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- Title
Molecular and clinical descriptions of patients with GABA<sub>A</sub> receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype–phenotype correlation.
- Authors
Maillard, Pierre‐Yves; Baer, Sarah; Schaefer, Élise; Desnous, Béatrice; Villeneuve, Nathalie; Lépine, Anne; Fabre, Alexandre; Lacoste, Caroline; El Chehadeh, Salima; Piton, Amélie; Porter, Louise Frances; Perriard, Caroline; Wardé, Marie‐Thérèse Abi; Spitz, Marie‐Aude; Laugel, Vincent; Lesca, Gaëtan; Putoux, Audrey; Ville, Dorothée; Mignot, Cyril; Héron, Delphine
- 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 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.
- Subjects
GENETIC variation; LITERATURE reviews; MOLECULAR structure; COHORT analysis; PEOPLE with epilepsy
- Publication
Epilepsia (Series 4), 2022, Vol 63, Issue 10, p2519
- ISSN
0013-9580
- Publication type
Article
- DOI
10.1111/epi.17336