Clinical and molecular analysis of epilepsy-related genes in patients with Dravet syndrome

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.

Figure 1

The schematic topology of the α-subunit of the sodium channel and the distribution of variants identified in our study. The α-subunit is composed of 4 homologous domains (DI–DIV) of 6 transmembrane segments each (S1–S6). S4 is the voltage zone. S5, S6, and the ring between them is the gate zone. Seven missense mutations were denoted by red triangles (p.L373W, p.A905D, p.F945L, p.F995L, p.D1443V, p.E1445K, and p.P1526L), 2 splice site mutations were indicated by green rectangles (c.2332-1G>C and c.1029-3C>A), and 2 frameshift mutations were in deep blue ellipses (p.l1412fs and p.V1026fs).

Figure 2

The SCN1A (c.2714C>A, p.A905D) variant was identified in Family 8. The variant was found in heterozygous state in mother with febrile seizures and 2 brothers with DS. The arrow denotes the position of the variant. DS = Dravet syndrome.

Figure 3

Genetic modifier was identified in Family 3 with SCN1A variant. The SCN1A c.2332-1G>C variant was de novo, and SLC6A8 c.1151-8C>T variant was inherited from his mother in Family 3. The arrow denotes the position of the variant.