Bone Marrow Failure

Gene: TYMS

Amber List (moderate evidence)

TYMS (thymidylate synthetase)
EnsemblGeneIds (GRCh38): ENSG00000176890
EnsemblGeneIds (GRCh37): ENSG00000176890
OMIM: 188350, Gene2Phenotype
TYMS is in 2 panels

2 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dyskeratosis congenita, digenic, MIM#620040

Lucy Spencer (Victorian Clinical Genetics Services)

Red List (low evidence)

8 families with dyskeratosis congenita and heterozygous variants in TYMS. 4 PTCs, 2 missense and 1 splice (2 families had the same frameshift). However in all families 1 unaffected parent was also heterozygous for the same TYSM variant.

The other parent in 3 of these families was then shown to carry a heterozygous variant in ENOSF1 which each affected child was also heterozygous for. ENOSF1 has been shown to modify TYMS expression at the RNA level by acting as an antisense molecule to TYMS. ENOSF1 partially overlaps TYMS on chromosome 18 and is transcribed in the opposite direction to TYMS. This paper is suggesting digenic inheritance.

The TYMS wild type parent from another family was seen to have a TYMSOS variant which was also observed along with the TYMS variant in their 2 affected children.

Immunoblotting showed a stark reduction in TYMS protein level in the cells of affected probands when compared to the parent carrier, wild-type parent, and the controls.

Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1.
Sources: Literature
Created: 1 Sep 2022, 7:04 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dyskeratosis congenita MONDO:0015780

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Dyskeratosis congenita, digenic, MIM#620040
Tags
digenic
OMIM
188350
Clinvar variants
Variants in TYMS
Penetrance
None
Publications
Panels with this gene

History Filter Activity

23 Sep 2022, Gel status: 2

Added Tag

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Tag digenic tag was added to gene: TYMS.

23 Sep 2022, Gel status: 2

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: TYMS were changed from Dyskeratosis congenita MONDO:0015780 to Dyskeratosis congenita, digenic, MIM#620040

1 Sep 2022, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

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

1 Sep 2022, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

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

1 Sep 2022, Gel status: 0

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

Lucy Spencer (Victorian Clinical Genetics Services)

gene: TYMS was added gene: TYMS was added to Bone Marrow Failure. Sources: Literature Mode of inheritance for gene: TYMS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TYMS were set to 35931051 Phenotypes for gene: TYMS were set to Dyskeratosis congenita MONDO:0015780 Review for gene: TYMS was set to RED