El Achkar CM , Harrer M , Smith L , Kelly M , Iqbal S , Maljevic S , Niturad CE , Vissers LELM , Poduri A , Yang E , Lal D , Lerche H , Møller RS , Olson HE , GABRB2 Working Group .

Boston Children's Hospital Translational Research Program, LE1030/16-1 Deutsche Forschungsgemeinschaft, legge 232 del 2016 DINOGMI Department of Excellence of MIUR, 856592 EU H2020 program, FKM 1861419N Fonds Wetenschappelijk Onderzoek, AZV NU20-04-00279 Ministerstvo Zdravotnictví Ceské Republiky, 5K12NS079414-02 NINDS NIH HHS , K23 NS107646-02 NINDS NIH HHS , R01NS069605 NINDS NIH HHS , NNF19OC0058749 Novo Nordisk Foundation Center for Basic Metabolic Research, BOF-FFB180053 Universiteit Antwerpen, K23 NS107646 NINDS NIH HHS , UM1 HG008900 NHGRI NIH HHS , R01 HG009141 NHGRI NIH HHS , K12 NS079414 NINDS NIH HHS , U54 HD090255 NICHD NIH HHS

                myoclonic-atonic epilepsy
                epilepsy

	FIGURE 1 Location of GABRB2 variants in our cohort, from the literature, and in control populations. (A) Variant location in individuals reported in this study (red text) and from the literature in a 2‐dimensional model of the GABRB2 protein. Red spheres: single cases; red triangles: recurrent variants. (B) Location of missense variants in affected individuals (red spheres) and normal controls from gnomAD (blue spheres) mapped on the experimentally solved model of human β2‐subunit (Protein Data Bank [PDB] ID: 6D6T, chain A and C).48 Disease‐associated variants are in regions lacking variation in controls. (C) Disease‐associated variant locations (red spheres) by β2‐subunit protein domain (PDB ID: 6D6T, chain A and C). The extracellular and helical transmembrane domains are highlighted in purple and green, respectively. Two functionally critical regions, the agonist binding region (yellow, harbors the patient variant: p.Tyr181Phe) and the allosteric effector binding region (pink, contains 12 patient variants) are also shown in the structure. (D) GABRB2 tolerance landscape using MetaDome.49 Functional domains are highlighted in purple. Vertical green lines in the schematic representation of the GABRB2 protein indicate the locations where (likely) pathogenic missense variants were observed. From this visualization, it can be concluded that all missense variants locate to regions of GABRB2 that are intolerant to functional variation
	FIGURE 2 Location of all disease‐associated variants (red spheres) mapped on the experimentally solved model of human β2‐subunit (Protein Data Bank ID: 6D6T, chain A and C)48 and variants associated with electroencephalographic encephalopathy (magenta spheres), movement disorder (orange spheres), and developmental disorder (brown spheres). Spatial distributions of variants by phenotypes show that patient variants located in the extracellular domain (in the dashed box) are mostly associated with developmental delay and less often with epileptic encephalopathy or movement disorder.
	FIGURE 3 Functional analysis in Xenopus oocytes of 4 de novo GABRB2 variants associated with developmental and epileptic encephalopathies. (A) Schematic representation of the β 2‐subunit of the γ–aminobutyric acid type A (GABAA) receptor showing the localization of the variants. (B) Normalized current response to 1mM GABA application for α1β2γ2s wild‐type (WT) receptors (n = 27), and receptors carrying the variants p.Val282Ala (V282A, n = 16), p.Pro252Leu (P252L, n = 14), p.Ile288Ser (I288S, n = 10), and p.Ile246Thr (I246T, n = 21) in the β2‐subunit. Shown are all data points for each oocyte and median with range ***p<0.001, ****p<0.0001 (Kruskal‐Wallis with Dunn's post‐hoc test). (C) Dose‐response curve for WT (n = 10), I246T (n = 16) and V282A (n = 16) containing receptors after application of different GABA concentrations ranging from 0.001 µM to 1mM and normalization to the maximal GABA response for each cell. (D) Dose‐response curve for WT (n = 21), p.Ile288Ser (I288S, n = 12) and p.Pro252Leu (P252L, n = 14) as in C. Shown in C and D are means ± SEM (error bars are sometimes smaller than symbol size).

