Submission Details

The relationship between MT-TW and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 3, 2023. The MT-TW gene encodes the mitochondrial transfer RNA (tRNA) for tryptophan. 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.

MT-TW was first reported in relation to maternally-inherited primary mitochondrial disease in 1995 in an individual with ataxia, hearing loss, and progressive cognitive decline associated with cerebellar atrophy (PMID: 7695240). Other associated features have been reported over time. While various names could be given to the constellation of features seen in those with MT-TW-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TW phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-TW 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 Limited. This current curation for the association with primary mitochondrial disease includes cases with LSS.

Evidence supporting the gene-disease relationship between MT-TW and primary mitochondrial disease includes case-level data and experimental data. This curation includes nine variants (m.5521G>A, m.5522G>A, m.5532G>A, m.5537_5538insT, m.5545C>T, m.5549G>A, m.5556G>A, m.5559A>G) in ten probands in ten publications (PMIDs: 7695240, 9266739, 9673981, 12776230, 15054399, 18337306, 19809478, 26524491, 23841600, 30937556). Single fiber testing and cybrid analyses further supported the pathogenicity of several of these variants (PMIDs: 9266739, 9673981, 15054399, 18337306, 19809478, 30937556). Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, microcephaly, developmental delay and regression, cognitive decline, fatigue, seizures, ataxia, chorea, muscle wasting, axonal neuropathy, diabetes, liver steatosis and fibrosis, constipation, recurrent vomiting, failure to thrive, pigmentary retinopathy, ptosis, optic atrophy, ophthalmoplegia, sensorineural hearing loss, and hypertrophic and dilated cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS to generalized atrophy and white matter involvement. Muscle biopsies showed ragged red fibers, COX-deficient fibers, and decreased respiratory chain enzyme activities. Metabolic laboratory investigation revealed elevated blood and cerebrospinal fluid lactate. Heteroplasmy levels in affected individuals were highest in muscle and/or liver when multiple tissues were assessed (25 - >95 % in muscle, 1 to >95% in blood, >95% in liver, 1-92% in skin fibroblasts, and 5% in urine when assessed).

Segregation evidence is scored as case-level data according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by known biochemical function and in vitro functional assays demonstrating altered mitochondrial function as a result of variants in MT-TW (PMIDs: 18337306, 19809478, 33340416).

In summary, there is definitive evidence to support the relationship between MT-TW and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and 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 on May 3, 2023.