Sanchis-Juan, AHasenahuer, MABaker, JAMcTague, ABarwick, KKurian, MADuarte, STCarss, KJThornton, JRaymond, FL2021-05-272021-05-272020Mol Genet Genomic Med . 2020 Jul;8(7):e1106http://hdl.handle.net/10400.17/3708Background: Cys-loop receptors control neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six missense variants in GABRA2, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE). We identified a novel de novo missense variant in GABRA2 in a patient with EIEE and performed protein structural analysis of the seven variants. Methods: The novel variant was identified by trio whole-genome sequencing. We performed protein structural analysis of the seven variants, and compared them to previously reported pathogenic mutations at equivalent positions in other Cys-loop receptors. Additionally, we studied the distribution of disease-associated variants in the transmembrane helices of these proteins. Results: The seven variants are in the transmembrane domain, either close to the desensitization gate, the activation gate, or in inter-subunit interfaces. Six of them have pathogenic mutations at equivalent positions in other Cys-loop receptors, emphasizing the importance of these residues. Also, pathogenic mutations are more common in the pore-lining helix, consistent with this region being highly constrained for variation in control populations. Conclusion: Our study reports a novel pathogenic variant in GABRA2, characterizes the regions where pathogenic mutations are in the transmembrane helices, and underscores the value of considering sequence, evolutionary, and structural information as a strategy for variant interpretation of novel missense mutations.engChildEpilepsyFemaleHumansLanguage DisordersMolecular Dynamics SimulationProtein DomainsProtein MultimerizationReceptors, GABA-AStereotyped BehaviorIon Channel GatingMutation, MissenseHDE NEU PEdjournal article10.1002/mgg3.1106