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 (c.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.

Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes

“…The gamma subunit oligomerizes in the endoplasmic reticulum (ER) with the other subunits and is required for postsynaptic GABAa receptor clustering [61,62]. To date, only about twenty mutations associated with different epileptic phenotypes have been described, from mild (FS, Febrile Seizures or CAE, Childhood Absence Epilepsy) to moderate (GEFS +, Generalized Epilepsy with Febrile Seizures +), to severe [61] Dravet syndrome (DS) [63], or early onset encephalopathy phenotype [64,65], but never underlying the RTT phenotype. Clinical heterogeneity may depend primarily on how the mutation interferes with the assembly of the mutant with the other subunits, causing mechanisms of haploinsufficiency or dominant negative suppression [61].…”

Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

“…GABRG2 (gamma-aminobutyric acid receptor, gamma-2): In a cohort of 5 patients harbouring a recurrent c.316G > A; p.A106T pathogenic variant, two had intractable, neonatal-onset epilepsy (not further characterized: one; ictal apnea: one), followed by focal versive, myoclonic and tonic-clonic seizures associated with hypotonia, severe DD, cortical visual impairment, and stereotypies in one [60].…”

Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders

“…The penetrance and the phenotype of variants in the GABRG2 can vary markedly even within the same family. Only recently a more severe epileptic encephalopathy phenotype was described in patients with highly penetrant de novo missense variants [4,6,7].…”