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Title: Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy
Austin Authors: Bagnall, Richard D;Crompton, Douglas E;Petrovski, Slavé;Lam, Lien;Cutmore, Carina;Garry, Sarah I;Sadleir, Lynette G;Dibbens, Leanne M;Cairns, Anita;Kivity, Sara;Afawi, Zaid;Regan, Brigid M;Duflou, Johan;Berkovic, Samuel F ;Scheffer, Ingrid E ;Semsarian, Christopher
Affiliation: Agnes Ginges Center for Molecular Cardiology, Centenary Institute, Sydney, NSW, Australia
Sydney Medical School, The University of Sydney, Camperdown, NSW, Australia
Neurology Department, Northern Health, Melbourne, Victoria, Australia
Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Institute for Genomic Medicine, Columbia University, New York, NY, USA
Department of Pediatrics and Child Health, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
Neurosciences Department, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia
Epilepsy Unit, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel
Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
Department of Forensic Medicine, Sydney, NSW, Australia
Department of Neurology, The Royal Children's Hospital, Parkville, Victoria, Australia
Florey Institute of Neurosciences and Mental Health, Melbourne, Victoria, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
Issue Date: Apr-2016
Date: 2016-02-02
Publication information: Annals of Neurology 2016; 79(4): 522-534
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. INTERPRETATION: 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.
DOI: 10.1002/ana.24596
ORCID: 0000-0002-1121-9513
Journal: Annals of Neurology
PubMed URL:
Type: Journal Article
Subjects: Arrhythmias, Cardiac
Death, Sudden
Respiration Disorders
Appears in Collections:Journal articles

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