Abstract:

Objective To investigate the phenotypic impact of dual variations in GABRG2 and SCN1A on genetic epilepsy with febrile seizures plus (GEFS+). Methods The clinical data of a 3-year-old girl and her three generations of family members who visited the Pediatric Internal Medicine Department due to "repeated convulsions" in May 2023 were collected. The genetic variations of this family were verified by whole exome sequencing (WES) and Sanger sequencing, and the genotype-phenotypic association was analyzed in combination with the literature. Results Among the 6 members of this family, 3 patients with SCN1A (c.5621G>A) mutations presented with febrile seizures (FS) or late-onset antiseizure medication-responsive epilepsy. Two individuals with isolated GABRG2 mutations presented with FS or incomplete penetrance. The proband, carrying dual mutations, manifested early-onset refractory epilepsy and status epilepticus. Two patients with the same single variant reported in the literature also showed FS. Protein interaction analysis revealed co-expression and functional synergy between SCN1A and GABRG2 in regulating neuronal excitability. Conclusions Dual mutations in SCN1A and GABRG2 may exacerbate epilepsy phenotypes through additive functional effects and genetic modifying mechanisms. Clinicians should be vigilant for synergistic interactions of dual variations in families with heterogeneous phenotypes, and timely genetic testing is critical to guide precision therapy and genetic counseling.

Key words: GEFS+, genotype-phenotype correlation, GABRG2 gene, SCN1A gene, dual gene variations