Case-control association study of rare nonsynonymous variants of SCN1A and KCNQ2 in acute encephalopathy with biphasic seizures and late reduced diffusion

Purpose: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by prolonged febrile seizures at onset and subsequent damage to the cerebral cortex of infants and children. The pathogenesis is suspected to be excitotoxicity leading to neuronal death. SCN1A and KCNQ2 are causative genes of genetic epilepsy including Dravet syndrome and Ohtahara syndrome. Here we conducted a case-control rare-variant association study of the two genes in AESD. Methods: The coding regions of SCN1A and KCNQ2 were sequenced by the Sanger method for 175 and 111 patients, respectively, with AESD. As control subjects, we used genetic data from 3554 subjects provided by the Integrative Japanese Genome Variation Database (iJGVD). Then we performed a case-control association study of rare missense and splice region variants (minor allele frequency < 0.005) of each gene with AESD using Weighted Sum Statistics (WSS) and Sequence Kernel Association Test (SKAT). Results: SCN1A rare variants had a significant association with AESD after correction for multiple tests (WSS, permutated p value 4.00 x 10(-3): SKAT, p value 2.51 x 10(-4)). The association was more significant when we focused on deleterious variants (WSS, permutated p = 9.00 x 10(-4); SKAT, p = 4.99 x 10(-5)). Although KCNQ2 rare nonsynonymous variants tended to be more frequent in patients than in controls, there was no significant difference. Conclusion: Our study provided statistical evidence of an association between SCN1A and AESD for the first time, and established SCN1A as one of the susceptibility genes for AESD.