Allen, De novo mutations in epileptic encephalopathies. 2013, Pubmed

Allen, De novo mutations in epileptic encephalopathies. 2013, Pubmed
Baldridge, The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results. 2017, Pubmed
Baulac, First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. 2001, Pubmed , Xenbase
Baumann, Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement. 2002, Pubmed , Xenbase
Bosch, Novel genetic causes for cerebral visual impairment. 2016, Pubmed
Brooks-Kayal, Developmental changes in human gamma-aminobutyric acidA receptor subunit composition. 1993, Pubmed
Burgess, The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures. 2019, Pubmed
Carecchio, Emerging Monogenic Complex Hyperkinetic Disorders. 2017, Pubmed
Carvill, GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. 2014, Pubmed
Cogliati, Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes. 2019, Pubmed
Dibbens, GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. 2004, Pubmed
Dibbens, The role of neuronal GABA(A) receptor subunit mutations in idiopathic generalized epilepsies. 2009, Pubmed , Xenbase
Grabenstatter, Molecular pathways controlling inhibitory receptor expression. 2012, Pubmed
Hamdan, High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. 2017, Pubmed
Heyne, De novo variants in neurodevelopmental disorders with epilepsy. 2018, Pubmed
Hirose, Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. 2014, Pubmed
Ishii, A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. 2017, Pubmed
Janve, Epileptic encephalopathy de novo GABRB mutations impair γ-aminobutyric acid type A receptor function. 2016, Pubmed
Johnston, A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes. 2014, Pubmed
Kang, Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome. 2016, Pubmed
Karczewski, The mutational constraint spectrum quantified from variation in 141,456 humans. 2020, Pubmed
Kelly, Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region. 2019, Pubmed
Kodera, De novo GABRA1 mutations in Ohtahara and West syndromes. 2016, Pubmed
Kwan, Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. 2010, Pubmed
Lachance-Touchette, Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy. 2011, Pubmed
Laurie, The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. 1992, Pubmed
Maljevic, Spectrum of GABAA receptor variants in epilepsy. 2019, Pubmed
Maljevic, A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy. 2006, Pubmed
May, Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study. 2018, Pubmed , Xenbase
Møller, Mutations in GABRB3: From febrile seizures to epileptic encephalopathies. 2017, Pubmed , Xenbase
Nishikawa, A de novo GABRB2 variant associated with myoclonic status epilepticus and rhythmic high-amplitude delta with superimposed (poly) spikes (RHADS). 2020, Pubmed
Olson, Genetic forms of epilepsies and other paroxysmal disorders. 2014, Pubmed
Papandreou, GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy. 2016, Pubmed
Reid, Multiple molecular mechanisms for a single GABAA mutation in epilepsy. 2013, Pubmed
Richards, Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 2015, Pubmed
Rochtus, Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort. 2020, Pubmed
Scheffer, ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. 2017, Pubmed
Shi, Synaptic clustering differences due to different GABRB3 mutations cause variable epilepsy syndromes. 2019, Pubmed
Sobreira, GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. 2015, Pubmed
Srivastava, A novel variant in GABRB2 associated with intellectual disability and epilepsy. 2014, Pubmed
Sun, SCN1A, SCN1B, and GABRG2 gene mutation analysis in Chinese families with generalized epilepsy with febrile seizures plus. 2008, Pubmed
Tanaka, Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. 2008, Pubmed
Tian, Impaired surface αβγ GABA(A) receptor expression in familial epilepsy due to a GABRG2 frameshift mutation. 2013, Pubmed
Urak, A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity. 2006, Pubmed
Wiel, MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. 2019, Pubmed
Yang, Phenotypic spectrum of patients with GABRB2 variants: from mild febrile seizures to severe epileptic encephalopathy. 2020, Pubmed
Yang, [Clinical features of epilepsies associated with GABRB2 variants]. 2019, Pubmed
Zhu, Structure of a human synaptic GABAA receptor. 2018, Pubmed