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Epilepsy
Original research
Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy
  1. Yan Ge1,
  2. Ding Ding2,
  3. Guoxing Zhu1,
  4. Patrick Kwan3,
  5. Wenzhi Wang4,
  6. Zhen Hong2,
  7. Josemir W Sander5,6
  1. 1 Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
  2. 2 Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Huashan Hospital, Fudan University, Shanghai, China
  3. 3 Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
  4. 4 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
  5. 5 NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
  6. 6 Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands
  1. Correspondence to Dr Ding Ding, Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Huashan Hospital, Fudan University, Shanghai 200040, China; dingding{at}huashan.org.cn

Abstract

Objective Sudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy-related mortality in young adults. It has been suggested that SUDEP may kill over 20 000 people with epilepsy in China yearly. The aetiology of SUDEP is unclear. Little is known about candidate genes for SUDEP in people of Chinese origin as most studies have ascertained this in Caucasians. No candidate genes for SUDEP in Chinese people have been identified.

Methods We performed whole exome sequencing (WES) in DNA samples collected from five incident cases of SUDEP identified in a large epilepsy cohort in rural China. We filtered rare variants identified from these cases as well as screened for SUDEP, epilepsy, heart disease or respiratory disease-related genes from previous published reports and compared them with publicly available data, living epilepsy controls and ethnicity-match non-epilepsy controls, to identify potential candidate genes for SUDEP.

Results After the filtering process, the five cases carried 168 qualified mutations in 167 genes. Among these genetic anomalies, we identified rare variants in SCN5A (1/5:20% in our cases), KIF6 (1/5:20% in our cases) and TBX18 (1/5:20% in our cases) which were absent in 330 living epilepsy control alleles from the same original cohort and 320 ethnicity-match non-epilepsy control alleles.

Conclusions These three genes were previously related to heart disease, providing support to the hypothesis that underlying heart disorder may be a driver of SUDEP risk.

https://doi.org/10.1136/jnnp-2019-321983

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    Footnotes

    • Contributors YG contributed with concept and design, analysis and interpretation of data, drafting of the manuscript, revision of the manuscript and critical revision of the manuscript for important intellectual content. DD contributed with DNA sample collection, obtaining the necessary research grants, concept and design, drafting of the manuscript, revision of the manuscript and critical revision of the manuscript for important intellectual content and study supervisor. GZ contributed with DNA sample collection, interpretation of data and revision of manuscript. PK contributed with DNA sample collection, interpretation of data and critical revision of the manuscript for important intellectual content. WW contributed with DNA sample collection, interpretation of data and revision of manuscript. ZH contributed with concept and design, study supervising, drafting of the manuscript, revision of the manuscript and critical revision of the manuscript for important intellectual content. JWS contributed with DNA sample collection, obtaining the necessary research grants, concept and design, drafting of the manuscript, revision of the manuscript and critical revision of the manuscript for important intellectual content.

    • Funding This study was funded by Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), Key Research Project of the Chinese Ministry of Science and Technology (2016YFC0904400), a NIH/NINDS grant (1R21NS069223-01) and National Natural Science Foundation of China (81271443). JWS is based at UCLH/UCL Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health's NIHR Research Centres funding scheme. He receives support from the Dr. Marvin Weil Epilepsy Research Fund and UK Epilepsy Society. PK is supported by a Medical Research Future Fund Practitioner Fellowship.

    • Competing interests JWS has received research funding from Eisai, and UCB, research support and personal fees from UCB, GW and Zogenix outside the submitted work. All other authors have no disclosures to report.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available on reasonable request.