CACNA1A variants may modify the epileptic phenotype of Dravet syndrome

Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Nav1.1 neuronal voltage-gated sodium channel, are considered the major cause of Dravet syndrome. In this study, we investigated genetic modifiers of this syndrome.We performed a mutational analysis of all coding exons of CACNA1A in 48 subjects with Dravet syndrome. To assess the effects of CACNA1A variants on the epileptic phenotypes of Dravet syndrome, we compared clinical features in two genotype groups: 1) subjects harboring SCN1A mutations but no CACNA1A variants (n = 20) and 2) subjects with SCN1A mutations plus CACNA1A variants (n = 20). CACNA1A variants detected in patients were studied using heterologous expression of recombinant human Cav2.1 in HEK 293 cells and whole-cell patch-clamp recording.Nine CACNA1A variants, including six novel ones, were detected in 21 of the 48 subjects (43.8%). Based on the incidence of variants in healthy controls, most of the variants seemed to be common polymorphisms. However, the subjects harboring SCN1A mutations and CACNA1A variants had absence seizures more frequently than the patients with only SCN1A mutations (8/20 vs. 0/20, p = 0.002). Moreover, the former group of subjects exhibited earlier onset of seizures and more frequent prolonged seizures before one year of age, compared to the latter group of subjects. The electrophysiological properties of four of the five novel Cav2.1 variants exhibited biophysical changes consistent with gain-of-function. We conclude that CACNA1A variants in some persons with Dravet syndrome may modify the epileptic phenotypes.

► We performed a mutational analysis of CACNA1A in 48 patients with Dravet syndrome. ► Nine variants including 6 novel variants were detected in 21 patients (43.8%). ► The patients having SCN1A and CACNA1A variants showed more severe seizure phenotypes. ► The biophysical properties of 4 novel Cav2.1 variants exhibited gain-of-function. ► CACNA1A variants could be potential genetic modifiers in Dravet syndrome.