Submission Details

The relationship between TUFM and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 2, 2023. The TUFM gene encodes the mitochondrial translation elongation factor Tu, an enzyme that facilitates translation elongation by GTP-mediated binding of aminoacyl-tRNAs to the ribosomal A site, where codon recognition occurs during mitochondrial translation protein synthesis.

TUFM was first reported in relation to autosomal recessive primary mitochondrial disease in 2007 (PMID: 17160893). While various names could be given to the constellation of features seen in those with TUFM-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TUFM 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 includes five variants in five probands across four publications (PMIDs: 17160893, 26741492, 28132884, 30903008). Affected individuals have clinical features falling in a spectrum, with those more severely affecting having early infantile-onset encephalopathy, brain anomalies, lactic acidosis, and risk of early death and others dilated cardiomyopathy and lactic acidosis without encephalopathy. Clinical features seen in affected individuals include Leigh syndrome spectrum disorders, lactic acidosis, dysplastic leukoencephalopathy, intrauterine growth restriction, hypertonia, spasticity, microcephaly, dilated cardiomyopathy, and respiratory failure. Dysmorphic features have also been noted (epicanthus, low-set ears, flat nasal bridge, high, arched palate, small hands and feet). Brain imaging showed diffuse cystic leukodystrophy, micropolygyria, and diffuse signal abnormality of the white matter in the centra semiovalia, putamina, and nuclei pallidi. Lab abnormalities include elevated lactate, pyruvate, ketones, transaminases, and ammonia. Mitochondrial respiratory chain enzyme deficiencies (complexes I and IV) are reported.

Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease and functional alteration studies in non-patient cells showing impaired binding to aminoacylated mitochondrial tRNAs and impaired mitochondrial translation (PMIDs: 19524667, 33340416).

In summary, there is moderate evidence to support the relationship between TUFM and autosomal recessive primary mitochondrial disease. 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 October 2, 2023 (SOP Version 9).