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

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 GABA_A -receptor-related disorders as a whole and seek possible genotype-phenotype correlations.

Methods: We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA_A -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 GABA_A -receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes.

Significance: GABA_A -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.

Keywords: GABA A receptor; channelopathy; developmental and epileptic encephalopathy; genetic generalized epilepsy.

FIGURE 1

(A) Epileptic phenotype and (B) cognitive status related to the γ‐aminobutyric acid (GABA) gene variant. EDEE: early developmental epileptic encephalopathy, ID: Intellectual disability

FIGURE 2

Interictal electroencephalography (EEG) recordings of patients with GABRB3 variants. (A) Patient 12, wakefulness. Asymptomatic episode of theta rhythmic pattern. (B) Patient 9, sleep. (C) Patient 11, wakefulness, asymptomatic. (D) Patient 10, wakefulness, asymptomatic bursts of slow wave, predominantly anterior

FIGURE 3

Location of pathogenic variants identified in GABRA1, GABRB2, GABRB3, and GABRG2 protein classified by the intellectual disability severity of the reported associated phenotype. Variants for which no information is available in the literature regarding the phenotype are not noted

FIGURE 4

Correlation between phenotype (A. severe ID, B. EDEE) and location of mutated GABA‐R protein domains in our cohort (n = 37). ID: intellectual disability, EDEE: early developmental epileptic encephalopathy, pathogenic variant location: N‐term, loop, and TM (transmembrane).

FIGURE 5

Correlation between phenotype (A. severe ID and B. EDEE) and location of mutated GABA‐R protein domains in our cohort and literature cases. ID: Intellectual disability, EDEE: Early developmental epileptic encephalopathy, pathogenic variant location: N‐term, loop, and TM (transmembrane)