Submission Details

WARS1 encodes the tryptophanyl-tRNA synthetase 1 that catalyzes the aminoacylation of tRNA(trp) with tryptophan, the first step of protein synthesis and an essential step in the cell's protein synthesis machinery. WARS1 functions in the same aminoacylation pathway as other known neuropathy genes, such GARS1, YARS1, and HARS1. In 2017, three families, two Taiwanese and one Belgian, were shown to carry the same heterozygous His257Arg missense variant in WARS1 co-segregating with a juvenile onset distal motor neuropathy phenotype (PMID: 28369220). The authors show evidence of a dominant-negative effect of the His257Arg mutation capable of dimerizing with the wild-type protein and impairing the overall aminoacylation function. When transfected into neuronal-like cells, an effect on neurite length was also observed. Two other WARS1 missense variants have been linked with this consistent juvenile onset HMN phenotype since then (PMID: 31321409). In these two families, significant segregation or de novo inheritance was shown, but functional evidence was absent. The phenotype in all five published WARS1 families is very consistent, a juvenile onset motor neuropathy phenotype affecting both upper and lower limbs without any sensory involvement. The panel concludes that the evidence for the pathogenicity of the His257Arg mutation is sufficient to link WARS1 to the motor neuropathy phenotype. More reports will solidify the gene-disease relationship in the future. Based on the curated evidence, we classify the gene-disease relationship of WARS1 and autosomal dominant motor neuropathy as limited, but with the advice to include it on panels.