Algorithmic assessment reveals functional implications of GABRD gene variants linked to idiopathic generalized epilepsy.

The γ-Aminobutyric acid type A receptors (GABA A Rs) function as heteropentameric chloride channels, crucial for primary inhibition in the mammalian brain. The GABRD gene encodes the δ subunit of GABA A Rs and is implicated in various disorders, including schizophrenia, epilepsy, and insomnia. However, the increasing number of variants of unknown clinical significance (VUS) within the GABRD gene poses a challenge to precision medicine and our understanding of relevant pathophysiology. The primary aim of this study is to address this challenge by predicting the most pathogenic GABRD VUS. Employing a combination of in silico algorithms, the study analyzes 82 GABRD gene VUS sourced from the ClinVar database. Initially, separate algorithms based on sequence homology were used to assess this VUS set. Subsequently, consensus variants predicted as pathogenic underwent further evaluation through a web server utilizing the algorithm based on structural homology. The resulting 11 VUS were then validated using in silico tools, assessing variant effects based on genetic and molecular data. This led to the determination of pathogenicity probability considering disease association and protein stability due to amino acid substitutions. The identification of specific variants (L111R, R114C, D123N, G150S, L243P) in the coding region of the GABRD gene, predicted as deleterious by multiple algorithms, suggests structural or functional consequences for pathogenicity. These evolutionarily conserved variants, mapped onto the extracellular domain of the δ subunit, were linked to idiopathic generalized epilepsy. These findings guide wet-lab experimentation and contribute to validating clinically significant genetic variants in the GABRD gene crucial for personalized and pharmacogenetic interventions.