Submission Details

The relationship between MT-TQ and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 17, 2023. The MT-TQ gene encodes the mitochondrial tRNA for glutamine, which is located from m.4329 – 4400 on the reverse 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-TQ was first reported in relation to maternally-inherited primary mitochondrial disease in 2000 (PMID: 10996779), in a boy with myopathy. Other associated features have been reported over time. While various names have been given to the constellation of features seen in those with MT-TQ-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TQ 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 three unique variants (m.4332G>A, m.4369_4370insA, m.4381A>G) in three probands across 3 publications (PMIDs: 11171912, 10996779, 17003408). Single fiber testing further supported the pathogenicity of several of these variants (PMIDs: 11171912, 11335700, 10996779). Age of onset in affected individuals was five years old, teens, and 20 years old. Clinical features in affected individuals included stroke-like episodes, hearing loss, myopathy, and Leber Hereditary Optic Neuropathy (LHON). Brain imaging was variable. Muscle biopsies showed ragged red fibers and COX-negative fibers. Metabolic screening labs were only reported in one individual and showed high cerebrospinal fluid (CSF) lactate with normal blood lactate. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (61-87% in muscle).

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 (PMID: 33340416).

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 GCEP notes that while at the time of this curation MT-TQ has a limited association with primary mitochondrial disease, it is plausible, and even likely, that additional cases will be reported in the future given the crucial role of MT-TQ in mitochondrial translation. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 17, 2023 (SOP Version 9).