Seizure 2025 Sep 13;131:378-381. doi: 10.1016/j.seizure.2025.08.010.

A new loss-of-function variant in SCN1A is associated with early-onset complex febrile seizures.

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OBJECTIVES: Pathogenic variants in the SCN1A gene are among the most common genetic causes of epilepsy and are predominantly linked to Generalized Epilepsy with Febrile Seizures Plus (GEFS+) or Dravet syndrome. We present a new variant in SCN1A in a child with treatment-resistant early-onset febrile seizures. METHODS: We performed genetic analysis in a child presenting with recurrent febrile seizures. Electrophysiological characterization of the identified variant was performed in Xenopus laevis oocytes and HEK293T cells. RESULTS: The child presented with complex febrile seizures at age 5 months, but by age 17 months the symptoms indicated an SCN1A-related epilepsy. Genetic analyses revealed a de novo missense variant in SCN1A (NM_001165963.1): c.998C>T, p.(Ala333Val) classified as a variant of uncertain significance. The variant was absent from ∼800 000 individuals in the gnomAD database and is not reported in clinical databases. Compared to wildtype, NaV1.1A333V channel activation and channel availability shifted to depolarized potentials. Na+ influx was substantially reduced for NaV1.1A333V, indicative of loss-of-function. SIGNIFICANCE: We identified a NaV1.1A333V variant in a patient with recurrent complex febrile seizures, and functional characterization suggests a loss-of-function phenotype. Functional characterization of SCN1A missense variants may provide personalized diagnostic information in individuals with epilepsy, and improve treatment.

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Species referenced: Xenopus laevis

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