Submission Details

The relationship between AARS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 18, 2022. The AARS2 gene encodes mitochondrial alanyl-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 AARS2 gene was first reported in relation to autosomal recessive mitochondrial disease in 2011 (PMID: 21549344). While various names have been given to the constellation of features seen in those with AARS2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the AARS2 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 11 unique variants, including two nonsense, one frameshift, one in-frame deletion, and seven missense variants. Multi-exon deletions are also reported in the literature (PMID: 30285085). Of note, the c.1774C>T (p.Arg592Trp) variant is a founder variant frequently observed in European populations (PMID: 25705216). Additional recurrent variants include c.149T>G (p.Phe50Cys) and c.595C>T (p.Arg199Cys); and some missense variants have been shown to have similar function to null alleles (PMID: 24808023). There are at least 20 probands from seven publications in 2011-2020 reported with pathogenic variants in this gene (PMIDs: 21549344, 24808023, 31099476, 30285085, 31705293, 25705216). The first individuals described were of Finnish descent and had hypertrophic cardiomyopathy, weakness, and lactic acidosis which was ultimately fatal. Subsequent publications have expanded the phenotype and there now appear to be two main categories: an infantile-onset, rapidly progressive cardiomyopathy with weakness and metabolic abnormalities (PMID: 25705216) or childhood to young adult-onset ovarian failure and leukoencephalopathy (PMID: 24808023). There have also been some patients reported without leukoencephalopathy but with clear cerebellar disease (PMID: 31705293). This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, patient cell studies showing profound respiratory chain deficiencies and mis-assembly, and E. Coli and mouse models (PMIDs: 29228266, 30285085, 24808023, 29980628).

In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 18, 2022 (SOP Version 8).