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Intellectual disability - microarray and sequencing v3.1459 CARS Arina Puzriakova Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891 to Microcephaly, developmental delay, and brittle hair syndrome, OMIM:618891
Intellectual disability - microarray and sequencing v3.437 CARS2 Arina Puzriakova Publications for gene: CARS2 were set to 25787132
Intellectual disability - microarray and sequencing v3.436 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v3.436 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v3.171 CARS Eleanor Williams Added comment: Comment on phenotypes: Added disease term which has now been added to OMIM.
Intellectual disability - microarray and sequencing v3.171 CARS Eleanor Williams Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay to Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891
Intellectual disability - microarray and sequencing v3.0 CARS2 Zornitza Stark reviewed gene: CARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30139652; Phenotypes: Combined oxidative phosphorylation deficiency 27, MIM#616672; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1022 CARS Louise Daugherty Tag new-gene-name tag was added to gene: CARS.
Intellectual disability - microarray and sequencing v2.1022 CARS Louise Daugherty commented on gene: CARS
Intellectual disability - microarray and sequencing v2.978 CARS Catherine Snow 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)
Intellectual disability - microarray and sequencing v2.782 CARS Konstantinos Varvagiannis 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
Added comment: Kuo et al. (2019 - doi.org/10.1016/j.ajhg.2019.01.006) 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 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).
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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.
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As a result, this gene can be considered for inclusion in the current panel as green (or amber).
Sources: Literature