LAUSR

Abstract Dravet syndrome is considered to be one of the most severe types of genetic epilepsy. Mutations in SCN1A gene have been found to be responsible for at least 80% of patients with Dravet syndrome, and 90% of these mutations arise de novo. The variable clinical phenotype is commonly observed among these patients with SCN1A mutations, suggesting that genetic modifiers may influence the phenotypic expression of Dravet syndrome. In the present study, we described the clinical, pathological, and molecular characteristics of 13 Han Chinese pedigrees clinically diagnosed with Dravet syndrome. By targeted-exome sequencing, bioinformatics analysis and Sanger sequencing verification, 11 variants were identified in SCN1A gene among 11 pedigrees including 7 missense mutations, 2 splice site mutations, and 2 frameshift mutations (9 novel variants and 2 reported mutations). Particularly, 2 of these Dravet syndrome patients with SCN1A variants also harbored SCN9A, KCNQ2, or SLC6A8 variants. In addition, 2 subjects were failed to detect any pathogenic mutations in SCN1A and other epilepsy-related genes. These data suggested that SCN1A variants account for about 84.6% of Dravet syndrome in our cohort. This study expanded the mutational spectrum for the SCN1A gene, and also provided clinical and genetic evidence for the hypothesis that genetic modifiers may contribute to the variable manifestation of Dravet syndrome patients with SCN1A mutations. Thus, targeted-exome sequencing will make it possible to detect the interactions of epilepsy-related genes and reveal their modification on the severity of SCN1A mutation-related Dravet syndrome.