Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/106389
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Type: Journal article
Title: Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy
Author: Bagnall, R.
Crompton, D.
Petrovski, S.
Lam, L.
Cutmore, C.
Garry, S.
Sadleir, L.
Dibbens, L.
Cairns, A.
Kivity, S.
Afawi, Z.
Regan, B.
Duflou, J.
Berkovic, S.
Scheffer, I.
Semsarian, C.
Citation: Annals of Neurology, 2016; 79(4):522-534
Publisher: John Wiley & Sons
Issue Date: 2016
ISSN: 0364-5134
1531-8249
Statement of
Responsibility: 
Richard D. Bagnall, Douglas E. Crompton, Slav, e Petrovski, Lien Lam, Carina Cutmore, Sarah I. Garry, Lynette G. Sadleir, Leanne M. Dibbens, Anita Cairns, Sara Kivity, Zaid Afawi, Brigid M. Regan, Johan Duflou, Samuel F. Berkovic, Ingrid E. Scheffer, and Christopher Semsarian
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.
Keywords: Respiration Disorders
Description: Accepted for publication Dec 20, 2015
Rights: © 2016 American Neurological Association
RMID: 0030041535
DOI: 10.1002/ana.24596
Grant ID: http://purl.org/au-research/grants/nhmrc/1059156
http://purl.org/au-research/grants/nhmrc/1006110
http://purl.org/au-research/grants/nhmrc/1046441
http://purl.org/au-research/grants/nhmrc/628952
Appears in Collections:Molecular and Biomedical Science publications

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