TSFM

Inheritance Pattern: AR

Disease ID:MONDO:0012512

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between TSFM and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of January 13, 2020. The TSFM gene encodes the mitochondrial translation elongation factor Ts. The TSFM gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID: 25037205). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants identified in three cases in three publications (PMIDs: 25037205, 27677415, 30297209). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, and functional alteration in patient cells (PMIDs: 27977873, 25613900, 17033963). In summary, there is moderate 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 classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 13, 2020 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0012512

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012512

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012512

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

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).