Intellectual disability
Gene: RARS

RARS (arginyl-tRNA synthetase)
EnsemblGeneIds (GRCh38): ENSG00000113643
EnsemblGeneIds (GRCh37): ENSG00000113643
OMIM: 107820, Gene2Phenotype
RARS is in 5 panels

4 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Created: 20 Oct 2020, 4:04 p.m. | Last Modified: 20 Oct 2020, 4:04 p.m.

Panel Version: 3.480

Created: 20 Oct 2020, 4:04 p.m.
Last Modified: 20 Oct 2020, 4:04 p.m.
Panel version: 3.480

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

Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 19 variants reported in at least 13 cases of Hypomyelinating Leukodystrophy exhibinting intellectual disability to varying degrees. Supportive functional studies were also reported.
Created: 23 Mar 2020, 3:40 p.m. | Last Modified: 23 Mar 2020, 3:40 p.m.

Panel Version: 3.13

New gene tag: new approved HGNC gene symbol for RARS is RARS1
Created: 23 Mar 2020, 2:49 p.m. | Last Modified: 23 Mar 2020, 2:49 p.m.

Panel Version: 3.12

Created: 23 Mar 2020, 2:49 p.m.
Last Modified: 23 Mar 2020, 2:49 p.m.
Panel version: 3.1510

Zornitza Stark (Australian Genomics)

Green List (high evidence)

15 families, DD/ID is part of the phenotype.
Created: 10 Mar 2020, 10:38 p.m. | Last Modified: 10 Mar 2020, 10:38 p.m.

Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy, hypomyelinating, 9 (# 616140)

Publications

31814314

Created: 10 Mar 2020, 10:38 p.m.
Last Modified: 10 Mar 2020, 10:38 p.m.
Panel version: 3.3

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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
Created: 15 Dec 2019, 9:15 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebral hypomyelination; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Nystagmus; Ataxia; Feeding difficulties

Publications

Created: 15 Dec 2019, 9:15 p.m.

Panel version: 3.0

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green

Phenotypes

Leukodystrophy, hypomyelinating, 9, OMIM:616140

Tags

new-gene-name

OMIM

107820

Clinvar variants

Variants in RARS

Penetrance

Complete

Publications

Panels with this gene