Dravet syndrome - genetic analysis of SCN1A and PCDH19 mutations for 17 Chinese children

Abstract

OBJECTIVE: In Dravet syndrome (DS), 80% of patients will have a mutation in the SCN1A gene, which encodes a voltage-gated sodium channel. A recent study demonstrated that 16%of SCN1A-negative patients had mutations in the protocadherin-19 (PCDH19) gene. The present study examines the genetic mutations in Chinese DS children and assesses the relationship between mutation and phenotype. DESIGN: Prospective cohort study. METHOD: DNA of 17 DS children seen at The University of Hong Kong was screened for SCN1A mutations using polymerase chain reaction and direct sequencing. SCN1Anegative female patients were then screened for PCDH19 mutation. RESULTS: For DS cases, 82% (14/17) had SCN1A mutations that included truncating mutations (6), splice site mutations (2) and missense mutations (6). These mutations affected Nav1.1 protein function on pathogenicity assessments including conservative, SIFT and Align-GVGD analyses. We found a relationship between the type of mutation and the degree of intellectual disability (P<0.05), with truncating/splice site mutations associated with moderate/severe mental retardation. At the onset of the disease, 79% (11/14) of DS patients with SCN1A mutations had features consistent with a diagnosis of autism spectrum disorder (ASD). Fifty-seven percent (8/14) had a history of vaccination-induced seizures. One of the two female SCN1A-negative patients had PCDH19 mutation. CONCLUSION: A high percentage of genetic mutations were identified in our Chinese cohort with DS. Pathogenicity assessments demonstrated that the mutations were linked to the phenotypes of DS. Our detection of a high frequency of ASD (79%) and vaccination-induced encephalopathy (57%) in those DS with SCN1A mutation suggests that patients with ASD with epilepsy or with vaccination-induced encephalopathy should be investigated for SCN1A mutations.