, complementation group B MIM# 209920, Bare Lymphocyte Syndrome, type II, complementation group B, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8713 | RFXAP | Danielle Ariti reviewed gene: RFXAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9118943, 32875002, 11258423; Phenotypes: Bare lymphocyte syndrome, type II, complementation group D MIM# 209920, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8702 | TCF3 | Zornitza Stark Phenotypes for gene: TCF3 were changed from to Agammaglobulinaemia 8, autosomal dominant, MIM# 616941 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8699 | TCF3 | Zornitza Stark reviewed gene: TCF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24216514, 28532655, 30063982, 8001124, 8001125; Phenotypes: Agammaglobulinaemia 8, autosomal dominant, MIM# 616941; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8696 | CD19 | Zornitza Stark changed review comment from: More than 5 unrelated families reported.; to: More than 5 unrelated families reported. Clinical features include increased susceptibility to infection, hypogammaglobulinaemia, and normal numbers of mature B cells in blood, indicating a B-cell antibody-deficient immunodeficiency disorder. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8671 | RGS10 |
Zornitza Stark gene: RGS10 was added gene: RGS10 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RGS10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RGS10 were set to 34315806; 34339853 Phenotypes for gene: RGS10 were set to Immunodeficiency; short stature Review for gene: RGS10 was set to RED Added comment: Three affected siblings with short stature and immunodeficiency and segregating biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals had recurrent infections, hypergammaglobulinaemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Limited functional data presented. Further experimental data linking RGS10 to immune function presented in PMID 34339853. Sources: Literature |
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| Mendeliome v0.8657 | NFKBIA | Zornitza Stark Phenotypes for gene: NFKBIA were changed from to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132; Ectodermal dysplasia; TCR/ BCR activation impaired; low memory and isotype switched B cells; decreased IgG and IgA; elevated IgM; poor specific antibody responses; diarrhoea; agammaglobulinaemia; ectodermal dysplasia; recurrent respiratory and gastrointestinal infections; colitis; variable defects of skin, hair and teeth | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8651 | NFKB1 | Zornitza Stark Phenotypes for gene: NFKB1 were changed from to Immunodeficiency, common variable, 12 MIM# 616576; Normal-low IgG, IgA, IgM; low-normal B cells; low switched memory B cells; hypogammaglobulinaemia; recurrent respiratory and gastrointestinal infections; Chronic obstructive pulmonary disease COPD; EBV proliferation; autoimmunity; alopecia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8644 | MAP3K14 | Zornitza Stark Phenotypes for gene: MAP3K14 were changed from to NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8641 | MAP3K14 | Zornitza Stark reviewed gene: MAP3K14: Rating: GREEN; Mode of pathogenicity: None; Publications: 10319865, 11238593, 12352969; Phenotypes: NIK deficiency, Poor T cell proliferation to antigen, Low B-cell numbers, Low NK number and function, recurrent bacterial/viral/ cryptosporidium infections, hypogammaglobulinaemia, decreased immunoglobulin levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8641 | LRBA | Zornitza Stark Phenotypes for gene: LRBA were changed from to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700; Normal-decreased CD4 numbers; T cell dysregulation; Low-normal B cells; Reduced IgG and IgA; Recurrent infections; chronic diarrhoea; inflammatory bowel disease; hypogammaglobulinaemia; pneumonitis; autoimmune disorders; thrombocytopaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | LRBA | Zornitza Stark reviewed gene: LRBA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22608502, 22721650, 25468195, 26206937, 33155142; Phenotypes: Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700, Normal-decreased CD4 numbers, T cell dysregulation, Low-normal B cells, Reduced IgG and IgA, Recurrent infections, chronic diarrhoea, inflammatory bowel disease, hypogammaglobulinaemia, pneumonitis, autoimmune disorders, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | NFKBIA | Danielle Ariti reviewed gene: NFKBIA: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 28597146, 23864385, 23708964; Phenotypes: Ectodermal dysplasia and immunodeficiency 2 MIM# 612132, Ectodermal dysplasia, TCR/ BCR activation impaired, low memory and isotype switched B cells, decreased IgG and IgA, elevated IgM, poor specific antibody responses, diarrhoea, agammaglobulinaemia, ectodermal dysplasia, recurrent respiratory and gastrointestinal infections, colitis, variable defects of skin, hair