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Dev Med Child Neurol. 2016 Apr;58(4):416-20. doi: 10.1111/dmcn.12976. Epub 2015 Dec 9.

GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy.

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Genetics and Genomics Medicine Unit, UCL Institute of Child Health, London, UK.
Department of Neurology, Great Ormond Street Hospital, London, UK.
Developmental Neurosciences Programme, UCL Institute of Child Health, London, UK.
Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge, UK.


The gamma-aminobutyric acid type A receptor β3 gene (GABRB3) encodes the β3-subunit of the gamma-aminobutyric acid type A (GABAA ) receptor, which mediates inhibitory signalling within the central nervous system. Recently, GABRB3 mutations have been identified in a few patients with infantile spasms and Lennox-Gastaut syndrome. We report the clinical and electrographic features of a novel case of GABRB3-related early-onset epileptic encephalopathy. Our patient presented with neonatal hypotonia and feeding difficulties, then developed pharmacoresistant epileptic encephalopathy, characterized by multiple seizure types from 3 months of age. Electroencephalography demonstrated ictal generalized and interictal multifocal epileptiform abnormalities. Using a SureSelectXT custom multiple gene panel covering 48 early infantile epileptic encephalopathy/developmental delay genes, a novel de novo GABRB3 heterozygous missense mutation, c.860C>T (p.Thr287Ile), was identified and confirmed on Sanger sequencing. GABRB3 is an emerging cause of early-onset epilepsy. Novel genetic technologies, such as whole-exome/genome sequencing and multiple gene panels, will undoubtedly identify further cases, allowing more detailed electroclinical delineation of the GABRB3-related genotypic and phenotypic spectra.

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