Submission Details

The relationship between MT-TF and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 16, 2023. The MT-TF gene encodes the mitochondrial tRNA for phenylalanine, which is located from m. 577 – 647 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.

MT-TF was first reported in relation to maternally-inherited primary mitochondrial disease in 1998 (PMID: 9771776), in a woman with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and a wide spectrum of associated features has been reported over time. While various names have been given to the constellation of features seen in those with MT-TF-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TF 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 16 unique variants (m.582T>C, m.583G>A, m.586G>A, m.590A>G, m.591C>T, m.602C>T, m.611G>A, m.616T>G, m.616T>C, m.618T>C, m.618T>G, m.622G>A, m.625G>A, m.641A>T, m.642T>C, m.643A>G) in 30 probands across 19 publications (PMIDs: 14659412, 9771776, 16806928, 21060018, 31463198, 32419253, 34607911, 21424749, 15184630, 20142618, 28267784, 31722346, 35472031, 9636664, 21882289, 16769874, 21914246, 31009750, 18977334). Cybrid studies and single fiber testing further supported the pathogenicity of several of these variants (PMIDs: 14659412, 16806928, 21060018, 32419253, 15184630, 21882289, 16769874, 18977334, 28267784). Age of onset in affected individuals varied from childhood to >60 years. Clinical features in affected individuals included mitochondrial myopathy, MELAS, myoclonic epilepsy and ragged red fibers (MERRF), chronic external progressive ophthalmoplegia (CPEO), Gitelman syndrome, epilepsy, epilepsia partialis continua (EPC), chronic kidney disease, retinal dystrophy, sensorineural hearing loss, neuropathy, and neurologic/cognitive/psychiatric decline. Some affected individuals had normal brain imaging while others had cerebral, cerebellar, and/or brainstem atrophy. Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals. Labs showed variable lactate levels (normal to elevated in blood, cerebrospinal fluid, and/or urine) and elevated creatine kinase (CK). Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed, and ranged from 58%-homoplasmic in muscle; 0-70% in hair, 0-homoplasmic in blood, fibroblast, and urine; and in one individual was 63% in a buccal sample.

The mechanism of disease appears to be loss of function. This gene-disease association is further supported by a known biochemical function shared with other genes associated with primary mitochondrial disease and functional alteration in patient cells (PMIDs: 33340416, 35472031, 34607911).

In summary, there is definitive evidence to support the relationship between MT-TF and 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 February 16, 2023 (SOP Version 9).