<i>SCN2A</i> variants are associated with familial and sporadic hemiplegic migraine

Familial hemiplegic migraine (FHM) is a severe autosomal dominant subtype of migraine with aura, characterized by transient motor weakness during attacks. Known genes (CACNA1A, ATP1A2, SCN1A, PRRT2) account for fewer than 20% of genetically diagnosed cases. To identify novel genetic contributors to FHM, we performed whole-genome linkage analysis and partial exome sequencing in a four-generation pedigree. A candidate ion channel gene (SCN2A) was subsequently screened in six additional pedigrees with multiple affected members and in a cohort of 594 unrelated probands with familial or sporadic hemiplegic migraine without mutations in known FHM genes. Functional consequences of identified variants were assessed using heterologous expression and automated patch clamp recording. The neurophysiological impact of SCN2A dysfunction was investigated using computational neuron models. We identified a heterozygous missense mutation (c.4438A>G, p.Lys1480Glu) in SCN2A, encoding the neuronal voltage-gated sodium channel NaV1.2, which co-segregated with the FHM phenotype. Additional SCN2A variants (c.769T>A, p.Phe257Ile, and c.3955C>G, p.Arg1319Gly) were found in a second family and a sporadic case, respectively. All variants were absent from the gnomAD database. All ten individuals carrying a SCN2A variant experienced typical hemiplegic migraine attacks beginning in childhood. Two children heterozygous for p.Phe257Ile also had self-limited infantile seizures during the first year of life. None of the affected individuals exhibited permanent cerebellar ataxia, intellectual disability, or recurrent febrile coma. Functional studies revealed altered voltage-dependent and kinetic properties in all three variants that elicited abnormal action potential firing in a computer model of a neuron, supporting their pathogenicity. These findings implicate SCN2A dysfunction in both familial and sporadic hemiplegic migraine, expanding the genetic landscape of migraine and the phenotypic spectrum associated with SCN2A variants.