Aminoacyl-tRNA synthetases (aaRS) are essential enzymes that charge tRNAs with their corresponding amino acids, playing a critical role in protein synthesis. All 37 nuclear-encoded ARS genes, comprising both cytosolic (ARS1) and mitochondrial (ARS2) isoforms, have now been linked to human disease. Pathogenic variants in these genes cause a wide range of phenotypes, from dominant peripheral neuropathies to recessive multisystemic disorders. Despite the high number of ARS variants identified, functional validation remains difficult, with over 80% of missense variants classified as VUS in public databases. Additionally, the role of non-canonical aaRS functions in disease remains an area requiring further exploration. Our laboratory developed a high-throughput LC-MS/MS-based aminoacylation assay to measure aaRS activity in patient-derived fibroblasts, aiding in variant classification. This functional approach has contributed to the diagnosis of nearly 200 patients and has uncovered complex variant effects, including thermolabile and splicing-defective forms. Therapeutically, amino acid supplementation and dietary interventions have shown effect in select cases, while gene therapy is being explored for dominant ARS-related neuropathies. Amenability to targeted interventions further underlines the need for correct interpretation of genetic variants, which are increasingly recognized as genetic testing is progressively used in the diagnostic work-up and functional assays. Additionally, natural history studies are essential to improve diagnosis, understand disease mechanisms, and guide and evaluate personalized treatment. This review underscores the critical need for integrated genomic and functional approaches to advance variant interpretation and therapeutic development in the era of NGS.
Mendes et al. (Fri,) studied this question.