Expanding the GEFS+ Spectrum: Functional Characterization Of A SCN1B Variant
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Epilepsy is the most common chronic pediatric neurologic disorder. Pathogenic variants in SCN1B , encoding the β1 subunit of voltage-gated Na + channels are associated with a spectrum of epileptic syndromes, including generalized epilepsy with febrile seizures plus (GEFS+). Here, we report a boy presenting with early-onset epilepsy, ataxia and language delay harboring the heterozygous SCN1B c.38T > C (p.Leu13Pro) variant. Segregation analysis across three generations revealed multiple affected carrier relatives in a pattern consistent with autosomal dominant inheritance with variable expressivity. The variant was absent from gnomAD and predicted to be deleterious by most in silico tools. Functional studies in Xenopus laevis oocytes and CHO-K1 cells demonstrated consistent deleterious effects on Nav1.1, Nav1.2, and Nav1.6 channels, including depolarizing shifts in activation, impaired recovery from inactivation, and reduced current density. Considering ACMG classification with our segregation, computational, and functional data, this variant meets criteria for classification as pathogenic. Our results also emphasize the importance of α–β subunit interaction in sodium channel function and its disruption as a potential pathogenic mechanism in epilepsy. Our findings expand the mutational and phenotypic spectrum of GEFS + and highlight the clinical importance of resolving variants of uncertain significance (VUS), which remain a major challenge in pediatric epilepsy genetics.
