Dravet syndrome is an intractable epileptic syndrome beginning in the first year 
of life. De novo mutations of SCN1A, which encode the Na(v)1.1 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 Ca(v)2.1 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 
Ca(v)2.1 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.