Novel variant in KARS1 in a consanguineous family with Intellectual Disability and hearing impairment: WES and in silico protein analysis.

Abstract

Intellectual Disability (ID) is a genetically heterogeneous neurodevelopmental disorder that imposes a substantial burden on families, with huge demands on healthcare services. Autosomal recessive forms are particularly prevalent in inbred populations, where rare homozygous variants often remain undiagnosed. Trio-based whole-exome sequencing (WES) has emerged as an effective diagnostic approach for resolving the etiology of unresolved cases. Herein, we report a homozygous missense variant in KARS1, a lysyl-tRNA synthetase (c.989 T > C, p.Leu330Pro), co-segregating with ID and hearing impairments in a consanguineous Arab family from Jordan. We integrated WES and in silico analyses to characterize the variant, including evolutionary, pathogenicity, splicing, stability, and comparative 3D modelling analyses. The variant was located in a highly conserved catalytic domain, and multiple pathogenicity classifiers predicted a deleterious impact. The molecular changes included a potential loss of the alpha helix and alterations to the catalytic/allosteric sites. Splicing analyses predicted disruption of exonic regulatory elements, forming a new enhancer motif and a net increase in exonic splicing enhancers. Additionally, the variant was predicted to be destabilizing, with decreased local interactions, including potential clashes with Glu301. The identified variant can potentially disrupt aminoacylation fidelity, and the impaired protein function may compromise both cytosolic and mitochondrial protein synthesis, leading to defective proteostasis, reduced energy production, and altered synaptic development. Our findings highlight the diagnostic value of trio-based WES and computational analyses in consanguineous populations, expand the genetic and phenotypic spectrum of KARS1-related dysfunctions, and support the inclusion of KARS1 in regional diagnostic panels for ID.