and teeth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | NFKB1 | Danielle Ariti reviewed gene: NFKB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26279205, 32278790, 27022143, 7834752; Phenotypes: Immunodeficiency, common variable, 12 MIM# 616576, Normal-low IgG, IgA, IgM, low-normal B cells, low switched memory B cells, hypogammaglobulinaemia, recurrent respiratory and gastrointestinal infections, Chronic obstructive pulmonary disease COPD, EBV proliferation, autoimmunity, alopecia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8623 | IL2RG | Zornitza Stark Phenotypes for gene: IL2RG were changed from to Combined immunodeficiency, X-linked, moderate MIM# 312863; Severe combined immunodeficiency, X-linked MIM# 300400; recurrent viral/fungal/bacterial infections; Low T/NK cells; Low Ig levels; lymphocytopaenia; hypogammaglobulinaemia; failure to thrive; diarrhoea; Pneumonia; Thymic hypoplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8620 | IL2RG | Zornitza Stark reviewed gene: IL2RG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301584, 8462096, 8401490, 7883965, 9399950; Phenotypes: Combined immunodeficiency, X-linked, moderate MIM# 312863, Severe combined immunodeficiency, X-linked MIM# 300400, recurrent viral/fungal/bacterial infections, Low T/NK cells, Low Ig levels, lymphocytopaenia, hypogammaglobulinaemia, failure to thrive, diarrhoea, Pneumonia, Thymic hypoplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8620 | IKZF1 | Zornitza Stark Phenotypes for gene: IKZF1 were changed from to Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8617 | IKZF1 | Zornitza Stark reviewed gene: IKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317; Phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8617 | ITK | Zornitza Stark Phenotypes for gene: ITK were changed from to Lymphoproliferative syndrome 1 MIM# 613011; Lymphadenopathy; Recurrent infections; Hypogammaglobulinaemia; Evidence of EBV infection; EBV associated B cell Lymphoproliferation; High EBV viral load; Normal-low serum Ig; Depleted CD4+ T cells; Anaemia; Thrombocytopaenia; Hepatosplenomegaly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8614 | ITK | Danielle Ariti reviewed gene: ITK: Rating: GREEN; Mode of pathogenicity: None; Publications: 19425169, 22289921, 25061172, 26056787, 9311799, 10213685; Phenotypes: Lymphoproliferative syndrome 1 MIM# 613011, Lymphadenopathy, Recurrent infections, Hypogammaglobulinaemia, Evidence of EBV infection, EBV associated B cell Lymphoproliferation, High EBV viral load, Normal-low serum Ig, Depleted CD4+ T cells, Anaemia, Thrombocytopaenia, Hepatosplenomegaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8586 | HMGB1 |
Ain Roesley changed review comment from: 1x de novo fs, no functional studies done but cited Itou 2011 - mouse and zebrafish studies demonstrated the role of HMGB1 in regulating digit number during embryonic limb development Sources: Literature; to: 1x de novo fs in a proband with severe mirror image foot polydactyly. No functional studies done but cited Itou 2011 - mouse and zebrafish studies demonstrated the role of HMGB1 in regulating digit number during embryonic limb development Sources: Literature |
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| Mendeliome v0.8586 | HMGB1 |
Ain Roesley gene: HMGB1 was added gene: HMGB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HMGB1 were set to 34159400 Phenotypes for gene: HMGB1 were set to Mirror image foot polydactyly Penetrance for gene: HMGB1 were set to unknown Review for gene: HMGB1 was set to RED Added comment: 1x de novo fs, no functional studies done but cited Itou 2011 - mouse and zebrafish studies demonstrated the role of HMGB1 in regulating digit number during embryonic limb development Sources: Literature |
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| Mendeliome v0.8542 | IKZF3 |
Zornitza Stark gene: IKZF3 was added gene: IKZF3 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: IKZF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IKZF3 were set to 34155405 Phenotypes for gene: IKZF3 were set to Immunodeficiency 84, MIM# 619437 Review for gene: IKZF3 was set to AMBER Added comment: Single family reported where heterozygous missense variant in this gene segregated with immunodeficiency in a mother and two children. Findings included low levels of B cells and impaired early B-cell development, variable T-cell abnormalities, hypogammaglobulinaemia, increased susceptibility to infection with Epstein-Barr virus (EBV). One individual developed lymphoma in adulthood. Mouse model recapitulated phenotype. Sources: Expert Review |
