Biallelic variants in WARS1 underlying autosomal recessive neurodevelopmental disorders have been reported in two recently published international studies led by researchers at the Institute of Human Genetics of the University Medical Center Göttingen. WARS1 is an aminoacyl-tRNA synthetase. This group of enzymes plays a crucial role in protein synthesis as they are responsible for linking transfer RNAs (tRNAs) with specific amino acids, corresponding to their sequence. During translation at ribosomes, amino acids delivered by tRNAs molecules are joined together to form a protein chain. For each amino acid, a specific tRNA synthetase exists, with tryptophanyl‐tRNA synthetase 1, encoded by WARS1, catalyzing the binding of tryptophanyl. Homozygous variants in this gene have only very recently been described as the genetic cause of an autosomal recessive neurogenetic disorder in a single family.

Two studies published in Human Mutation have now expanded the clinical spectrum of WARS1-associated autosomal recessive neurolodevelopmental disorders. Bögershausen et al. identified a pathogenic homozygous missense variant in four patients from two families with a clinical phenotype of microcephaly, developmental delay, intellectual disability and brain anomalies. In their study, they also identified a patient carrying a variant in SARS1, another aminoacyl-tRNA synthetase, who presented with an overlapping phenotype. The authors of the study defined an emerging spectrum of diseases which they term aminoacyl-tRNA synthetase-related neurodevelopmental disorders with/without microcephaly. In the Lin et al. study, biallelic WARS1 variants (a missense and a start-loss variant) were identified in three patients with developmental delay and intellectual disability as well as other variable clinical features including hearing impairment. The researchers performed functional analyses in a zebrafish model recapitulating the human phenotype and confirmed variant pathogenity. Their investigations also implied one exon of the WARS1 gene as essential for hearing, a result that is supported by studying isoform use in the mouse inner ear.