Biallelic SCN1A variants with divergent epilepsy phenotypes.

Area of Science:

• Genetics
• Neurology
• Epilepsy

Background:

• Pathogenic SCN1A variants are typically linked to autosomal dominant epilepsy syndromes like Dravet syndrome and GEFS+.
• Homozygous SCN1A variants are rare but have been reported, suggesting a potential for different clinical presentations.

Purpose of the Study:

• To report two new cases of homozygous SCN1A variants with distinct epilepsy phenotypes.
• To expand the understanding of the phenotypic spectrum associated with biallelic SCN1A variants.

Main Methods:

• Retrospective review of two unrelated patients with different homozygous SCN1A variants.
• Literature review of all published cases of biallelic SCN1A pathogenic variants, focusing on epilepsy phenotypes.

Main Results:

• Patient 1: Homozygous c.1676T>A (p.Ile559Asn) variant, early afebrile seizures, profound developmental delay, macrocephaly.
• Patient 2: Homozygous c.4970G>A (p.Arg1657His) variant, early prolonged febrile seizures, moderate developmental delay, diagnosed with Dravet syndrome.
• Combined analysis of 18 cases: 50% Dravet syndrome, 33% GEFS+, with phenotypes ranging from controlled epilepsy to refractory epilepsy and developmental delay.

Conclusions:

• Biallelic SCN1A variants present a wider phenotypic spectrum than previously recognized.
• Some patients exhibit typical Dravet/GEFS+ features, while others present with developmental delay without febrile seizures or status epilepticus.
• Further research is needed to establish definitive genotype-phenotype correlations for SCN1A variants.