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| Mendeliome v0.8538 | LCK | Zornitza Stark Phenotypes for gene: LCK were changed from to Immunodeficiency 22 MIM# 615758; Recurrent infections; Immune dysregulation; autoimmunity; Low CD4+; low CD8+; restricted T cell repertoire; poor TCR signaling; Normal IgG/IgA; high IgM; failure to thrive; diarrhoea; lymphopaenia; hypogammaglobulinaemia; anaemia; thrombocytopaenia; CD4+ T-cell lymphopaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8533 | LCK | Zornitza Stark reviewed gene: LCK: Rating: AMBER; Mode of pathogenicity: None; Publications: 22985903, 1579166, 11021796; Phenotypes: Immunodeficiency 22 MIM# 615758, Recurrent infections, Immune dysregulation, autoimmunity, Low CD4+, low CD8+, restricted T cell repertoire, poor TCR signaling, Normal IgG/IgA, high IgM, failure to thrive, diarrhoea, lymphopenia, hypogammaglobulinemia, anaemia, thrombocytopaenia, CD4+ T-cell lymphopenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8527 | DNMT3B | Zornitza Stark Phenotypes for gene: DNMT3B were changed from to Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860; facial dysmorphic features; flat nasal bridge; developmental delay; macroglossia; bacterial/opportunistic infections (recurrent); malabsorption; cytopaenia; malignancies; multiradial configurations of chromosomes 1, 9, 16; Hypogammaglobulinaemia; agammaglobulinaemia; variable antibody deficiency; decreased immunoglobulin production; low T/B/NK cells | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8524 | DNMT3B | Zornitza Stark reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20587527, 10555141, 17359920, 9718351, 10647011, 11102980, 12239717; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860, facial dysmorphic features, flat nasal bridge, developmental delay, macroglossia, bacterial/opportunistic infections (recurrent), malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia, agammaglobulinaemia, variable antibody deficiency, decreased immunoglobulin production, low T/B/NK cells; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8481 | CIITA | Zornitza Stark Phenotypes for gene: CIITA were changed from to Bare Lymphocyte Syndrome, type II, complementation group A MIM# 209920; varied ID; bronchiolitis; pneumonia; severe autoimmune cytopaenia; CD4 T-cell lymphopaenia; hypogammaglobulinemia; absence of antigen-induced immune response; chronic diarrhoea; recurrent respiratory infections; recurrent gastroenteritis; failure to thrive; liver/biliary tract disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8478 | CIITA | Zornitza Stark reviewed gene: CIITA: Rating: GREEN; Mode of pathogenicity: None; Publications: 8402893, 9099848, 11862382, 28676232, 24789686, 20197681, 11466404, 15821736, 12910265; Phenotypes: Bare Lymphocyte Syndrome, type II, complementation group A MIM# 209920, varied ID, bronchiolitis, pneumonia, severe autoimmune cytopaenia, CD4 T-cell lymphopaenia, hypogammaglobulinemia, absence of antigen-induced immune response, chronic diarrhoea, recurrent respiratory infections, recurrent gastroenteritis, failure to thrive, liver/biliary tract disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8478 | CD40LG | Zornitza Stark Phenotypes for gene: CD40LG were changed from to Immunodeficiency, X-linked, with hyper-IgM MIM# 308230; Severe opportunistic infections (recurrent), idiopathic neutropaenia; dysgammaglobulinaemia hepatitis; cholangitis; cholangiocarcinoma; autoimmune blood cytopenias; haemolytic anaemia; thrombocytopaenia; diarrhoea; peripheral neuroectodermal tumours | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8468 | CD40LG | Danielle Ariti reviewed gene: CD40LG: Rating: GREEN; Mode of pathogenicity: None; Publications: 7679801, 7679206, 8094231, 9933119, 15358621, 15997875, 7678782, 7915248, 15367912, 7518839, 16311023, 9933119, 12402041, 7882172, 33475257; Phenotypes: mmunodeficiency, X-linked, with hyper-IgM MIM# 308230, Severe opportunistic infections (recurrent), idiopathic neutropaenia, dysgammaglobulinaemia hepatitis, cholangitis, cholangiocarcinoma, autoimmune blood cytopenias, haemolytic anaemia, thrombocytopaenia, diarrhoea, peripheral neuroectodermal tumours; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8318 | 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 v0.8091 | OAS1 | Zornitza Stark Phenotypes for gene: OAS1 were changed from to Autoinflammatory immunodeficiency; infantile-onset pulmonary alveolar proteinosis; hypogammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8087 | OAS1 | Zornitza Stark reviewed gene: OAS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34145065, 29455859; Phenotypes: Autoinflammatory immunodeficiency, infantile-onset pulmonary alveolar proteinosis, hypogammaglobulinaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7983 | TRPM6 | Zornitza Stark Phenotypes for gene: TRPM6 were changed from to Hypomagnesaemia 1, intestinal (MIM#602014) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7967 | TRPM6 | Kristin Rigbye reviewed gene: TRPM6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 1, intestinal (MIM#602014), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7734 | 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 v0.7706 | RAB11B | Zornitza Stark commented on gene: RAB11B: NDAGSCW is a neurodevelopmental disorder characterized by severely delayed psychomotor development apparent from infancy. Affected individuals have delayed and difficulty walking, intellectual disability, absent speech, and variable additional features, including hip dysplasia, tapering fingers, and seizures. Brain imaging shows decreased cortical white matter, often with decreased cerebellar white matter, thin corpus callosum, and thin brainstem. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7561 | 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 v0.7557 | SPI1 |
