Richard D Bagnall1,2, Douglas E Crompton3,4, Slavé Petrovski4,5, Lien Lam1,2, Carina Cutmore1,2, Sarah I Garry4, Lynette G Sadleir6, Leanne M Dibbens7, Anita Cairns8, Sara Kivity9, Zaid Afawi10, Brigid M Regan4, Johan Duflou2,11, Samuel F Berkovic4, Ingrid E Scheffer4,12,13,14, Christopher Semsarian1,2,15. 1. Agnes Ginges Center for Molecular Cardiology, Centenary Institute, Sydney, Australia. 2. Sydney Medical School, University of Sydney, Sydney, Australia. 3. Neurology Department, Northern Health, Melbourne, Australia. 4. Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia. 5. Institute for Genomic Medicine, Columbia University, New York, NY. 6. Department of Pediatrics and Child Health, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand. 7. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia. 8. Neurosciences Department, Lady Cilento Children's Hospital, Brisbane, Australia. 9. Epilepsy Unit, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel. 10. Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel. 11. Department of Forensic Medicine, Sydney, Australia. 12. Department of Neurology, The Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia. 13. Florey Institute of Neurosciences and Mental Health, Melbourne, Australia. 14. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia. 15. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
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.
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.
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