Key result
Biallelic SCN1A variants were associated with a broad phenotypic spectrum, with 50% of 18 cases diagnosed with Dravet syndrome and 33% with GEFS+.
Case Report (n=18)
Biallelic SCN1A variants present with a broad phenotypic spectrum, ranging from typical Dravet/GEFS+ to developmental delay without febrile seizures.
Homozygous SCN1A variants may produce divergent epilepsy phenotypes; leaves open full genotype-phenotype mapping and counseling implications.
PURPOSE: Pathogenic SCN1A variants most commonly cause autosomal dominant Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+). However, rare homozygous SCN1A variants have also been reported. We report two new cases of homozygous SCN1A variants associated with divergent epilepsy phenotypes. METHODS: We retrospectively reviewed the charts of two unrelated patients with different homozygous SCN1A variants. We also reviewed all published cases of biallelic SCN1A pathogenic variants, focusing on the epilepsy phenotypes. RESULTS: Patient 1 had a homozygous c. 1676T>A, (p. Ile559Asn) variant of uncertain significance, inherited from asymptomatic parents. Patient 1 exhibited early afebrile seizures controlled by first-line anti-seizure medications and no febrile seizures or status epilepticus, as well as profound developmental delay, macrocephaly, and mild dysmorphic features. Patient 2 had a homozygous pathogenic c. 4970G>A, (p. Arg1657His) variant carried by asymptomatic parents. This patient presented with early, recurrent, and prolonged febrile seizures, moderate developmental delay, and motor dysfunction and was diagnosed with Dravet syndrome. We identified 16 further cases from the literature. Including our cases, 9/18 (50 %) were diagnosed with Dravet syndrome and 6/18 (33 %) with GEFS+. The mean age of seizure onset was 7 months (range 3-19 months). Phenotypes ranged from intact neurodevelopment with controlled epilepsy to profound developmental delay and refractory epilepsy. CONCLUSION: These cases highlight and expand the phenotypic spectrum associated with biallelic SCN1A variants. While some patients present typically for Dravet/GEFS+, others may present with developmental delay in the absence of febrile seizures or status epilepticus. Further studies are needed to confirm genotype-phenotype relationships.
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Li et al. (2025) conducted a case report in Biallelic SCN1A variants (n=18). Biallelic SCN1A variants was evaluated on Epilepsy phenotypes. Biallelic SCN1A variants were associated with a broad phenotypic spectrum, with 50% of 18 cases diagnosed with Dravet syndrome and 33% with GEFS+.
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