Zornitza Stark gene: SPI1 was added gene: SPI1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SPI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SPI1 were set to 33951726 Phenotypes for gene: SPI1 were set to Agammaglobulinaemia Review for gene: SPI1 was set to GREEN Added comment: Six unrelated individuals reported, four with de novo variants, two unphased. Some functional data. Sources: Literature |
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| Mendeliome v0.7358 | JMJD1C |
Zornitza Stark gene: JMJD1C was added gene: JMJD1C was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: JMJD1C were set to 26181491; 32996679 Phenotypes for gene: JMJD1C were set to Intellectual disability Review for gene: JMJD1C was set to GREEN Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity. Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679). Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype. Sources: Expert Review |
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| Mendeliome v0.7004 | PRIM1 |
Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature |
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| Mendeliome v0.7003 | PRIM1 |
Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature |
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| Mendeliome v0.7003 | PRIM1 |
Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature |
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| Mendeliome v0.7003 | PRIM1 |
Zornitza Stark gene: PRIM1 was added gene: PRIM1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRIM1 were set to 33060134 Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950 Review for gene: PRIM1 was set to AMBER Added comment: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature |
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| Mendeliome v0.6766 | LRRC8A | Bryony Thompson reviewed gene: LRRC8A: Rating: RED; Mode of pathogenicity: None; Publications: 14660746; Phenotypes: ?Agammaglobulinemia 5 MIM#613506; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6501 | PCBD1 |
Michelle Torres edited their review of gene: PCBD1: Added comment: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; Changed phenotypes: MODY, Hyperphenylalaninemia, BH4-deficient, D 264070 |
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| Mendeliome v0.6494 | PCBD1 |
Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY |
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| Mendeliome v0.6490 | PCBD1 |
Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY |
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| Mendeliome v0.6342 | CLCN6 | Zornitza Stark Phenotypes for gene: CLCN6 were changed from Benign partial epilepsy; febrile seizures; NCL to Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities, MIM# 619173; Neurodegeneration; Benign partial epilepsy; febrile seizures; NCL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6340 | CLCN6 | Zornitza Stark edited their review of gene: CLCN6: Changed phenotypes: Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities, MIM# 619173, Neurodegeneration, Benign partial epilepsy, febrile seizures, NCL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6311 | OTUD5 | Zornitza Stark edited their review of gene: OTUD5: Added comment: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; Changed rating: GREEN; Changed publications: 33131077, 33523931; Changed phenotypes: Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6149 | NOS1AP |
Zornitza Stark edited their review of gene: NOS1AP: Added comment: Nephrotic syndrome type 22 (NPHS22) is an autosomal recessive renal disease characterized by onset of progressive kidney dysfunction in infancy. Affected individuals usually present with edema associated with hypoproteinemia, proteinuria, and microscopic hematuria. Renal biopsy shows effacement of the podocyte foot processes, glomerulosclerosis, and thickening of the glomerular basement membrane. The disease is steroid-resistant and progressive, resulting in end-stage renal disease usually necessitating kidney transplant. Two unrelated families and animal model. No PMID yet: https://advances.sciencemag.org/content/7/1/eabe1386; Changed rating: GREEN; Changed phenotypes: Nephrotic syndrome, type 22, MIM# 619155; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Mendeliome v0.6141 | NDUFC2 |
