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

GABAA 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 their common molecular structure and physiological role, it seemed interesting to describe a putative phenotype associated with GABAA -receptor-related disorders as a whole and seek possible genotype/phenotype correlations.We collected clinical, electrophysiological, therapeutic, and molecular data from patients affected with GABAA receptor subunit variants (GABRA1, GABRB2, GABRB3, GABRG2) through a national French collaboration using the EPIGENE network and compared them to the one already described in the literature.We gathered the reported patients in 3 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 GABAA receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes.GABAA 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.