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The γ-aminobutyric acid type A (GABA_A) receptor is one of the three main classes of receptors activated by GABA, the principal inhibitory neurotransmitter in the central nervous system. Mutations in genes encoding various subunits of this receptor (GABRA1, GABRA2, GABRA4, GABRA5, GABRB1, GABRB3, GABRD, GABRG1, GABRG2, and GABRG3) are implicated in a number of neurological and developmental disorders, including epilepsy and autism. To date, no human genetics studies have implicated mutations in GABRB2, encoding the ß2 subunit of the GABA_A receptor, with neurodevelopmental disorders. Here we present a 12 year old girl with intellectual disability and epilepsy, who was discovered by whole exome sequencing to have a de novo heterozygous missense variant in exon 4 of GABRB2 (c.236T>C; p.M79T). This variant is likely pathogenic, based on in silico analyses as well as the fact that it results in the non-conservative substitution of a non-polar amino acid with a polar amino acid at a position that is evolutionarily conserved across multiple species. Moreover, there is compelling evidence from structural comparisons between human GABRB2 and the C. elegans glutamate-gated chloride channel GluClα that the M79 residue may play a role in ligand binding. Our findings underscore the need for further investigation into the mechanisms by which mutations in GABRB2 contribute to neurological and developmental dysfunction.

Epilepsy; intellectual disability; GABRB2; GABAA receptor