Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome
Gene: TARS
After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber.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: Adding this gene as Amber as currently only two unrelated individuals have been reported with variants and trichothiodystrophy (PMID: 31374204). Familial segregation was not reported in either case. Functional studies demonstrate the variants exert a loss-of-function effect but an additional case would help corroborate this gene-disease association (added 'watchlist' tag). At present, CARS1 is the only aminoacyl tRNA synthetase gene for which sufficient evidence has been reported to warrant a Green rating on this panel.Created: 18 Nov 2021, 3:32 p.m. | Last Modified: 18 Nov 2021, 3:32 p.m.
Panel Version: 2.25
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, 4:11 p.m. | Last Modified: 5 Nov 2021, 4:11 p.m.
Panel Version: 2.18
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Trichothiodystrophy
Name: threonyl-tRNA synthetase 1; Symbol: TARS1; HGNC ID: 11572
Current Status: Not in R227 Panel. This gene was added to the DDG2P panel in Sept 2019 as a amber gene and the reviwer noted the following: "Non-photosensitive trichothiodystrophy. Disease confidence rating in DDG2P: probable. DDG2P mutation consequence: loss of function. DDG2P allelic requirement: biallelic." Proposed change: GREEN
Supporting Evidence:
Theil et al (2021) published a multi-centre WES/WGS sequencing study which screened in a group of 24 NPS-TTD individuals with no molecular diagnosis. TTD18PV and TTD5VI are unrelated individuals initially diagnosed with TTD were found to have the following predicted pathogenic variants in the TARS1 gene:
TTD18PV: TARS1 c.826A>G p.(Lys276Glu) and TARS1 c.1912C>T p.(Arg638Ter)
TTD5VI: Homozygous TARS1 c.680T>C (p.Leu227Pro).
Testing of additional individuals with unresolved NPS-TTD by the authors did not identify any further bi-allelic variants suggesting in their cohort of 47, TARS1 variants account for 4% of NPS-TTD cases.
In-silico analysis suggest that missense variants result in amino acid substitutions that are close to the core catalytic domain of the protein which may affect its catalytic activity. Quantitative RT-PCR analysis showed only a slight reduction in total TARS mRNA levels in TTD18PV’s primary fibroblasts, while allelic-specific qRT-PCR analysis showed that 90% of the total TARS mRNA molecules are from the missense p.(Lys276Glu) TARS variant with the remaining only 10% from the c.1912C>T variant allele. Immunoblot analysis of whole-cell extracts from both patient’s fibroblasts revealed an approximate 20% reduction in the total cellular amount of full-length TARS. This is consistent with these missense variants causing protein instability.
Based on a total of 47 NPS-TTD individuals for bi-allelic TARS1 variants, the authors suggest that TARS1 variants account for 4% of NPS-TTD cases.
References: Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Theil AF et al. Am J Hum Genet, 2019 Aug 1. PMID 31374204
Sources: Expert listCreated: 27 Oct 2021, 10:37 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Trichothiodystrophy 7, nonphotosensitive
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Source NHS GMS was added to TARS.
Tag watchlist tag was added to gene: TARS.
Gene: tars has been classified as Amber List (Moderate Evidence).
Mode of pathogenicity for gene: TARS was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Publications for gene: TARS were set to PMID 31374204
Phenotypes for gene: TARS were changed from Trichothiodystrophy 7, nonphotosensitive to Trichothiodystrophy 7, nonphotosensitive, OMIM:618546
Tag new-gene-name tag was added to gene: TARS.
gene: TARS was added gene: TARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Expert list Mode of inheritance for gene: TARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TARS were set to PMID 31374204 Phenotypes for gene: TARS were set to Trichothiodystrophy 7, nonphotosensitive Penetrance for gene: TARS were set to Complete Mode of pathogenicity for gene: TARS was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: TARS was set to GREEN