A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype. Issue 4 (12th February 2022)

• Record Type: Journal Article
• Authors: Vogel, Florian D.; Krenn, Martin; Westphal, Dominik S.; Graf, Elisabeth; Wagner, Matias; Leiz, Steffen; Koniuszewski, Filip; Augé‐Stock, Maximilian; Kramer, Georg; Scholze, Petra; Ernst, Margot
• Is Part Of: Epilepsia. Volume 63:Issue 4(2022)
• Page Start: e35
• Page End: e41
• Publication Date: 2022-02-12
• Subjects: Drug‐resistant epilepsy -- early‐onset epilepsy -- GABAA receptors -- neurosteroid -- tonic inhibition -- trio exome sequencing; Epilepsy -- Periodicals; 616.853
• DOI: 10.1111/epi.17188
• Languages: English
• ISSNs: 0013-9580

Abstract

Abstract: Variants in γ‐aminobutyric acid A (GABAA ) receptor genes cause different forms of epilepsy and neurodevelopmental disorders. To date, GABRA4, encoding the α4‐subunit, has not been associated with a monogenic condition. However, preclinical evidence points toward seizure susceptibility. Here, we report a de novo missense variant in GABRA4 (c.899C>T, p.Thr300Ile) in an individual with early‐onset drug‐resistant epilepsy and neurodevelopmental abnormalities. An electrophysiological characterization of the variant, which is located in the pore‐forming domain, shows accelerated desensitization and a lack of seizure‐protective neurosteroid function. In conclusion, our findings strongly suggest an association between de novo variation in GABRA4 and a neurodevelopmental disorder with epilepsy.