Zornitza Stark gene: NDUFC2 was added gene: NDUFC2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NDUFC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NDUFC2 were set to 32969598 Phenotypes for gene: NDUFC2 were set to Mitochondrial complex I deficiency, nuclear type 36, MIM# 619170 Review for gene: NDUFC2 was set to AMBER Added comment: Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome. Two unrelated families reported, some functional data. Sources: Expert list |
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| Mendeliome v0.6035 | SCAMP5 | Zornitza Stark edited their review of gene: SCAMP5: Added comment: PMID 33390987: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.; Changed publications: 31439720, 33390987 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5553 | KDM4B |
Kristin Rigbye gene: KDM4B was added gene: KDM4B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KDM4B were set to PMID: 33232677 Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects Review for gene: KDM4B was set to GREEN Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In a knockout mouse the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. Sources: Literature |
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| Mendeliome v0.5507 | USP7 | Zornitza Stark edited their review of gene: USP7: Added comment: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay, behavioral abnormalities, such as autism, and mild dysmorphic facies. Additional features are variable, but may include hypotonia, feeding problems, delayed walking with unsteady gait, hypogonadism in males, and ocular anomalies, such as strabismus. Some patients develop seizures and some have mild white matter abnormalities on brain imaging.; Changed publications: 26365382, 30679821; Changed phenotypes: Hao-Fountain syndrome, MIM# 616863, Intellectual disability, Autism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5474 | SEC61A1 | Elena Savva reviewed gene: SEC61A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28782633, 27392076; Phenotypes: Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056, Hypogammaglobulinaemia, Neutropaenia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5400 | POLE | Zornitza Stark Phenotypes for gene: POLE were changed from to FILS syndrome, 615139; IMAGE-I syndrome, 618336; {Colorectal cancer, susceptibility to, 12}, 615083 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5393 | POLE | Elena Savva reviewed gene: POLE: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 30503519, 23230001; Phenotypes: FILS syndrome, 615139, IMAGE-I syndrome, 618336, {Colorectal cancer, susceptibility to, 12}, 615083; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5222 | MPP5 |
Konstantinos Varvagiannis gene: MPP5 was added gene: MPP5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MPP5 were set to 33073849 Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality Penetrance for gene: MPP5 were set to unknown Review for gene: MPP5 was set to GREEN Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants. Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features. All were investigated by exome sequencing (previous investigations not mentioned). One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro). All variants had in silico predictions in favor of a deleterious effect (CADD score >24). The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK p55 subfamily), determining cell polarity at tight junctions. Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided] The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness. Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision. Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice. Sources: Literature |
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| Mendeliome v0.5200 | ODC1 | Zornitza Stark Phenotypes for gene: ODC1 were changed from Intellectual disability; macrocephaly; dysmorphism to Neurodevelopmental disorder with alopecia and brain imaging abnormalities (NEDABIA), MIM#619075 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5198 | ODC1 | Zornitza Stark edited their review of gene: ODC1: Changed phenotypes: Neurodevelopmental disorder with alopecia and brain imaging abnormalities (NEDABIA), MIM#619075 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4879 | MAG | Zornitza Stark Phenotypes for gene: MAG were changed from Spastic paraplegia 75, autosomal recessive, MIM# 616680 to Spastic paraplegia 75, autosomal recessive, MIM# 616680; Cerebellar ataxia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4878 | MAG | Zornitza Stark changed review comment from: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported.; to: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4860 | 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 v0.4797 | ANGPT2 | Zornitza Stark Publications for gene: ANGPT2 were set to https://stm.sciencemag.org/content/12/560/eaax8013 