Submission Details

The relationship between GTPBP3 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 23, 2024. The GTPBP3 gene encodes the GTP-binding protein 3 important for modification of the uridine at the wobble base of five mitochondrial transfer RNAs (Gln, Glu, Lys, LeuUUR, Trp), which is critical for mitochondrial translation.

GTPBP3 was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 25434004). While various names have been given to the constellation of features seen in those with GTPBP3-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the GTPBP3 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, GTPBP3 was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on January 13, 2020 (SOP v7), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the three cases included in the LSS curation.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 16 variants (10 missense, three frameshift, one in-frame deletion, one termination, and one splice site variant) in 12 probands from two publications (PMIDs: 25434004, 34276756). Age of onset ranges from infancy to adolescence. The outcomes are variable as some individuals live into the teens and at least one reported individual lived to the third decade (PMID: 37029485). Clinical features include hypertrophic cardiomyopathy, arrhythmia, lactic acidosis, LSS, developmental delay, seizures, feeding difficulty, and intrauterine growth restriction. Variable respiratory chain enzyme deficiencies have been reported in skeletal muscle.

The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical function of GTPBP3 in modification of mitochondrial tRNAs, functional alteration in patient and non-patient cells, rescue in patient cells, and zebrafish and worm models (PMIDs: 25434004, 29390138, 30916346, 28732077).

In summary, there is definitive evidence to support the relationship between GTPBP3 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 23, 2024 (SOP Version 10).