Submission Details

The relationship between TYMP and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 2, 2023. The TYMP gene encodes thymidine phosphorylase (TP), which catalyzes the conversion of thymidine to thymine and 2-deoxy-D-ribose 1-phosphate. Thymidine-to-thymine conversation is important for nucleoside catabolism.

The TYMP gene was first reported in relation to autosomal recessive mitochondrial neurogastrointestinal encephalopathy (MNGIE) in 1999 (PMID: 9924029). While various names have been given to the constellation of features seen in those with TYMP-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TYMP phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine unique missense variants, three canonical splice variants, and two frameshift variants reported in 14 unrelated individuals described in two publications (PMIDs: 9924029, 15781193). Additional cases are available in the literature, but the maximum for genetic evidence has been reached. MNGIE is a multisystem disorder caused by TP deficiency that results in severe gastrointestinal dysmotility and skeletal muscle abnormalities due to mtDNA depletion and the accumulation of mtDNA deletions and duplications in various tissues over time. While intrafamilial phenotypic variability and patients with incomplete or atypical clinical manifestations have been described, MNGIE is the only phenotype that has been reported in association with variants in TYMP. Later-onset disease has been described for some variants with a less severe impact on TP function. The mechanism of disease is loss of function.

This gene-disease relationship is also supported by a role in mitochondrial DNA maintenance shared with other genes associated with primary mitochondrial disease; rescue of TYMP mRNA and protein levels, TP activity, and nucleoside catabolism via delivery of an intact copy of the human gene in patient cells; and improved disease-related plasma metabolite levels and clinical measures of disease following enzyme replacement therapy in human patients (PMIDs: 12077348, 21451581, 30959750). Of note, mice with knockout of TP do not show a phenotype since, unlike humans, mice can use uridine phosphorylase (UP) to clear thymidine, compensating for the absence of TP. However, a mouse model with double knockout of TP and UP recapitulates some clinical and biochemical features of the disorder, which can be rescued by wildtype gene expression (PMID: 21451581).

In summary, there is definitive evidence to support the relationship between TYMP and autosomal recessive primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 2, 2023 (SOP Version 9).