Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

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• 作者：Monica Coll ; Catarina Allegue ; Sara Partemi…
• 关键词：SUDEP ; Epilepsy ; Sudden cardiac death ; Next ; generation sequencing
• 刊名：International Journal of Legal Medicine
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：130
• 期：2
• 页码：331-339
• 全文大小：529 KB
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• 作者单位：Monica Coll (1)
  Catarina Allegue (1)
  Sara Partemi (4)
  Jesus Mates (1)
  Bernat Del Olmo (1)
  Oscar Campuzano (1) (2)
  Vincenzo Pascali (4)
  Anna Iglesias (1)
  Pasquale Striano (5)
  Antonio Oliva (4)
  Ramon Brugada (1) (2) (3)
  
  1. Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain
  4. Institute of Public Health, Section of Legal Medicine, Catholic University, Largo F. Vito 1, 00168, Rome, Italy
  2. Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain
  5. Pediatric Neurology and Neuromuscular Diseases Unit, Department of Neurosciences, Instituto G. Gaslini, University of Genova, Genoa, Italy
  3. Cardiac Genetics Unit, Cardiology Service, Hospital Josep Trueta, Girona, Spain
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Forensic Medicine
  Medical Law
  Medicine/Public Health, general
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1437-1596

文摘

Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy.