GABA(A) Receptor Subunit (γ2, δ, β1-3) Variants in Genetic Epilepsy: A Comprehensive Summary of 206 Clinical Cases

Epilepsy is identified in individuals who experienced 2 or more unprovoked seizures occurring over 24 hours apart, which can have a profound impact on a person's neurobiological, cognitive, psychological, and social well-being. Epilepsy is considerably diverse, with classifications such as genetic epilepsy that result directly from a known or presumed genetic variant with the core symptoms of seizures. The GABAA receptor primarily functions as a heteropentamer, containing 3 of 8 subunit types: alpha, beta, gamma, delta, epsilon, pi, theta, and rho. In the adult brain, the GABAA receptor is the primary inhibitory component in neural networks. The involvement of GABAA receptors in the pathogenesis of epilepsy has been proposed. We extensively reviewed all relevant clinical data of previously published cases of GABAA receptor subunit gamma 2, delta, beta 1-3 variants included in PubMed up to February 2024, including the variant types, loci, postulated mechanisms, their relevant regions, first onset ages, and phenotypes. We summarized the postulated mechanisms of epileptic pathogenesis. We also divided the collected 206 cases of epilepsy into 4 epileptic phenotypes: genetic generalized epilepsies, focal epilepsy, developmental and epileptic encephalopathies, and epilepsy with fever sensibility. We showed that there were significant differences in the likelihood of the gamma 2, beta 2, and beta 3 subunit variants causing genetic generalized epilepsies, focal epilepsy, developmental and epileptic encephalopathies, and epilepsy with fever sensibility. Patients with the beta 3 subunit variant seemed related to an earlier first onset age. Our review supports that GABAA receptor subunit variants are a crucial area of epilepsy research and treatment exploration.