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Intellectual disability

Gene: NARS

Green List (high evidence)
NARS (asparaginyl-tRNA synthetase)
EnsemblGeneIds (GRCh38): ENSG00000134440
EnsemblGeneIds (GRCh37): ENSG00000134440
OMIM: 108410, Gene2Phenotype
NARS is in 6 panels

3 reviews

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 3.1510

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Created: 9 Dec 2020, 2:02 p.m. | Last Modified: 9 Dec 2020, 2:02 p.m.
Panel Version: 3.648
Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Created: 9 Dec 2020, 2:02 p.m. | Last Modified: 9 Dec 2020, 2:02 p.m.
Panel Version: 3.648
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.
Created: 9 Dec 2020, 2 p.m. | Last Modified: 9 Dec 2020, 2:17 p.m.
Panel Version: 3.648

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

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

Publications

Created: 9 Dec 2020, 2 p.m.
Last Modified: 9 Dec 2020, 2:17 p.m.
Panel version: 3.648

Konstantinos Varvagiannis (Other)

Green List (high evidence)

[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
Created: 2 Aug 2020, 2:03 p.m. | Last Modified: 2 Aug 2020, 2:11 p.m.
Panel Version: 3.219

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy

Publications

Created: 2 Aug 2020, 2:03 p.m.
Last Modified: 2 Aug 2020, 2:11 p.m.
Panel version: 3.219

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
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
Tags
new-gene-name
OMIM
108410
Clinvar variants
Variants in NARS
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

10 Mar 2022, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review was removed from gene: NARS.

9 Mar 2022, Gel status: 3

Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Green was added to NARS. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

20 Jan 2021, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag for-review tag was added to gene: NARS.

9 Dec 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: nars has been classified as Amber List (Moderate Evidence).

9 Dec 2020, Gel status: 0

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: NARS were set to 32738225

9 Dec 2020, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

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

16 Nov 2020, Gel status: 0

Added Tag

Sarah Leigh (Genomics England Curator)

Tag new-gene-name tag was added to gene: NARS.

2 Aug 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

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