Mutations known to cause cardiac sudden death contribute to SUDEP

Douglas E. Crompton and colleagues from Northern Health in Melbourne looked at the demographic and clinical information on SUDEP cases from 2 major centers in Australia and performed whole exome sequencing to identify rare genetic variants in these patients.

They compared genes with an increased prevalence of rare pathogenic variants in SUDEP patients with 2936 control exomes. The study findings were, presented at the 2015 American Epilepsy Society Annual Meeting in Philadelphia.

For the present study they analysed whole exome sequences from 62 SUDEP cases. The mean age at epilepsy onset was 10.5 years, while the mean age of SUDEP was 28 years. The male to female ratio was 1.2:1

The cardiac sudden related death gene NOSAP1, the long QT syndrome gene KCNH2 and the focal epilepsy gene DEPDC5 were ranked among the top 30 genes of the entire exome interrogated (n=15,294 genes).

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.

According to the study authors the discovery of mutations known to cause cardiac sudden death in nearly one quarter of their SUDEP cohort suggests that cardiac dysrhythmia may contribute to pathophysiology in a proportion of SUDEP cases.

The researchers further suggest that these findings raise 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 in their cohort might signal a particular SUDEP predisposition in patients with these mutations. Although no single gene reached exome-wide significance in their study cohort the collapsing analysis (unconstrained by prior hypothesis as to which genes are relevant) identifies genes which are biologically plausible as contributors to SUDEP.

Analyses of larger SUDEP cohorts hold promise for identifying hitherto unsuspected genes as contributors in SUDEP pathophysiology, providing vital insights into pathophysiology and ultimately prevention of SUDEP.

Reference:

Crompton DE, Bagnall R, Petrovski S, et al. Abstract 3.339|C.01. Identifying genetic variants underlying sudden unexpected death in epilepsy (SUDEP). Presented at: American Epilepsy Society Annual Meeting; Dec. 4-8, 2015; Philadelphia.