A novel variant in GABRB2 associated with intellectual disability and epilepsy

Abstract

The γ-aminobutyric acid type A (GABAA) 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, GABRA6, GABRB1, GABRB3, GABRG1, GABRG2, GABRG3, and GABRD) 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 β2 subunit of the GABAA 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. Our findings underscore the need for further investigation into the mechanisms by which mutations in GABRB2 contribute to neurological and developmental dysfunction.

A panel of four genes accurately differentiates benign from malignant thyroid nodules

“…This gene was found to be related to mental diseases, like schizophrenia [33, 34]. A recent study revealed that GABRB2 is highly upregulated in thyroid cancer [35].…”

Novel genetic causes for cerebral visual impairment

“…One de novo GABRB2 variant, in the N-terminal extracellular domain implicated in GABA-binding, has been reported in a patient with ID and febrile seizures, tonic clonic convulsions, and partial seizures. 68 Variants in other genes encoding GABA type A-receptor subunits have been identified in different epilepsy syndromes, making GABRB2 a likely explanation for the phenotype in our patient.…”

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

“…Sequence variants of unknown significance in GABRB2 could possibly contribute to intellectual disability and epilepsy (Srivastava et al, 2014). An association with autism has been reported for SNPs in GABRA4 and an association with generalized epilepsy has been suggested for GABRA6 (Ma et al, Prasad et al, 2014).…”