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

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, Na_V1.1^A333V channel activation and channel availability shifted to depolarized potentials. Na⁺ influx was substantially reduced for Na_V1.1^A333V, indicative of loss-of-function.

Significance

We identified a Na_V1.1^A333V 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.