GABRG1 variant as a potential novel cause of epileptic encephalopathy, hypotonia, and global developmental delay

Epileptic encephalopathies (EEs) are severe brain disorders with excessive ictal (seizure) and interictal (electrographic epileptiform discharges) activity in developing brain which may result in progressive cognitive and neuropsychological deterioration. In contrast to regular epilepsy where the treatment goal is to prevent the seizure (ictal) recurrence, in patients with EE the goal is to treat both ictal as well as interictal activity to prevent further progression. With the introduction of genetic sequencing technologies over the past 20 years, there is growing recognition of the genetic basis of EE, with the majority due to monogenic causes. Monogenic etiologies of EE include pathogenic variants in the gamma-aminobutyric acid type A receptor (GABA-A) encoding gene family. We present a 2-year-old patient with EE, hypotonia, and global developmental delays. Clinical trio exome sequencing showed a novel, de novo variant in GABRG1. GABRG1 encodes the gamma 1 subunit of the GABA-A receptor. To date, there has not been an association of EE with pathogenic variants in GABRG1. This variant is predicted to be damaging to protein structure and function, and the patient's phenotype is similar to those with pathogenic variants in other members of the GABA-A receptor encoding gene family.