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

作者：Pierre‐Yves Maillard, Sarah Baer, Élise Schaefer, Béatrice Desnous, Nathalie Villeneuve, Anne Fabienne Lepine, Alexandre Fabre, Caroline Lacoste, Salima El Chehadeh, Amélie Piton, Louise Frances Porter, Caroline Perriard, Marie‐Thérèse Abi Wardé, Marie‐Aude Spitz, Vincent Laugel, Gaëtan Lesca, Audrey Putoux, Dorothee M. Ville, Cyril Mignot, Delphine Héron, Rima Nabbout, Giulia Barcia, Marlène Rio, Agathe Roubertie, Pierre Meyer, Véronique Paquis‐Flucklinger, Olivier Patat, Jérémie Lefranc, Marion Gérard, Julietta de Bellescize, Laurent Villard, Anne de Saint Martin, Mathieu Milh · 发表于：Epilepsia · 年份：2022 · DOI：10.1111/epi.17336 · 被引用次数：82 · 研究领域：Neuroscience and Neuropharmacology Research、Epilepsy research and treatment、RNA and protein synthesis mechanisms

Abstract 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 GABAA‐receptor–related disorders as a whole and seek possible genotype–phenotype correlations. Methods We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABAA‐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 GABAA‐receptor subunit gene, whereas N‐terminal variants seemed to be related to milder phenotypes. Significance GABAA‐receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes de...