Novel IARS1 variants cause syndromic developmental disorder with epilepsy in a Chinese patient and the literature review

Abstract

AbstractBackgroundIsoleucinyl‐tRNA synthetase (IARS) is encoded by the IARS1 gene and catalyzes the binding of isoleucine to specific tRNA.ObjectiveThis study aims to investigate the pathogenicity of novel IARS1 variants and the genotype–phenotype association, in order to expand the spectrum of pathogenic variants and phenotypes of IARS1‐related disease and provide new evidence for the phenotypic spectrum of IARS1 variants.MethodsClinical data of the proband were collected, and trio whole‐exome sequencing (WES) was performed on the proband and the parents. Candidate variants were validated using Sanger sequencing. Bioinformatics software was utilized to analyze the functional consequences of identified variants and predict their potential deleteriousness.ResultsA 17‐month‐old female patient presented with microcephaly, left external ear malformation, decreased muscle strength and tone in all limbs, epileptic seizures, global developmental delay, and developmental regression. Trio WES identified compound heterozygous variants in the IARS1 gene, c.120‐1G>A and c.2164C>A, which were novel pathogenic and likely pathogenic variants, respectively. The phenotype of developmental regression has not been reported before. Only one patient with IARS1 compound heterozygous variants has been reported in the world to have an epileptic phenotype, and this is the second patient with an epileptic phenotype. Bioinformatics analysis revealed that the splicing variant disrupted the canonical splice donor site, while the missense variant altered the local electrostatics of the IARS1 protein surface, potentially leading to functional abnormalities.ConclusionThis study identified novel IARS1 variants and the phenotype of developmental regression, expanding the spectrum of pathogenic variants and phenotypes of IARS1‐related diseases and providing new evidence for the rare phenotype of epileptic seizures caused by IARS1 variants.