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4548 | KIAA1161 | Zornitza Stark edited their review of gene: KIAA1161: Added comment: In a cohort study comprising 435 individuals with primary brain calcification, 38 individuals identified with mono-allelic variants in this gene, in addition to 14 with bi-allelic variants. Clinical and imaging penetrance of individuals with bi-allelic variants were 100%, whereas among individuals with heterozygous variants, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG variants, individuals with heterozygous variants had brain calcifications with much lower calcification scores (P < 2e-16). HGNC approved name is MYORG.; Changed publications: 30656188, 30649222, 30460687, 29910000, 31951047; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4531 | IBA57 |
Zornitza Stark changed review comment from: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.; to: MMDS3: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable. SPG74: Three families with spastic paraparesis as a feature of the condition. |
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| 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 v0.4510 | MAG | Zornitza Stark Marked gene: MAG as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4510 | MAG | Zornitza Stark Gene: mag has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4510 | MAG | Zornitza Stark Phenotypes for gene: MAG were changed from to Spastic paraplegia 75, autosomal recessive, MIM# 616680 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4509 | MAG | Zornitza Stark Publications for gene: MAG were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4508 | MAG | Zornitza Stark Mode of inheritance for gene: MAG was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4507 | MAG | Zornitza Stark reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 26179919, 31402626, 32629324; Phenotypes: Spastic paraplegia 75, autosomal recessive, MIM# 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4496 | FNIP1 |
Arina Puzriakova gene: FNIP1 was added gene: FNIP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FNIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FNIP1 were set to 32181500; 32905580 Phenotypes for gene: FNIP1 were set to Hypertrophic Cardiomyopathy; Primary Immunodeficiency; Agammaglobulinemia; Neutropenia Review for gene: FNIP1 was set to GREEN Added comment: - PMID: 32181500 (2020) - Three patients from two independent consanguineous families with homozygous variants (c.3353G>A, p.Ser1118Asn and c.1289delA, p.His430Profs7*) in the FNIP1 gene. Both variants segregated with the disease phenotype in each family. Clinically, patients presented with combined immunodeficiency, cardiac findings (hypertrophic cardiomyopathy, Wolff‐Parkinson‐White syndrome), and myopathy of skeletal muscles with motor DD. Authors note phenotypic overlap with the murine model of FNIP1 deficiency, but no functional analyses of the variants or patient cells were performed. - PMID: 32905580 (2020) - Three cases from unrelated families, all harbouring novel biallelic variants in FNIP1. Clinical manifestations in all patients include hypertrophic cardiomyopathy, severe and/or recurrent infections, absent circulating B-cells, and agammaglobulinemia; as well as either severe or intermittent neutropenia in two cases. Functional studies showed impairment of B-cell metabolism, including disruptions to mitochondrial numbers/activity and the PI3K/AKT pathway. Sources: Literature |
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| Mendeliome v0.4463 | NAXE | Zornitza Stark changed review comment from: Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.; to: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.4309 | ZSWIM6 |
Zornitza Stark changed review comment from: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype. MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X) identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype. MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp |
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| Mendeliome v0.4309 | ZSWIM6 |
Zornitza Stark changed review comment from: MIM #617865 A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype. MIM#603671: recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype. MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp |
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| Mendeliome v0.4299 | ANGPT2 |
Zornitza Stark gene: ANGPT2 was added gene: ANGPT2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ANGPT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ANGPT2 were set to https://stm.sciencemag.org/content/12/560/eaax8013 Phenotypes for gene: ANGPT2 were set to Primary lymphoedema Review for gene: ANGPT2 was set to GREEN Added comment: Five unrelated individuals reported with primary lymphedema and variants in this gene, together with functional data. Sources: Literature |
