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. 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. (PsycINFO Database Record (c) 2016 APA, all rights reserved)Agnes Ginges Center for Molecular Cardiology, Centenary Institute, Sydney, NSW, Australia. Release Date: 20160512. Publication Type: Journal (0100), Peer Reviewed Journal (0110). Format Covered: Electronic. Document Type: Journal Article. Language: EnglishGrant Information: Semsarian, Christopher. Major Descriptor: Epilepsy; Mortality Rate; Respiration. Classification: Neurological Disorders & Brain Damage (3297). Population: Human (10). Location: Australia. Methodology: Empirical Study; Quantitative Study. References Available: Y. Page Count: 13. Issue Publication Date: Apr, 2016. Publication History: Accepted Date: Dec 20, 2015; Revised Date: Dec 14, 2015; First Submitted Date: Apr 28, 2015. Copyright Statement: American Neurological Association. 2016.Sponsor: National Health and Medical Research Council. Grant: 1059156; 1006110. Other Details: Practitioner Fellowships. Recipients: Semsarian, Christopher; Scheffer, Ingrid E. <br />Sponsor: National Health and Medical Research Council. Grant: 1046441. Recipients: No recipient indicated <br />Sponsor: Health Research Council of New Zealand, New Zealand. Recipients: No recipient indicated <br />Sponsor: CURE. Recipients: No recipient indicated <br />Sponsor: National Health and Medical Research Council. Grant: 628952. Recipients: No recipient indicated <br />