The relationship between DARS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 4, 2022. The DARS2 gene encodes mitochondrial aspartyl-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 DARS2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2007 in 30 families (PMID: 17384640). While various names have been given to the constellation of features seen in those with DARS2-related disease, most commonly “leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation” (LBSL), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the DARS2 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. Affected individuals have been reported with leukoencephalopathy with brainstem and spinal cord involvement, developmental delay, ataxia, muscle weakness/atrophy, tremor, and neuropathy. Almost all published cases have compound heterozygous variants, and 95% of the cases have one splice-site variant at the 3'-end of intron 2. This curation included 14 unique variants including four intronic, four stop-gained, three consensus splice site, and three missense variants from three publications (PMIDs: 17384640, 33977142, 21493805). The mechanism of disease appears to be loss of function either at the transcript or protein level. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration studies in HEK293 cells showing disrupted enzyme activity, and lack of rescue of oxidative growth by pathogenic missense variants in MDS1, the yeast (S. cerevisae) orthologue of DARS2, in yeast cells deleted for MDS1 (PMIDs: 24639874, 33977142).
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 May 4, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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