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| Mendeliome v0.3950 | SEC61A1 | Zornitza Stark Phenotypes for gene: SEC61A1 were changed from to Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056; Hypogammaglobulinaemia; Neutropaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3947 | SEC61A1 | Zornitza Stark reviewed gene: SEC61A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27392076, 32325141, 28782633; Phenotypes: Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056, Hypogammaglobulinaemia, Neutropaenia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3838 | RAI1 | Zornitza Stark Phenotypes for gene: RAI1 were changed from to Smith-Magenis syndrome (MIM#182290) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3835 | RAI1 | Kristin Rigbye reviewed gene: RAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 11404004, 12652298, 15788730; Phenotypes: Smith-Magenis syndrome (MIM#182290), AD, IC; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3368 | GRM7 | Zornitza Stark Phenotypes for gene: GRM7 were changed from Epilepsy, microcephaly, developmental delay to Epilepsy, microcephaly, developmental delay; neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA), MIM#618922 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3367 | GRM7 | Zornitza Stark edited their review of gene: GRM7: Changed phenotypes: Epilepsy, microcephaly, developmental delay, neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA), MIM#618922 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3325 | TBC1D2B |
Zornitza Stark gene: TBC1D2B was added gene: TBC1D2B was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBC1D2B were set to 32623794 Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality Review for gene: TBC1D2B was set to GREEN Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants. Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations. All were born to non-consanguineous couples and additional investigations were performed in some. Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses. In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts. TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation. Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24. Sources: Expert Review |
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| 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 v0.2624 | MEPE |
Zornitza Stark gene: MEPE was added gene: MEPE was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MEPE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MEPE were set to 30287925 Phenotypes for gene: MEPE were set to hereditary congenital facial paresis; otosclerosis Review for gene: MEPE was set to AMBER Added comment: Single four-generation family reported with variant in this gene segregating nonprogressive HCFP and mixed hearing loss (HL). Damaging variants (truncating/frameshift) found to be enriched in otosclerosis cohort (p = 0.0006–0.0060). Sources: Literature |
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| Mendeliome v0.1944 | IL2RB |
Zornitza Stark gene: IL2RB was added gene: IL2RB was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: IL2RB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL2RB were set to 31040184; 31040185 Phenotypes for gene: IL2RB were set to Immunodeficiency 63 with lymphoproliferation and autoimmunity, MIM# 618495; Lymphoproliferation, lymphadenopathy, hepatosplenomegaly, autoimmune haemolytic anaemia, dermatitis, enteropathy, hypergammaglobulinaemia, recurrent viral (EBV, CMV) infections Review for gene: IL2RB was set to GREEN Added comment: Five families reported. Sources: Expert list |
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| Mendeliome v0.1917 | LIG1 |
Zornitza Stark gene: LIG1 was added gene: LIG1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: LIG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIG1 were set to 30395541 Phenotypes for gene: LIG1 were set to Combined immunodeficiency; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis Review for gene: LIG1 was set to GREEN Added comment: Five individuals from three families. Sources: Expert list |
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| Mendeliome v0.1788 | ZNF462 | Zornitza Stark Added comment: Comment when marking as ready: Multiple congenital anomaly syndrome characterised by variable but usually mild global developmental delay and common craniofacial abnormalities, including ptosis, abnormal head shape, downslanting palpebral fissures, epicanthal folds, arched eyebrows, and short upturned nose. Many patients have hypotonia and feeding difficulties. A few patients show agenesis of the corpus callosum on brain imaging. Most cases occur sporadically, but there are rare familial cases that show highly variable expressivity in the phenotypic manifestations. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1725 | ISCA1 |
