Pathogenic variants in γ-aminobutyric acid type A (GABAA) receptor subunit genes are increasingly associated with epilepsy and neurodevelopmental disorders. Pathogenic variants in GABRA2, encoding the α-2 subunit of GABAA receptors, have been recently reported. This study aims to better delineate the phenotypic spectrum of GABRA2 pathogenic variants. We conducted a retrospective multicenter study, analyzing six new patients with GABRA2 pathogenic variants identified through a French national collaboration. Clinical, electroencephalographic (EEG), and genetic data were reviewed alongside a literature analysis of eight previously reported cases. Two distinct electroclinical phenotypes were identified. The most severe, in four of six patients, featured early infantile developmental and epileptic encephalopathy with an EEG pattern of rapid rhythms suggestive of GABAergic hyperactivity. The milder phenotype, in two of six patients, included later onset, drug-responsive epilepsy with moderate developmental delay. A literature review confirmed these phenotypes and supported genotype-phenotype correlations, with transmembrane domain variants more frequently associated with severe phenotypes. This study refines the phenotypic spectrum of GABRA2-related disorders, highlighting two distinct electroclinical phenotypes. The identification of a recognizable EEG pattern of unusual rapid rhythms for age may be a biomarker for early diagnosis of a severe phenotype and suggests a potential underlying gain-of-function mechanism, to be confirmed by functional studies.
Keywords: GABRA2; EEG biomarker; GABA; GABAA receptor; developmental and epileptic encephalopathy; electroclinical phenotypes.
© 2025 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.