Dravet Syndrome-Genetic analysis of SCN1A and PCDH19 mutations for 17 Chinese children

Abstract

BACKGROUND: For Dravet syndrome (DS), 80% had mutation in SCN1A gene, which encoded a voltage-gated sodium channel. Recent study demonstrated that 16% of SCN1A-negative patients had mutations in protocadherin-19 (PCDH19) genes. OBJECTIVES: The present study examined the genetic mutations in Chinese DS children and assesses the relationship between mutation and phenotype. METHODS: DNA of 17 DS in The University of Hong Kong was screened for SCN1A mutation using polymerase chain reaction and direct sequencing. SCN1A-negative female patients were then screened for PCDH19 mutation. RESULTS: For DS, 82% (14/17) had SCN1A mutations- truncating mutations (6), splice site mutations (2) and missense mutations (6). These mutations affected Nav1.1 protein functions by 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 evolution of the disease, 79% (11/14) of DS patients with SCN1A mutations had features which fit into the diagnostic criteria of autism spectrum disorder (ASD). 57% (8/14) had history of vaccination-induced seizures. One of the two female SCN1A-negative patients had PCDH19 mutation. CONCLUSIONS: High percentage of genetic mutations was identified in our Chinese cohort of Dravet Syndrome. Pathogenicity assessment demonstrated that the mutations were linked to the phenotypes of Dravet syndrome. Our detection of high frequency of ASD (79%) and vaccination-induced encephalopathy (57%) in those DS with SCN1A mutation suggested evaluating ASD with epilepsy or vaccination induced encepalopathic children for any relationship between SCN1A mutations.