title: Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.
abstract: OBJECTIVE
  The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants.
  
  
  METHODS
  Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools.
  
  
  RESULTS
  The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide.
  
  
  CONCLUSIONS
  A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.
authors.affiliation: Agnes Ginges Center for Molecular Cardiology, Centenary Institute, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bagnall
authors.affiliation: Neurology Department, Northern Health, Melbourne, Australia.|Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Crompton
authors.affiliation: Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.|Institute for Genomic Medicine, Columbia University, New York, NY.
authors.forename: Slavé
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: Agnes Ginges Center for Molecular Cardiology, Centenary Institute, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Lien
authors.initials: L
authors.lastname: Lam
authors.affiliation: Agnes Ginges Center for Molecular Cardiology, Centenary Institute, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Carina
authors.initials: C
authors.lastname: Cutmore
authors.affiliation: Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
authors.forename: Sarah I
authors.initials: SI
authors.lastname: Garry
authors.affiliation: Department of Pediatrics and Child Health, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
authors.forename: Lynette G
authors.initials: LG
authors.lastname: Sadleir
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.affiliation: Neurosciences Department, Lady Cilento Children's Hospital, Brisbane, Australia.
authors.forename: Anita
authors.initials: A
authors.lastname: Cairns
authors.affiliation: Epilepsy Unit, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.affiliation: Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
authors.forename: Brigid M
authors.initials: BM
authors.lastname: Regan
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, Australia.|Department of Forensic Medicine, Sydney, Australia.
authors.forename: Johan
authors.initials: J
authors.lastname: Duflou
authors.affiliation: Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.|Department of Neurology, The Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia.|Florey Institute of Neurosciences and Mental Health, Melbourne, Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Agnes Ginges Center for Molecular Cardiology, Centenary Institute, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.|Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003645:Death, Sudden / Q000209:etiology*; D004827:Epilepsy / Q000235:genetics*; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012120:Respiration Disorders / Q000235:genetics*; D055815:Young Adult