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| Intellectual disability - microarray and sequencing v3.1511 | VARS2 | Arina Puzriakova Tag for-review was removed from gene: VARS2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1510 | VARS2 | Sarah Leigh commented on gene: VARS2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1509 | VARS2 |
Arina Puzriakova Source Expert Review Green was added to VARS2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v3.300 | VARS2 | Arina Puzriakova Classified gene: VARS2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.300 | VARS2 | Arina Puzriakova Gene: vars2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.299 | VARS2 | Arina Puzriakova Tag for-review tag was added to gene: VARS2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | VARS2 |
Zornitza Stark gene: VARS2 was added gene: VARS2 was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: VARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VARS2 were set to 24827421; 25058219; 29137650; 29314548; 31064326 Phenotypes for gene: VARS2 were set to Combined oxidative phosphorylation deficiency 20, OMIM #615917 Review for gene: VARS2 was set to GREEN gene: VARS2 was marked as current diagnostic Added comment: ID is part of the phenotype of this metabolic disorder. Sources: Expert list |
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| Intellectual disability - microarray and sequencing 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 - microarray and sequencing v2.1022 | VARS | Louise Daugherty Tag new-gene-name tag was added to gene: VARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1022 | VARS | Louise Daugherty commented on gene: VARS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.978 | VARS |
Catherine Snow Source Expert Review Green was added to VARS. Added phenotypes Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, 617802 for gene: VARS Publications for gene VARS were changed from 26539891; 29691655; 30275004 to 26539891; 30275004; 29691655 Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v2.510 | VARS |
Konstantinos Varvagiannis gene: VARS was added gene: VARS was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: VARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VARS were set to 26539891; 29691655; 30275004 Phenotypes for gene: VARS were set to # 617802. NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND CORTICAL ATROPHY; NDMSCA Penetrance for gene: VARS were set to Complete Review for gene: VARS was set to GREEN gene: VARS was marked as current diagnostic Added comment: PMID: 26539891 is the first report on individuals with biallelic pathogenic variants in VARS. 3 individuals from 2 consanguineous families are briefly reported. The phenotype was similar in all 3, consisting of severe developmental delay, microcephaly, seizures and cortical atrophy. Subjects from the first family were homozygous for a missense variant in the tRNA synthetase catalytic domain [p.(L885F)]. The patient from the second family was homozygous for a missense SNV affecting the anticodon-binding domain [p.(R1058Q)]. PMID: 29691655 reports on a further patient born to non-consanguineous parents, with 2 in-trans pathogenic variants in VARS. The phenotype consisted of progressive microcephaly (OFC at birth -2SD, at the age of 2 months -4SD), global developmental delay, seizures and progressive cerebral and cerebellar atrophy. An affected brother presented with more severe phenotype (OFC -6SD at birth and -8SD at 2 months of age), seizures, hearing loss but was deceased and unavailable for genetic testing. cDNA studies demonstrated absence of the reference allele for the missense mutation downstream the splice variant (in line with a reduced or absent mRNA allele harboring the splice variant). Similarly, mRNA expression studies demonstrated 50-60% reduction in the transcripts (due to NMD of the allele with the splice SNV). Western blot showed severe reduction in protein levels (more pronounced compared to what would be expected by mRNA expression) presumably secondary to decreased protein stability due to the missense variant. Severe defects in aminoacylation were further confirmatory of a pathogenic role of these variants. The missense variant was affecting the anticodon-binding domain, important for aminoacylation. PMID: 30275004 reports on 2 siblings with developmental delay, intellectual disability, severe speech impairment and microcephaly, similar to what has been described for the disorder. Clinical findings were somewhat different from previous studies in that microcephaly was acquired, while seizures and cortical atrophy were not part of the phenotype. Both sibs were compound heterozygous for 2 missense variants, though only one of these mutations affected the anticodon binding domain and the other was in the N-terminal region of the protein. Previous metabolic studies and extensive genetic testing (karyotype, CMA, MECP2, FMR1) was normal. Epilepsy was a feature in 4 of the 6 individuals for whom genetic testing was possible (or 5/7 in total). VARS belongs to the family of amino acyl-tRNA synthetases (ARSs). Mutations in several cytoplasmic ARSs are associated with severe neurological manifestations including seizures, intellectual disability associated with microcephaly. VARS is included in gene panels for intellectual disability (but not for epilepsy) offered by different diagnostic labs. As a result this gene can be considered for inclusion in the ID and epilepsy panel as green (or amber). Sources: Expert Review, Literature |
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