Abstracts

Rationale: Dravet syndrome (DS) is an epileptic encephalopathy of infantile onset caused by SCN1A mutations or microdeletions. The SCN1A gene test is of great value in diagnosing DS. However, we sometimes encounter cases in which the pathogenicity of a variant cannot be assessed because parental samples are not available, and/or the variant has not been associated with DS previously. SCN1A variants are also found in populations without any seizure history. Here we show the location characteristics of pathogenic SCN1A variants which are found in 285 Japanese DS patients and compare them with non-pathogenic variants in a large public database. Methods: SCN1A variants in DS patients were identified by PCR-Sanger sequencing, gene panel sequencing or multiplex ligation-dependent probe amplification (MLPA). The Exome Aggregation Consortium (ExAC) database with 2,264 variant in more than 60,000 "control" samples was used as source of non-pathogenic variants. We compared the distributions of truncating mutations and missense mutations of the DS patients with those in the ExAC database. Results: The ExAC database had no truncating variants. There is an increased frequency of truncating (but not missense) mutations in the non-coding C-terminus. Unlike truncation mutations, missense mutations showed a clustering pattern at a higher density in the S4 voltage sensor and pore loops. Missense variants are found at a lower density in the domain I-II and II-III linkers and the first three segments of domain II. There is no such pattern in non-pathogenic variants. Conclusions: We found significant differences in variant distributions between truncating mutations, missense mutations and non-pathogenic variants across the SCN1A sequence. These specific localization patters of pathogenic mutations should help to determine the pathogenicity of SCN1A variants. Funding: Research reported in this abstract was supported by a Dravet Syndrome Foundation grant to MFH and SH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Dravet Syndrome Foundation. This work was also supported by a Grant-in-Aid for Young Scientists (B) (23791201) (A.I.), Grant-in-Aid for Scientific Research (A) (24249060 and 151402548)(S.H.), Grant-in-Aid for Challenging Exploratory Research (25670481) (S.H.), Bilateral Joint Research Projects (S.H.) from Japan Society for the Promotion of Science (JSPS), Grants for Scientific Research on Innovative Areas (221S0002 and 25129708) (A.I and S.H.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), MEXT-supported Program for the Strategic Research Foundation at Private Universities 2013-2017 (S.H.), A grant for Practical Research Project for Rare/Intractable Diseases (15ek0109038a) from Japan Agency for Medical Research and development (AMED), Grant-in-aid for the Research on Measures for Intractable Diseases (H26-Nanji-Ippan-051 and 049) (S.H.) from the Ministry of Health, Labor and Welfare, Intramural Research Grant (24-7 and 27-5) for Neurological and Psychiatric Disorders of NCNP (S.H.), the Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University (S.H.), Grants from The Mitsubishi Foundation (S.H.) and Takeda Scientific Foundation (S.H.), the Kobayashi Magobei Foundation (A.I.), and the Kurozumi medical foundation (A.I.), and the Japan Epilepsy Research Foundation Grant (A.I.).