Submission Details

The relationship between MT-TD and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 19, 2023. The MT-TD gene encodes the mitochondrial tRNA for aspartic acid, which is located from m.7518-7585 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 have been given to the constellation of features seen in those with MT-TD-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TD phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

MT-TD was first reported in relation to maternally-inherited primary mitochondrial disease in 1998 and 1999 (PMIDs: 9811342, 10488907), however current population data suggests these variants are benign (gnomAD v.3.1.2), so these cases were excluded from this gene curation. The first case considered for this gene curation was reported in 2005 (PMID: 16059939) in a 12-year-old girl with exercise intolerance, myopathy, elevated creatine kinase (CK), and elevated serum lactate. Subsequent publications have shown a consistent phenotype involving a mitochondrial myopathy (variable age of onset) with lactic acidosis and ataxia. Sensorineural hearing loss and neuropathy have also been reported. Muscle biopsy often shows classic findings of mitochondrial myopathy with COX-negative fibers, ragged red fibers, and paracrystalline inclusions. OXPHOS deficiencies are also observed in muscle (PMID: 16059939).

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 3 unique missense variants. These variants were generally present at high levels of heteroplasmy in muscle tissue and at lower to undetectable levels in other tissues such as blood, saliva, buccal tissue, urine, and fibroblasts, highlighting the diagnostic importance of muscle biopsy in MT-TD-related primary mitochondrial disease. Single fiber studies were performed in several individuals with results supporting variant pathogenicity. In summary, this curation included 3 probands across 7 publications from 1998-2015 (PMIDs: 9811342, 10488907, 16059939, 18676632, 23696415, 25447692, 27536005).

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 (PMID: 30030363 ). Respiratory deficient yeast strains due to a single variant in MT-TD have been created and compelling rescue studies have been performed (PMIDs: 7024270, 3054486). E. coli carrying the m.7526A>G variant were also shown to have significantly decreased aminoacylation rates (PMID: 19535463).

In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 19, 2023 (SOP Version 9).