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| Mendeliome v2.0 | MARS1 | Gene symbol changed from MARS to MARS1 during gene set migration (ENSG00000166986 -> ENSG00000166986) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9354 | MARS | Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved gene name is MARS1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9351 | MARS | Zornitza Stark changed review comment from: Association with CMT: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease.; to: Association with CMT and mono-allelic variants: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9351 | MARS | Zornitza Stark changed review comment from: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease.; to: Association with CMT: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3643 | NARS |
Zornitza Stark gene: NARS was added gene: NARS was added to Mendeliome. 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 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 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). Sources: Literature |
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