Pathogenic SCN2A variants are associated with familial and sporadic hemiplegic migraine

Abstract

Abstract Background: Familial hemiplegic migraine is a severe autosomal dominant subtype of migraine with aura characterized by transient motor weakness during attacks. Previously identified genes CACNA1A, ATP1A2, SCN1A and PRRT2 account for less than 20% of cases with hemiplegic migraine referred for genetic diagnosis. Objectives and Methods: To identify a novel gene, we conducted a whole-genome linkage analysis combined with mini-exome sequencing in a four-generation pedigree with hemiplegic migraine. A candidate ion channel gene was analyzed for mutations in six other affected pedigrees comprising at least three available affected members, and in a large panel of unrelated probands with hemiplegic migraine referred for molecular diagnosis, all without mutations in the known genes. The functional consequences of the identified variants were determined. Results: In the discovery pedigree, we identified a heterozygous missense mutation (c.4438A>G, p.Lys1480Glu) in the neuronal voltage-gated sodium channel gene SCN2A, which cosegregated with the hemiplegic migraine phenotype. We detected another mutation (c.769T>A, p.Phe257Ile) cosegregating with hemiplegic migraine in a second family, in which two members also had infantile seizures. A third variant (c.3955C>G, p.Arg1319Gly) was found in a sporadic hemiplegic migraine case. All three SCN2A variants were absent in the genome aggregation database gnomAD. Heterologous expression in HEK293T cells coupled with automated patch clamp recording demonstrated abnormal voltage-dependent and kinetic properties of all three SCN2A variants. Conclusions:Dysfunction of the neuronal sodium channel SCN2A can be associated with familial and sporadic hemiplegic migraine. Our finding expands the genetic landscape for migraine and contributes to the diverse genotype-phenotype spectrum associated with SCN2A.