Akiko Shibata1, Mariko Kasai2, Hiroshi Terashima3, Ai Hoshino4, Taku Miyagawa5, Kenjiro Kikuchi6, Atsushi Ishii7, Hiroshi Matsumoto8, Masaya Kubota9, Shinichi Hirose7, Akira Oka10, Masashi Mizuguchi4. 1. Department of Developmental Medical Sciences, School of International Health, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Pediatrics, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: asasano-tky@umin.ac.jp. 2. Department of Developmental Medical Sciences, School of International Health, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Pediatrics, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 3. Department of Pediatrics, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Neurology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. 4. Department of Developmental Medical Sciences, School of International Health, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 5. Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Department of Human Genetics, School of International Health, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 6. Division of Neurology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama-shi, Saitama 330-8777, Japan. 7. Department of Pediatrics, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka-shi, Fukuoka 814-0180, Japan. 8. Department of Pediatrics, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan. 9. Division of Neurology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. 10. Department of Pediatrics, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Abstract
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 × 10-3: SKAT, p value 2.51 × 10-4). The association was more significant when we focused on deleterious variants (WSS, permutated p = 9.00 × 10-4; SKAT, p = 4.99 × 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.
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 × 10-3: SKAT, p value 2.51 × 10-4). The association was more significant when we focused on deleterious variants (WSS, permutated p = 9.00 × 10-4; SKAT, p = 4.99 × 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.
Keywords:
Acute encephalopathy with biphasic seizures and late reduced diffusion; Genetic risk factor; KCNQ2; Rare variant association analysis; SCN1A; Severe febrile seizures