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

I E Christophersen; J De Waele; Aaberg Km; Henning S; P H Backe; M A Kulseth; I L Mero; F Bosmans

doi:10.1016/j.seizure.2025.08.010

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

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

Authors

I E Christophersen¹, J De Waele², Aaberg Km³, Henning S⁴, P H Backe⁵, M A Kulseth⁶, I L Mero⁷, F Bosmans⁸

Affiliations

¹ Department of medical genetics, Oslo University Hospital, Oslo, Norway; Department of medical research, Bærum hospital, Vestre Viken Hospital Trust, Gjettum, Norway. Electronic address: ingrid.elisabeth.christophersen@ous-hf.no.
² Molecular physiology and neurophysics group, Department of Basic and Applied Medical Sciences, University of Ghent, Ghent, Belgium. Electronic address: jandwael.DeWaele@UGent.be.
³ The National Center for Epilepsy (SSE), Oslo University Hospital, G.F. Henriksens vei 23, 1300 Sandvika, Norway. Electronic address: kaaabe@ous-hf.no.
⁴ Department of Children and Adolescents, Drammen Hospital, Vestre Viken Health Trust, Drammen, Norway. Electronic address: susanne.henning@vestreviken.no.
⁵ Department of medical genetics, Oslo University Hospital, Oslo, Norway; Department of Microbiology, Oslo University Hospital, Oslo, Norway; Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: Paul.Hoff.Backe@rr-research.no.
⁶ Department of medical genetics, Oslo University Hospital, Oslo, Norway. Electronic address: makulset@ous-hf.no.
⁷ Department of medical genetics, Oslo University Hospital, Oslo, Norway. Electronic address: inger-lise.mero@ous-hf.no.
⁸ Molecular physiology and neurophysics group, Department of Basic and Applied Medical Sciences, University of Ghent, Ghent, Belgium; Experimental Pharmacology, Department of Pharmaceutical Sciences, Faculty of Medicine and Pharmaceutical Sciences, Vrije Universiteit Brussel, Jette, Belgium. Electronic address: Frank.Bosmans@UGent.be.

PMID: 40834683
DOI: 10.1016/j.seizure.2025.08.010

Abstract

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.

Keywords: Anti-seizure medication; Epilepsy; Febrile seizures; Na(V)1.1; SCN1A.

Publication types

Case Reports

MeSH terms

Animals
HEK293 Cells
Humans
Infant
Loss of Function Mutation* / genetics
Mutation, Missense
NAV1.1 Voltage-Gated Sodium Channel* / genetics
Seizures, Febrile* / genetics
Seizures, Febrile* / physiopathology
Xenopus laevis

Substances

NAV1.1 Voltage-Gated Sodium Channel
SCN1A protein, human