Submission Details

The relationship between TRIT1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 13, 2022. The TRIT1 gene encodes tRNA isopentenyltransferase 1, which catalyzes the transfer of an isopentyl group from dimethylallyl pyrophosphate onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs that bind to codons containing uridine. Of note, modifications of cytosolic tRNAs and mitochondrial tRNAs (mt-tRNAs) occur at nucleotide positions 34 and 37 in the anticodon loop. This promotes translational fidelity and efficiency by optimizing codon-anticodon fit within the ribosome.

The TRIT1 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 24901367). While various names have been given to the constellation of features seen in those with TRIT1-related disease (including combined oxidative phosphorylation deficiency 35), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TRIT1 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 15 variants (nine missense, two frameshift, three stop-gained, and one intronic) identified in ten probands from eight publications (PMIDs: 24901367, 28185376, 30977854, 31140736, 32088416, 32948376, 35568357, 35418828). Age of onset was typically in the first year of life. Features included infantile/early childhood onset epilepsy, global developmental delay, variable intellectual disability, and some with structural abnormalities (dysmorphisms, structural brain changes, mild congenital heart defects). Muscle biopsies showed COX-negative fibers and reduced activities of mitochondrial respiratory chain complexes I/III/IV. Brain imaging revealed microcephaly, septo-optic dysplasia, cerebral atrophy, and agenesis of the corpus callosum. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function (mt-tRNA processing for mitochondrial translation) shared with other genes associated with primary mitochondrial disease, functional alteration in patient cells, model organisms, and rescue in patient cells (PMIDs: 24901367, 32376682, 26857223).

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. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 13, 2022 (SOP Version 9).