Objective: We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in the gene GABRB2, coding for the γ-aminobutyric acid type A (GABA A) receptor subunit β2. Methods: We recruited and systematically evaluated 25 individuals with variants in GABRB2, 17 of whom are newly described and 8 previously reported with additional clinical data. Functional analysis was performed using a Xenopus laevis oocyte model system. Results: Our cohort of 25 individuals from 22 families with variants in GABRB2 demonstrated a range of epilepsy phenotypes from genetic generalized epilepsy to developmental and epileptic encephalopathy. Fifty-eight percent of individuals had pharmacoresistant epilepsy; response to medications targeting the GABAergic pathway was inconsistent. Developmental disability (present in 84%) ranged from mild intellectual disability to severe global disability; movement disorders (present in 44%) included choreoathetosis, dystonia, and ataxia. Disease-associated variants cluster in the extracellular N-terminus and transmembrane domains 1–3, with more severe phenotypes seen in association with variants in transmembrane domains 1 and 2 and the allosteric binding site between transmembrane domains 2 and 3. Functional analysis of 4 variants in transmembrane domains 1 or 2 (p.Ile246Thr, p.Pro252Leu, p.Ile288Ser, p.Val282Ala) revealed strongly reduced amplitudes of GABA-evoked anionic currents. Interpretation: GABRB2-related epilepsy ranges broadly in severity from genetic generalized epilepsy to developmental and epileptic encephalopathies. Developmental disability and movement disorder are key features. The phenotypic spectrum is comparable to other GABA A receptor-encoding genes. Phenotypic severity varies by protein domain. Experimental evidence supports loss of GABAergic inhibition as the mechanism underlying GABRB2-associated neurodevelopmental disorders. ANN NEUROL 2021;89:573–586.
Bibliografisk noteFunding Information:
H.E.O. was supported by the NIH National Institute of Neurologic Disorders and Stroke (K23 NS107646‐02 and NINDS 5K12NS079414‐02), and by the Administrative Core of Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (1U54HD090255). A.P. was supported by the Boston Children's Hospital Translational Research Program. R.S.M. was supported by the Novo Nordisk Foundation (NNF19OC0058749). H.L. was supported by the German Research Foundation (FOR‐2715, grant LE1030/16‐1). Sarah Weckhuysen of the Working Group receives funding from the Research Foundation‐Flanders (FKM 1861419 N), University of Antwerp (BOF‐FFB180053), and the European Union H2020 program (856592). Pasquale Striano and Federico Zara of the Working Group developed this work within the framework of the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, Department of Excellence of the Italian Ministry of Education, University and Research 2018‐2022 (legge 232 del 2016). Katalin Sterbova of the Working Group is supported by Ministry of Health of the Czech Republic (AZV NU20‐04‐00279). Sequencing and analysis for Individual #10 was provided by the Broad Institute of Massachusetts Institute of Technology and Harvard Center for Mendelian Genomics (Broad Center for Mendelian Genomics) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute (UM1 HG008900) and in part by the National Human Genome Research Institute (R01 HG009141). GABRB2 GABRB2 GABRB2
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