TARS2

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between TARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 24, 2021. The TARS2 gene encodes mitochondrial threonyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits. The TARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID: 24827421). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four variants in two cases in two publications (PMID: 24827421, 33153448). 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 and expression (PMIDs: 27977873, 25613900). In summary, there is limited 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 May 24, 2021 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0014398

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0014398

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014398

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TARS2* and *TARS2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 16, 2024. The *TARS2* gene encodes mitochondrial threonyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of protein subunits of oxidative phosphorylation complexes I, III, IV, and V. The *TARS2* gene was first reported in relation to autosomal recessive *TARS2*-related primary mitochondrial disease in 2014 (PMID: 24827421). *TARS2* has been associated with a single disease entity to date; combined oxidative phosphorylation deficiency 21 [OMIM# 615918]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *TARS2*-related primary mitochondrial disease. Of note, *TARS2* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on May 24, 2021 (SOP v7), with a final classification of Limited. This current curation for the association with *TARS2*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 unique variants (nine missense, one nonsense, one intronic) identified in seven unrelated cases from three publications (PMIDs: 24827421, 33153448, 34508595), although at least 24 probands have been reported to date (see PMID: 37454282 for report of a large cohort with literature review). Age of onset is typically in the first year of life and outcomes vary from death early in life to living in the third decade. The most common reported clinical features include severe developmental delay, regression, limb hypertonia, and seizures. More rare features include renal tubular acidosis, hearing loss, hepatic steatosis, and cardiomyopathy. Muscle biopsies show variable respiratory chain enzyme deficiencies. Brain imaging shows cerebellar atrophy and/or basal ganglia involvement. Blood lactate is elevated. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies in patient cells (PMID: 24827421), and a zebrafish model (PMID: 37454282). In summary, there is definitive evidence to support the relationship between *TARS2* and autosomal recessive *TARS2*-related 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 December 16, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0014398

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014398

Submitter: Orphanet