Submission Details

The relationship between WARS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 16, 2022. The WARS2 gene encodes mitochondrial tryptophanyl-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 WARS2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2017 (PMID: 28236339). While various names have been given to the constellation of features seen in those with WARS2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the WARS2 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 10 unique variants, including one nonsense, two frameshift, one in-frame deletion, one exonic deletion, and five missense variants. Of note, c.37T>G (p.Trp13Gly) is a common recurrent variant which is reported at a high allele frequency in gnomAD v3.1.2 (AF 0.003152) and was also reported in six homozygotes in previous versions of gnomAD (v2.1.1). However, this GCEP agreed that, despite the relatively high allele frequency, the mitochondrial localization and consistent reduced WARS2 expression on western blotting from mitochondrial protein extracts in patient fibroblasts were supportive of pathogenicity in the setting of a second more deleterious variant on the other allele, likely indicating this is a hypomorphic allele (PMIDs: 29120065, 32120303, 34890876, 28236339). More than 20 probands from numerous publications have been reported between 2017-2022, and seven probands from six publications were included in this curation (PMIDs: 28236339, 28650581, 29120065, 30920170, 34890876, 31684799). The condition was first described in a 17-year-old Iranian female with childhood onset athetosis, ataxia, muscle weakness, intellectual disability, and aggressive behavior. She had a sibling with similar medical concerns. Subsequent reported cases have demonstrated the spectrum of medical problems seen in those with WARS2-related disorders, with features ranging from neonatal lactic acidosis with multi-organ failure, to infantile or childhood onset levodopa-responsive parkinsonism, and/or a variable movement disorder with or without intellectual disability and seizures. Additional features seen in affected individuals include leukoencephalopathy, global brain atrophy, cardiomyopathy, optic atrophy, and retinitis pigmentosa (PMIDs: 28905505, 28650581, 29120065, 34890876, 31684799). Loss-of-function is implicated as a mechanism of disease. This gene-disease relationship is also supported by its known biochemical function that is shared with other genes associated with primary mitochondrial disease, patient cell data showing impact on WARS2 expression, as well as Drosophila melanogaster and mouse model data (PMIDs: 30920170, 30566859, 34890876).

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 June 16, 2022 (SOP Version 9).