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
γ-Aminobutyric acid (GABA) -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 interes...
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Veröffentlicht in: | Epilepsia (Copenhagen) 2022-10, Vol.63 (10), p.2519-2533 |
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Sprache: | eng |
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Zusammenfassung: | γ-Aminobutyric acid (GABA)
-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
-receptor-related disorders as a whole and seek possible genotype-phenotype correlations.
We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA
-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.
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
-receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes.
GABA
-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. |
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ISSN: | 0013-9580 1528-1167 |
DOI: | 10.1111/epi.17336 |