Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype

Abstract

Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.316 G > A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.

Keywords: Epilepsy; GABRG2; genetics; missense; phenotype; seizures.

Figure 1:. Representative EEGs

Patient 1 - Seizure with head drop and behavioral arrest at 5 years old, generalized spikes followed by relative voltage attenuation, fast generalized spike-wave complexes. Patient 2 - Runs of spike and slow wave at 1 Hz. EEG obtained at 10 years old. Patient 3 - Sleep epileptiform discharges at 6 years old. High amplitude spike and polyspike discharges with prominence in the temporal-occipital regions bilaterally (T5-O1, T6-O2). Patient 4 - Bilateral peak waves in the frontal areas. EEG obtained at 12 years old. Patient 5 - Stage II sleep with symmetrical sleep spindles at 4 months old. Excess beta range activity and frequent bifrontal, synchronous spike and wave discharges.