Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/106389
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dc.contributor.authorBagnall, R.en
dc.contributor.authorCrompton, D.en
dc.contributor.authorPetrovski, S.en
dc.contributor.authorLam, L.en
dc.contributor.authorCutmore, C.en
dc.contributor.authorGarry, S.en
dc.contributor.authorSadleir, L.en
dc.contributor.authorDibbens, L.en
dc.contributor.authorCairns, A.en
dc.contributor.authorKivity, S.en
dc.contributor.authorAfawi, Z.en
dc.contributor.authorRegan, B.en
dc.contributor.authorDuflou, J.en
dc.contributor.authorBerkovic, S.en
dc.contributor.authorScheffer, I.en
dc.contributor.authorSemsarian, C.en
dc.date.issued2016en
dc.identifier.citationAnnals of Neurology, 2016; 79(4):522-534en
dc.identifier.issn0364-5134en
dc.identifier.issn1531-8249en
dc.identifier.urihttp://hdl.handle.net/2440/106389-
dc.descriptionAccepted for publication Dec 20, 2015en
dc.description.abstractObjective: 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.en
dc.description.statementofresponsibilityRichard 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 Semsarianen
dc.language.isoenen
dc.publisherJohn Wiley & Sonsen
dc.rights© 2016 American Neurological Associationen
dc.subjectRespiration Disordersen
dc.titleExome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsyen
dc.typeJournal articleen
dc.identifier.rmid0030041535en
dc.identifier.doi10.1002/ana.24596en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1059156en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1006110en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1046441en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/628952en
dc.identifier.pubid226859-
pubs.library.collectionMolecular and Biomedical Science publicationsen
pubs.library.teamDS03en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
Appears in Collections:Molecular and Biomedical Science publications

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