MT-TI

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between *MT-TI* and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 3, 2021. The *MT-TI* gene encodes the mitochondrial transfer RNA (tRNA) for 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 and thus impaired OXPHOS enzyme activities. The *MT-TI* gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 2004 (PMID: 15121771). Evidence supporting the relationship between *MT-TI* and Leigh syndrome spectrum includes case-level data and experimental data. This curation included two variants in 3 cases (1 with m.4290T>C, 2 with m.4296G>A) from 3 publications (PMIDs: 15121771, 21982779, 23395828). Segregation information is scored as case level evidence according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Loss of function is implicated as the mechanism of disease. 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 limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 3, 2021 (SOP Version 8).

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0005045

Submitter: ClinGen

MT-TI is a mitochondrial gene that encodes for mitochondrially-encoded tRNA for isoleucine, it is located on the heavy stand of mitochondrial DNA spanning 69 nucleotides 4263-4331. MT-TI was first reported in association with hypertrophic cardiomyopathy in 1996 (Merante et al. 1996, PMID: 8889580). Three variants have been seen in five probands in three publications (PMIDs: 8889580, 12767666, 37124643). One homoplastic variant m.4300A>G is seen in most cases, including in a family segregating to 16 affected family members. Each variant has supporting histochemical and biochemical functional evidence from patient biopsies. This gene-disease relationship is also supported by expression studies (PMID: 8889580, 34265302). In summary, there is MODERATE evidence supporting the relationship between MT-TI and hypertrophic cardiomyopathy. The ClinGen Hereditary Cardiovascular Disease GCEP approved this classification on the meeting date December 18, 2023.