The relationship between TSFM and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 6, 2023. The TSFM gene encodes the mitochondrial translation elongation factor Ts, an enzyme that catalyzes the exchange of guanine nucleotides on the translation elongation factor Tu (encoded by TUFM) during the elongation step of mitochondrial protein translation.
TSFM was first reported in relation to autosomal recessive primary mitochondrial disease in 2006 (PMID: 17033963). While various names could be given to the constellation of features seen in those with TSFM-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TSFM phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, TSFM was first curated by this GCEP 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 cases with LSS.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes seven variants in 10 probands across eight publications (PMIDs: 17033963, 22277967, 21741925, 25037205, 30297209, 27677415, 30911037, 35071363). Affected individuals are variably affected and there is no clear genotype-phenotype correlation. Clinical features seen in affected individuals include LSS disorders, lactic acidosis, seizures, dystonia, ataxia, hyperkinetic movement disorder, axonal sensorimotor neuropathy, muscle weakness, rhabdomyolysis, dilated cardiomyopathy, hypertrophic cardiomyopathy, respiratory failure, hepatomegaly, infantile liver failure, optic atrophy, and sensorineural hearing loss. Laboratory findings include elevated lactate, ammonia, and creatine kinase; and ketosis. Muscle biopsies show ragged red fibers, COX-deficient fibers, and combined deficiencies of mitochondrial respiratory chain enzyme complexes I, II, and IV.
Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by known biochemical function and functional alteration in patient cells (PMIDs: 33340416, 17033963).
In summary, there is definitive evidence to support the relationship between TSFM and autosomal recessive primary mitochondrial disease, including that more than three years have elapsed since the first proposal of the association. 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 September 6, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.