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| Intellectual disability v3.1513 | NARS | Arina Puzriakova Tag for-review was removed from gene: NARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.1510 | NARS | Sarah Leigh commented on gene: NARS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.1509 | NARS |
Arina Puzriakova Source Expert Review Green was added to NARS. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Intellectual disability v3.714 | NARS | Ivone Leong Tag for-review tag was added to gene: NARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.648 | NARS |
Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)' Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)' Total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data. |
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| Intellectual disability v3.648 | NARS |
Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)' Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 6 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)' Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data. |
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| Intellectual disability v3.648 | NARS | Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.648 | NARS | Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.648 | NARS | Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.648 | NARS | Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.647 | NARS | Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.647 | NARS | Arina Puzriakova Publications for gene: NARS were set to 32738225 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.646 | NARS | Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.549 | NARS | Sarah Leigh Tag new-gene-name tag was added to gene: NARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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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