The relationship between TK2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 6, 2023. The TK2 gene encodes mitochondrial thymidine kinase 2, a mitochondrial deoxyribonucleoside kinase that phosphorylates thymidine, deoxycytidine, and deoxyuridine. Defects of this protein lead to impaired synthesis of mtDNA precursors leading to mtDNA depletion.
The TK2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2001 (PMID 11687801), in individuals with infantile onset severe myopathy. While various names have been given to the constellation of features seen in those with TK2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TK2 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 11 unique variants (six missense, two frameshift, three stop-gained variants) from three publications (PMIDs: 11687801, 16908738, 29602790) although there are over 100 cases reported in the medical literature. Age of onset varies from infancy to adulthood and outcomes range from death in infancy to being alive in adulthood at the time of report. Features seen in affected individuals include myopathy (muscle weakness that leads to respiratory failure in some), seizures, dysarthria, dysphagia, respiratory insufficiency, ophthalmoplegia, and sensorineural hearing loss. Muscle biopsies show mitochondrial DNA depletion and combined mitochondrial respiratory chain enzyme deficiencies. The mechanism of disease appears to be loss of function.
This gene-disease relationship is also supported by its known biochemical function, knockout mouse model, and knock-in mouse model with a variant found in a patient showing ataxic, progressive muscle weakness and TK2 deficiency phenotype (PMIDs: 33340416, 15639197, 18467430, 20123860).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 6, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.