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| Intellectual disability v4.51 | KDM2B |
Mike Spiller gene: KDM2B was added gene: KDM2B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KDM2B were set to PMID: 36322151; 35128353; 35710456 Review for gene: KDM2B was set to GREEN Added comment: van Jaarsveld et al 2022 PMID: 36322151 Majority of variants are missense, strong evidence for hotspot in CXXC domain.(7 different de Novo missenses + 1 de Novo in frame del. Same inframe del also found de novo in NHS GMS patient. All absent from gnomAD, region highly constrained). Also 3 LOF SNVs and 3 patients with deletions including this gene, although not all are de novo and most also have potential alternate causes. All have developmental delay. Almost all have intellectual disability ranging from mild to moderate, speech delay common..7 with cardiac abnormalities, 4 with kidney abnormalities. Also 2 variants published in this region in PMID: 35710456, 35904121. KDM2B methylation episignature recorded. CXXC variants show strong clustering, highly distinct from control dataset. LOF variants (including dels) also reported to show distinct episignature from controls, and from CXXC variants. While the data supports a KDM2B LOF episignature, this is not as clear, and may not be as specific, as the CXXC signature. Mouse model also supports importance of CXXC domain, with mice heterozygous for CXXC-deleted KDM2B showing neurological defects (PMID: 35128353). Evidence very strong for CXXC missenses less clear for haploinsufficiency. Overall sufficient evidence from cases and episignature evidence to include as green for ID. Sources: Literature |
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| Intellectual disability v3.659 | AARS | Arina Puzriakova Phenotypes for gene: AARS were changed from EARLY-ONSET EPILEPTIC ENCEPHALOPATHY WITH PERSISTENT MYELINATION DEFECT. to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.219 | NARS |
Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model). As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy. Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model). As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy. Sources: Literature |
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| Intellectual disability v3.219 | NARS |
Konstantinos Varvagiannis gene: NARS was added gene: NARS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NARS were set to 32738225 Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy Penetrance for gene: NARS were set to Complete Review for gene: NARS was set to GREEN Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model). As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy. Sources: Literature |
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| Intellectual disability v3.0 | RARS |
Konstantinos Varvagiannis gene: RARS was added gene: RARS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RARS were set to 31814314; 28905880; 24777941 Phenotypes for gene: RARS were set to Cerebral hypomyelination; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Nystagmus; Ataxia; Feeding difficulties Penetrance for gene: RARS were set to Complete Review for gene: RARS was set to GREEN Added comment: Biallelic pathogenic RARS1 variants cause Leukodystrophy, hypomyelinating, 9 (# 616140). The current review was based primarily on PMID: 31814314 (Mendes et al, 2019) providing details on 20 affected individuals from 15 families. 5 of these patients were included in a previous publication (Wolf et al, 2014 - PMID: 24777941) sharing authors with this study. Clinical presentation and severity can be highly variable. However, among the 15 patients of relevant age (5/20 deceased at an early age), ID was observed in 13 (in 6/13 mild-moderate, in 7/13 severe/profound). Epilepsy was reported in half (10/20) with seizures being refractory to treatment in most and the phenotype corresponding to an infantile epileptic encephalopathy. DD and seizures were the presenting feature in 7 and 5 patients respectively, while in other cases presenting features were less specific (eg. failure to thrive in 1/20, irritabilty in 2/20). As a result the gene appears to be relevant to both DD/ID and epilepsy panels. RARS1 encodes the cytoplasmic arginyl-tRNA synthetase 1, which is a component of the aminoacyl-tRNA synthetase complex (OMIM and Wolf et al, 2014 - PMID: 24777941). Aminoacyl-tRNA synthetases catalyze the aminoacylation ('charging') of tRNA by (with) their cognate amino acid. Utilisation of alternative initiation codons, from a single mRNA transcript, results in translation of a long and a short protein isoform (Zheng et al 2006 - PMID: 16430231). The long isoform is needed for the formation of the multi-synthetase complex (MSC), while the short is free in the cytoplasm and does not have any interaction with the MSC. The long isoform appears to be essential for protein synthesis (discussed with several refs provided in PMID: 28905880 - Nafisinia et al, 2017). The role of variants has been supported in several patients by additional studies - among others : [PMID 31814314] Impaired Arginyl-tRNA synthetase activity was demonstrated in fibroblasts from 3 patients. Activity was normal in one additional individual compound heterozygous for a variant affecting initiation codon and a missense one. Western blot however demonstrated presence mainly of the short protein isoform. The authors suggest that this isoform possibly contributed to enzymatic activity. The long isoform which is needed for the MSC complex was only represented by a faint band in the Western Blot of the same individual. [PMID: 28905880] Using fibroblasts from an affected subject homozygous for a missense variant (NM_002887.3:c.5A>G / p.Asp2Gly) and controls, a 75% reduction of the long isoform was shown upon WB. The short isoform was present at similar levels. As the N-terminus (of the long isoform) mediates interaction with the MSC (and AIMP1), assembly of the latter was 99% reduced in patient fibroblasts. Proliferation of patient fibroblasts was significantly reduced when cultured in a medium with limited arginine, a finding which was thought to reflect inefficient protein synthesis. Mutations in other genes encoding for aminoacyl-tRNA synthetases (eg. AARS1, VARS1) or scaffolding proteins of the multisynthetase complex (eg. AIMP1 and AIMP2) lead to neurodevelopmental disorders with overlapping phenotype [most genes rated green in both the ID and epilepsy panel]. Sources: Literature |
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| Intellectual disability v2.1022 | AARS | Louise Daugherty Tag new-gene-name tag was added to gene: AARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.1022 | AARS | Louise Daugherty commented on gene: AARS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.811 | TCF20 | Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following recent external review by Konstantinos Varvagiannis (Dec 2018 and Feb 2019). The Torti et al., 2019 article (PMID:30739909) describes 27 individuals from 24 families with novel TCF20 variants. All 27 individuals had developmental delay/intellectual disability (DD/ID). Together with the individual in PMID:30525188 (Snoeijen-Schouwenaars et al 2019, Supplementary Table 2) and the additional evidence listed by Konstantinos Varvagiannis, these papers provide additional cases since the Amber rating in July 2018, and support that ID is a consistent feature amongst TCF20 patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | AARS | Tord Jonson reviewed AARS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||