Submission Details

The relationship between MT-TI and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 5, 2023. The MT-TI gene encodes the mitochondrial tRNA for isoleucine. 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-TI was first reported in association with maternally inherited primary mitochondrial disease in 2004 (PMID: 1512771) in an individual with Leigh syndrome spectrum (LSS). Subsequent publications have shown a spectrum of phenotypes in those with MT-TI – related primary mitochondrial disease in addition to LSS including myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), in addition to rhabdomyolysis, cardiomyopathy, encephalopathy, exercise intolerance, muscle weakness, hypertension2, hypercholesterolemia, and hypomagnesemia. While various names have been given to the constellation of features seen in those with MT-TI-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TI phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-TI was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on February 3, 2021 (SOP v8), with a final classification of limited. The scope of this current curation encompasses cases of primary mitochondrial disease, which includes LSS.

Evidence supporting the gene-disease relationship between MT-TI and primary mitochondrial disease includes case-level data and experimental data. This curation included eight unique variants (m.4269A>G, m.4289T>C, m.4290T>C, m.4291T>C, m.4296G>A, m.4298G>A, m.4300A>G, m.4308G>A) present in 14 probands from 13 publications (PMIDs: 15121771, 21982779, 23395828, 16120360, 9473477, 12767666, 10065021, 7646516, 20884012, 21292040, 1632786, 23696415, 34607911). Three of these variants were reviewed by the ClinGen Mitochondrial Disease Variant Curation Expert Panel (m.4298G>A classified as VUS, m.4300A>G classified as likely pathogenic, and m.4308G>A classified as VUS). There is functional evidence supporting several of these variants, including single fiber studies (PMID: 9473477), cybrid studies (PMID: 7518448), and aminoacylation (PMID: 12655007). Heteroplasmy levels of MT-TI can be variable in tissues from the same individual. In general, variants tend to be lower in tissues such as blood, saliva, and buccal swab and urine and muscle heteroplasmy levels tend to be higher.

This gene-disease association is also supported by known biochemical function and functional alteration in non-patient cells (PMIDs: 27977873, 15121771).

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 June 5, 2023 (SOP Version 9).