Annual Meeting Abstracts: View

  • (Abst. 3.339|C.01), 2015
  • Identifying genetic variants underlying sudden unexpected death in epilepsy (SUDEP)
  • Authors: D. E. Crompton, R. Bagnall, S. Petrovski, B. Regan, S. I. Garry, S. Berkovic, C. Semsarian, I. Scheffer
  • Content:

    Rationale: The leading cause of epilepsy-related mortality is sudden unexpected death in epilepsy (SUDEP). The causes of SUDEP are poorly understood. We used whole exome sequencing in a large cohort of subjects who have died of SUDEP to explore the hypothesis that rare genetic variants contribute to SUDEP risk.Methods: Demographic and clinical information on SUDEP cases was collected from two major centres in Australia. Whole exome sequencing was performed to identify rare genetic variants in the SUDEP cases. In silico study of variants included a collapsing analysis (unconstrained by prior hypothesis as to which genes are relevant) to rank genes with an increased prevalence of pathogenic rare variants in the SUDEP cohort compared to 2,936 control exomes. In addition a candidate gene study of cardiac arrhythmia, respiratory control and epilepsy genes was performed.Results: Clinical data and whole exome sequences were ascertained for 62 SUDEP cases (54 definite SUDEP, 2 definite SUDEP plus, 6 probable SUDEP). The mean age at epilepsy onset was 10·5 ± 8·2 years (range 0-34 years) and the mean age at SUDEP was 28 ± 11·9 years (range 1-53 years). There was a slight male predominance (1·2:1). The collapsing analysis ranked the cardiac sudden related death gene NOSAP1 (p=0.00024), the long QT syndrome gene KCNH2 (p=0·0039), and the focal epilepsy gene DEPDC5 (p=0·00016) within the top 30 genes of the whole exome (15,294 genes interrogated). Six SUDEP cases (10%) had mutations in genes commonly responsible for the cardiac arrhythmia disorder long QT syndrome, while eight cases (13%) had mutations in other cardiac arrhythmia genes. Fifteen cases (24%) had sixteen mutations in known epilepsy genes, including six individuals with mutations in the focal epilepsy gene DEPDC5.Conclusions: The discovery of mutations known to cause cardiac sudden death in nearly one quarter of our SUDEP cohort suggests that cardiac dysrhythmia may contribute to pathophysiology in a proportion of SUDEP cases and raises the possibility that SUDEP might be preventable in some cases by restricting the use of anti-epileptic drugs known to prolong QT interval and, in selected cases, by recommending beta blockers, pacemakers or implantable cardioverter-defibrillators. The high prevalence of DEPDC5 mutations (10%) might reflect a particular SUDEP predisposition in patients with mutations of DEPDC5. This may be because of subtle cardiorespiratory abnormalities coexist with epilepsy in these individuals. Crucially, our collapsing analysis identifies genes which are biologically plausible as contributors to SUDEP, although no single gene reached exome-wide significance in our study cohort. Analyses of larger SUDEP cohorts holds promise for identifying hitherto unsuspected genes as contributors in SUDEP pathophysiology, providing vital insights into pathophysiology and ultimately prevention of SUDEP.