Zornitza Stark gene: ISCA1 was added gene: ISCA1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ISCA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ISCA1 were set to 28356563; 32092383; 31016283; 30113620; 30105122 Phenotypes for gene: ISCA1 were set to Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613 Review for gene: ISCA1 was set to GREEN gene: ISCA1 was marked as current diagnostic Added comment: Multiple unrelated families reported. Severe disorder characterised by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Rat model results in early lethality. Founder variant c.259G > A, p.(Glu87Lys) reported in Indian families. Sources: Expert list |
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| Mendeliome v0.1029 | EGF | Zornitza Stark Phenotypes for gene: EGF were changed from to Hypomagnesemia 4, renal, MIM#611718 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1026 | EGF | Zornitza Stark reviewed gene: EGF: Rating: RED; Mode of pathogenicity: None; Publications: 17671655; Phenotypes: Hypomagnesemia 4, renal, MIM#611718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.788 | TDP2 |
Zornitza Stark gene: TDP2 was added gene: TDP2 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: TDP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TDP2 were set to 31410782; 30109272; 24658003 Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23; OMIM #616949 Review for gene: TDP2 was set to GREEN Added comment: ID is part of the phenotype: 4 families with 6 affected patients, with functional evidence. 1 family with 3 affected sibs with homozygous splice site mutation in the TDP2 gene. Patient cell extracts showed absence of the full-length TDP2 protein and absence of 5-prime TDP activity, consistent with a loss of function, although 3-prime TDP activity, conferred by TDP1, was normal. In addition, patient lymphoblastoid cells were hypersensitive to the TOP2 poison etoposide. The findings indicated impaired capacity for double-strand break repair. 1 unrelated Egyptian patient with a similar disorder was homozygous for a truncating mutation in the TDP2 gene 1 unrelated Caucasian patient with same homozygous splice site mutation in the TDP2 gene. Western blot analysis did not detect TDP2 protein in patient primary skin fibroblasts. Patient fibroblasts showed an inability to rapidly repair topoisomerase-induced DNA double-strand breaks in the nucleus and also showed a profound hypersensitivity to this type of DNA damage. Complementation of patient cells with recombinant human TDP2 restored normal rates of nuclear DSB repair. Sources: Expert list |
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| Mendeliome v0.715 | IGHM |
Zornitza Stark gene: IGHM was added gene: IGHM was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: IGHM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IGHM were set to 12370281; 8890099 Phenotypes for gene: IGHM were set to Agammaglobulinemia 1, MIM# 601495 Review for gene: IGHM was set to GREEN Added comment: Multiple families reported; please note a 40kb deletion as well as SNVs. Sources: Expert list |
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| Mendeliome v0.660 | AIMP2 |
Zornitza Stark gene: AIMP2 was added gene: AIMP2 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: AIMP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AIMP2 were set to 29215095 Phenotypes for gene: AIMP2 were set to Leukodystrophy, hypomyelinating, 17 618006 Review for gene: AIMP2 was set to RED Added comment: Two apparently unrelated consanguineous families, however same homozygous variant identified in both. Affected individuals had early-onset multifocal seizures, spasticity, poor overall growth, and microcephaly (up to -10 SD). Brain imaging showed multiple abnormalities, including cerebral and cerebellar atrophy, thin corpus callosum, abnormal signals in the basal ganglia, and features suggesting hypo- or demyelination Sources: Expert list |
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| Mendeliome v0.0 | MAGT1 |
Zornitza Stark gene: MAGT1 was added gene: MAGT1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MAGT1 was set to Unknown |
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| Mendeliome v0.0 | MAGI2 |
Zornitza Stark gene: MAGI2 was added gene: MAGI2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MAGI2 was set to Unknown |
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| Mendeliome v0.0 | MAGEL2 |
Zornitza Stark gene: MAGEL2 was added gene: MAGEL2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MAGEL2 was set to Unknown |
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| Mendeliome v0.0 | MAGED2 |
Zornitza Stark gene: MAGED2 was added gene: MAGED2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MAGED2 was set to Unknown |
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| Mendeliome v0.0 | MAG |
Zornitza Stark gene: MAG was added gene: MAG was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MAG was set to Unknown |
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