Phenotypic variation in a family with GABRG2-related epilepsy caused by a novel missense variant.

Purpose: The gamma-aminobutyric acid type A receptor subunit gamma-2 (GABRG2) gene is a well-known causative gene for genetic epilepsy with febrile seizures plus (GEFS+), exhibiting a broad phenotypic spectrum. This study aimed to describe the clinical variability among family members with a novel GABRG2 variant.

Methods: We analyzed the clinical and genetic findings of three sisters and their father. Genetic testing using whole-exome sequencing was performed for patients 1 and 2 and their parents. Patient 3 was not genetically tested but is clinically suspected to have the same condition.

Results: A novel heterozygous missense variant in GABRG2 (c.964G>A; p.Ala322Thr) was identified in patient 1, patient 2, and their father. Patient 1 developed drug-resistant epilepsy requiring multiple anti-seizure medications (ASMs). Patient 2 exhibited milder epilepsy, controlled with a single ASM. Patient 3 has remained seizure-free under low-dose ASM. The father had febrile and afebrile seizures in childhood but has been seizure-free for over 10 years with ASMs. This intrafamilial phenotypic variability was observed despite all affected individuals carrying the same variant.

Conclusion: This report highlights the wide phenotypic spectrum of GABRG2-related epilepsy within a single family. Although the identified variant is located in the M2 segment of GABRG2, which is functionally important, the clinical presentations varied substantially. These findings suggest that additional genetic, structural, or epigenetic modifiers may contribute to the phenotypic heterogeneity in GABRG2-associated epilepsy, and underscore the limitations of genotype-based phenotype prediction.