Molecular and clinical descriptions of patients with GABA(A) receptor gene variants ( GABRA1, GABRB2, GABRB3, GABRG2 ): A cohort study, review of literature, and genotype–phenotype correlation

OBJECTIVE: γ‐Aminobutyric acid (GABA)(A)‐receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABA(A)‐receptor–related disorders as a whole and seek possible genotype–phenotype correlations. METHODS: We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA(A)‐receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature. RESULTS: We gathered the reported patients in three epileptic phenotypes: 15 patients with fever‐related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABA(A)‐receptor subunit gene, whereas N‐terminal variants seemed to be related to milder phenotypes. SIGNIFICANCE: GABA(A)‐receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics.