Submission Details

The relationship between MT-TK and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 17, 2023. The MT-TK gene encodes the mitochondrial tRNA for lysine, which is located from m.8295-8364 on the heavy strand of the mitochondrial DNA (mtDNA). Defects of this tRNA lead to impaired mitochondrial translation, which leads to decreased synthesis of mtDNA-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, III, IV, and V, resulting in impaired OXPHOS enzyme activities.

While various names could be given to the constellation of features seen in those with MT-TK-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TK phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-TK was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on May 17, 2021 (SOP v8), with a final classification of definitive. This current curation for the association with primary mitochondrial disease includes cases with LSS.

MT-TK was first reported in relation to maternally-inherited primary mitochondrial disease in 1990 (PMID:2112427), in an individual with myoclonic epilepsy and ragged red fibers (MERRF). Subsequent publications have described a wide spectrum of phenotypes seen in those with MT-TK pathogenic variants including MERRF, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome spectrum, and mitochondrial neurogastrointestinal encephalopathy (MNGIE), as well as lipomas, myopathy, hypertrophic cardiomyopathy, hearing loss, diabetes, and episodic ataxia (PMIDs: 9380435, 19618438, 17410322, 25559684, 1361099, 10868777, 35821181, 36675808).

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 7 unique missense variants, 4 of which have been reviewed by the Mitochondrial Disease Variant Curation Expert Panel (VCEP) and classified as pathogenic or likely pathogenic (m.8313G>A, m.8344A>G , m.8356T>C, m.8363G>A). The 3 other variants have not yet been reviewed by the VCEP but had single fiber studies supportive of pathogenicity. There is a substantial amount of functional evidence for these variants, including numerous cybrid analyses, single fiber studies, and respiratory chain studies showing clear evidence of OXPHOS defects (PMIDs: 19618438, 12737626, 17410322, 1848674, 7739567, 15554876). Heteroplasmy levels of MT-TK variants can vary across multiple tissues from the same individual (PMIDs: 35821181, 1361099). In summary, 8 probands from 8 publications were included in this curation, however, there are many more cases reported in the literature (PMIDs: 10868777, 17410322, 35821181, 1361099, 36675808, 25559684, 19618438, 9380435).

This gene-disease association is also supported by functional implication given protein interaction with the multitude of other mitochondrial translation proteins linked to primary mitochondrial disease and compelling single fiber data from patients’ cells (not included in case scoring) that were indicative of mitochondria dysfunction, and a mouse model of the m.8328G>A variant (PMIDs: 30030363, 10220860, 28729369, 24510903).

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. 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 April 17, 2023 (SOP Version 9).