Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome
Gene: CARS
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 31 Jan 2023, 4:31 p.m. | Last Modified: 31 Jan 2023, 4:31 p.m.
Panel Version: 2.27
Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least four individuals from three unrelated families harbouring different biallelic variants in the CARS gene. Clinical presentation includes ID and brittle hair and nails, features which overlap with the trichothiodystrophy component of this panel. Some supportive functional studies included.Created: 18 Nov 2021, 2:36 p.m. | Last Modified: 18 Nov 2021, 2:36 p.m.
Panel Version: 2.20
TARS, AARS, MARS and CARS are all genes for closely related amino-acyl-tRNA synthetases, with very similar functions, the only difference being the amino acid being activated. It therefore makes no biological sense to give them different review status. It would make more sense to regard them as one group, for which now at least eight trichothiodystrophy families have been identified (2 TARS, 2 AARS, 1 MARS, 3 CARS).Created: 5 Nov 2021, 4:10 p.m. | Last Modified: 5 Nov 2021, 4:10 p.m.
Panel Version: 2.18
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Trichothiodystrophy
Name: cysteinyl-tRNA synthetase 1; Symbol: CARS1 ; HGNC ID: 1493
Current Status: Not in R227 Panel. This gene was added to the DDG2P panel in March 2019 as a amber gene and the reviewer noted the following: "Microcephaly Developmental Delay and Brittle Hair and Nails. DDG2P Disease confidence: probable. DDG2P mode of pathogenicity/mutation consequence: loss of function. DDG2P mode of inheritance: biallelic." Proposed change: GREEN
The CARS1 genes was added to the DDG2P panel in March 2019 as an amber gene and the reviewer noted the following: "Microcephaly Developmental Delay and Brittle Hair and Nails. DDG2P Disease confidence: probable. DDG2P mode of pathogenicity/mutation consequence: loss of function. DDG2P mode of inheritance: biallelic."
In Kuo et al (2019) reported the identification of bi-allelic CARS1 variants in four affected individuals from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails.
Case 1: CARS1 c.1138C>T p.(Gln380Ter) and CARS1 c.1022G>A p.(Arg341His) Case 2 and 3 (related): CARS1 c.1076C>T p.(Ser359Leu) and CARS1 c.1199T>A p. (Leu400Gln)
Case 4: Homozygous CARS1 c.2061dup p.(Ser688fs).
In-silico analysis predict that the variants result in a truncated protein or affect a highly conserved amino acid. Immunoblot analysis using CARS antibodies on protein isolated from the patient’s fibroblast confirmed the presence of a stable truncated protein for c.1138C>T nonsense variant, while the amount of full-length CARS protein was significantly reduced for the c.2061dup frameshifting variant. A possible explanation for this result is the extreme 3’ location of the variant which could allow it to escape nonsense mediated decay. Analysis of the CARS protein from Case 4 showed no change in the level of full-length CARS protein. Yeast complementation studies indicate that the p.(Gln380Ter), p. (Leu400Gln) and p.(Ser688fs) variants prevented yeast cell growth, consistent with a loss-of-function effect. Severely reduced cell growth was observed with the p.(Arg341His) and p.(Ser359Leu) variants, aminoacylation assays showed that these variants reduce enzyme activity. These results all support that each variant results in loss of function.
This report confirms that individuals with two loss of function CARS1 variants are involved in multi-system, recessive disorder that includes microcephaly, developmental delay, and brittle hair and nails. Clinical phenotypes that overlap with TTD individuals.
References: Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails. Kuo ME, et al. Am J Hum Genet, 2019 Mar 7. PMID 30824121
Sources: Expert listCreated: 27 Oct 2021, 10:41 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Microcephaly; Developmental Delay; Brittle Hair
Publications
Tag Q4_21_rating was removed from gene: CARS.
Source Expert Review Green was added to CARS. Source NHS GMS was added to CARS. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Publications for gene: CARS were set to PMID 30824121
Gene: cars has been classified as Amber List (Moderate Evidence).
Tag Q4_21_rating tag was added to gene: CARS.
Tag new-gene-name tag was added to gene: CARS.
Phenotypes for gene: CARS were changed from Microcephaly; Developmental Delay; Brittle Hair to Microcephaly, developmental delay, and brittle hair syndrome, OMIM:618891
gene: CARS was added gene: CARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Expert list Mode of inheritance for gene: CARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CARS were set to PMID 30824121 Phenotypes for gene: CARS were set to Microcephaly; Developmental Delay; Brittle Hair Penetrance for gene: CARS were set to Complete Review for gene: CARS was set to GREEN