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Intellectual disability

Gene: CARS

Green List (high evidence)

CARS (cysteinyl-tRNA synthetase)
EnsemblGeneIds (GRCh38): ENSG00000110619
EnsemblGeneIds (GRCh37): ENSG00000110619
OMIM: 123859, Gene2Phenotype
CARS is in 3 panels

3 reviews

Louise Daugherty (Genomics England Curator)

Added new-gene-name tag, new approved HGNC gene symbol for CARS is CARS1
Created: 6 Sep 2019, 2:14 p.m. | Last Modified: 6 Sep 2019, 2:14 p.m.
Panel Version: 2.1022

Catherine Snow (Genomics England)

Comment on list classification: Expert review by Konstantinos Varvagiannis on CARS. Kuo et al. (PMID:30824121) report on 4 individuals from 3 families with biallelic pathogenic CARS variants. All with common features of microcephaly, developmental delay, brittle hair and nails All 4 were presented as adults in the publication. All showed developmental delay as children and mild to moderate cognitive disabilities as adults a phenotype applicable to the ID panel.

CARS is currently not associated with a phenotype in OMIM and is in G2P as Disease: Microcephaly Developmental Delay and Brittle Hair and Nail although no list of phenotypes have been assigned to the G2P entry.
Overall sufficient (>3) unrelated cases of developmental delay in patients with CARS variants, to warrant a Green rating.

Created: 16 May 2019, 12:47 p.m. | Last Modified: 17 Jul 2019, 10:32 a.m.
Panel Version: 0.200

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Kuo et al. (2019 - report on 4 individuals from 3 families with biallelic pathogenic CARS variants.

Common features included microcephaly, DD, brittle hair and nails. All 4 were adults and presented with motor, language and cognitive disabilities.

Reported genotypes (and variants) included [NM_001751.5 and NP_001742.1]:
- c.1138C>T (p.Gln380*) and c.1022G>A (p.Arg341His) (1 individual)
- c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln) (2 sibs)
- c.2061dup (p.Ser688Glnfs ∗2) in homozygous state (1 individual - no reported consanguinity)

Segregation studies confirmed the in trans occurrence of the variants in affected individuals and carrier state in unaffected parents or other family members.

CARS encodes Cysteinyl-tRNA synthetase an aminoacyl-tRNA synthetase (ARS). ARSs are a group of enzymes responsible for ligating amino acids to cognate tRNA molecules. CARS is responsible for charging cysteine to tRNA molecules in the cytoplasm (CARS2 is responsible for charging cysteine to tRNA molecules in mitochondria).

Mutations in several ARSs have been linked to disorders with features overlapping to CARS-related phenotype.

Studies included:
- Western blot (pat. fibroblasts) confirmed expression of stable truncated p.Ser688Glnfs ∗2 but absence of the predicted truncating p.Gln380*. Expression in fibroblasts from the individual with compound heteroz. for the missense variants was similar to controls.
- Subcellular localization did not appear to be affected.
- Aminocacylation was significantly reduced (~40-80%) using protein lysates from affected individual fibroblasts (all families) supporting a LoF effect.
- A yeast complementation assay suggested LoF/hypomorphic effect with no or reduced yeast cell growth depending on the variant tested (hypomorphic variants: Arg341His and Ser359Leu). Aminoacylation assays (in yeast) showed reduced activity (by 50% and 84% respectively) for the 2 hypomorphic variants (compatible with the observations in patient fibroblasts).
- Conservation and the presumed effect of individual variants (in catalytic domain, truncation upstream of anticodon-binding domain or in a region affecting binding specificity of CARS and tRNA-cys) also supported pathogenicity.

All individuals demonstrated strikingly similar hair-shaft anomalies upon polarized light microscopy (eg. trichorrhexis/tiger-tail patterns/abnormal shaft diameter) in line with macroscopical observations of fine brittle hair suggesting a common underlying genetic cause (presumably explained by high cysteine content of keratins).
CARS is not associatated with any phenotype in OMIM, nor in G2P.
The gene is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories.
As a result, this gene can be considered for inclusion in the current panel as green (or amber).
Sources: Literature
Created: 2 Mar 2019, 10:45 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Microcephaly; Neurodevelopmental delay; Brittle hair; Fragile nails


Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review
  • Expert Review Green
  • Expert Review
  • Brittle hair
  • Fragile nails
  • Microcephaly
  • Neurodevelopmental delay
Clinvar variants
Variants in CARS
Panels with this gene

History Filter Activity

6 Sep 2019, Gel status: 3

Added Tag

Louise Daugherty (Genomics England Curator)

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

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to CARS. Source Expert Review was added to CARS. Added phenotypes Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay for gene: CARS Publications for gene CARS were changed from to 30824121 Rating Changed from No List (delete) to Green List (high evidence)

2 Mar 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: CARS was added gene: CARS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CARS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CARS were set to Microcephaly; Neurodevelopmental delay; Brittle hair; Fragile nails Penetrance for gene: CARS were set to Complete Review for gene: CARS was set to GREEN