Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome

Gene: TARS

Amber List (moderate evidence)

TARS (threonyl-tRNA synthetase)
EnsemblGeneIds (GRCh38): ENSG00000113407
EnsemblGeneIds (GRCh37): ENSG00000113407
OMIM: 187790, Gene2Phenotype
TARS is in 2 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

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

Alan Lehmann (University of Sussex/GSTT)

Green List (high evidence)

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

Michael Yau (Genetics, Viapath)

Green List (high evidence)

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 list
Created: 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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Trichothiodystrophy 7, nonphotosensitive, OMIM:618546
Tags
watchlist new-gene-name
OMIM
187790
Clinvar variants
Variants in TARS
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

18 Nov 2021, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist tag was added to gene: TARS.

18 Nov 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: tars has been classified as Amber List (Moderate Evidence).

18 Nov 2021, Gel status: 0

Set mode of pathogenicity

Arina Puzriakova (Genomics England Curator)

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

18 Nov 2021, Gel status: 0

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: TARS were set to PMID 31374204

18 Nov 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: TARS were changed from Trichothiodystrophy 7, nonphotosensitive to Trichothiodystrophy 7, nonphotosensitive, OMIM:618546

18 Nov 2021, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

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

27 Oct 2021, Gel status: 0

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

Michael Yau (Genetics, Viapath)

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