TARS2 – Combined Oxidative Phosphorylation Defect Type 21

This summary integrates case‐report and multi‐patient evidence supporting a strong association between TARS2 (HGNC:30740) and combined oxidative phosphorylation defect type 21 (MONDO_0014398). Multiple independent studies have reported compound heterozygous variants in TARS2 in patients presenting with clinical features such as global developmental delay, increased circulating lactate, hearing impairment, and other neuromuscular symptoms (PMID:33153448, PMID:36150709).

In the genetic evidence, affected individuals often carry compound heterozygous missense variants, with segregation analysis confirming that each variant is inherited from a different parent. For example, one pivotal report identified the variant c.470C>G (p.Thr157Arg) in a non‐consanguineous Chinese family, supporting the autosomal recessive inheritance pattern (PMID:33153448). Additional affected family members with consistent phenotypes further solidify the association.

Functional studies have contributed significantly to the understanding of the pathogenic mechanism. In vitro assays, yeast modeling, and biochemical analyses have demonstrated that TARS2 variants adversely affect protein stability and catalytic activity. These data indicate impaired mitochondrial translation which is concordant with the clinical phenotype observed in COXPD21 patients (PMID:26811336, PMID:34508595).

The combined weight of the genetic and functional evidence categorizes the gene-disease relationship as Strong. At least four unrelated probands have been documented in independent studies, with compound heterozygosity confirmed by molecular analyses and supportive in vitro experiments addressing the pathogenicity of the TARS2 mutations (PMID:33153448, PMID:38482264).

There is minimal conflicting evidence. While mitochondrial encephalomyopathies can present heterogeneously, the consistency of clinical and experimental findings specifically pertaining to COXPD21 supports the clinical utility of TARS2 testing. Further studies may augment the available evidence but already exceed the ClinGen scoring cap.

Key Take‑home: The robust genetic and functional evidence linking TARS2 to combined oxidative phosphorylation defect type 21 renders this association highly valuable for diagnostic decision‑making, commercial development, and future research publication.

References

• BMC Medical Genetics • 2020 • Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy PMID:33153448
• Neuropediatrics • 2024 • TARS2 Variants Cause Combination Oxidative Phosphorylation Deficiency-21: A Case Report and Literature Review PMID:36150709
• Balkan Journal of Medical Genetics : BJMG • 2023 • Expanding the Phenotypic Spectrum: Chronic Kidney Disease in a Patient with Combined Oxidative Phosphorylation Defect 21 PMID:38482264
• The Journal of Biological Chemistry • 2016 • A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces Both Structural and Functional Defects PMID:26811336
• Human Molecular Genetics • 2022 • Elucidating the Molecular Mechanisms Associated with TARS2-related Mitochondrial Disease PMID:34508595

Evidence Based Scoring (AI generated)