Submission Details

The relationship between CARS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 19, 2022. CARS2 encodes the mitochondrial cysteinyl tRNA aminoacyl synthetase, which plays a role in mitochondrial translation. There is also some evidence to suggest CARS2 also plays a critical role in persulfide biosynthesis (PMID:29079736).

CARS2 was first reported in relation to autosomal recessive mitochondrial disease in 2014 (PMID: 25361775). While various names have been given to the constellation of features seen in those with CARS2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the CARS2 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 included five unique variants: three missense variants, one in frame deletion, and a variant which results in exon 6 skipping (c.655G>A). There are three probands across three publications from 2014-2018 (PMIDs: 25361775, 25787132, 30139652). The condition was first described in a Turkish man with childhood onset myoclonic seizures, quadriparesis, white matter disease, brain atrophy and hyperammonemia. Subsequent publications have shown the CARS2 phenotype is predominantly an infantile-childhood onset early refractory epileptic encephalopathy with developmental regression, and hepatopathy and global atrophy on brain MRI, noted to resemble Alpers Huttenlocher Syndrome (PMID: 30139652). Tissue biopsy evidence was suggestive of a translation defect in some but not all patients.

This gene-disease association is also supported by functional evidence including known protein interaction with the multitude of other mitochondrial translation proteins, patient cell data showing profound respiratory chain mis-assembly, rescue of assembly in patient cells, as well as an embryonic lethal homozygous mouse knockout, and studies in HEK293T cells showing mitochondrial translation aberration when particular variants were incorporated into the cell line (PMIDs: 25787132, 29980628, 29079736). Of note, there are interesting data supporting CARS2 function in persulfide biosynthesis with a variety of rescue studies In HEK293T cells that carried different variants, indicating that certain variants impact the tRNA synthetase activity while others impact persulfide biosynthesis (PMID: 29079736). The persulfide studies were reviewed and the expert panel elected to not score these data as more work is required to understand the mechanism of action between impaired persulfide biosynthesis and mitochondrial dysfunction resulting in clinical disease.

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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 19, 2022 (SOP Version 8).