GenSuD

Sudden cardiac death (SCD) is a major health burden in industrialized countries, with an incidence close to 1/1000 inhabitants/year. In most cases, SCD results from ventricular fibrillation (VF), occurring as the initial manifestation of a previously ignored cardiovascular disease. SCD can be the first symptom of rare inherited arrhythmia disorders. Among these disorders, the Brugada syndrome (BrS) and the early repolarization syndrome, or ‘J-wave syndromes’ (JWS), are highly amenable to genetic studies and can be used as models to yield molecular insights relevant to the broader problem of SCD. GenSuD aims to explore familial forms of JWS, to identify new genetic factors modulating disease risk and to address the relative involvement of all known susceptibility genes for inherited cardiac arrhythmias in the population burden of SCD. GenSuD relies on the largest clinical bio-banks worldwide for JWS and SCD. Recent technological developments in genomics, together with our rapidly increasing knowledge on the role of non-coding regions of the genome, have now set the stage to: 1- Seek for new susceptibility genes for JWS, i.e. genes harbouring rare genetic variants causally related with J-wave syndromes, by whole-exome sequencing. 2- Explore the relative contributions of all known susceptibility genes for inherited cardiac arrhythmias to the burden of SCD in the young adult, by a targeted NGS-based approach. 3- Extend a recently published genome-wide association study on BrS, in order to stratify the risk of SCD in this highly exposed population, by performing a full genome sequencing-association study on selected index cases of BrS. Each newly identified gene will be functionally tested by electrophysiological studies on isolated murine cardiomyocytes expressing the transgene and/or on human cardiomyocytes differentiated from iPS cells derived from patients carrying rare gene variants. All GenSuD partners are international leaders in their respective research fields on Sudden Cardiac Death. Together, they provide GenSuD with complementary expertise in genetics, genomics, bioinformatics, statistical genetics, epidemiology and cardiovascular physiology. None of them could have tackled this multidisciplinary project on their own: GenSuD will reinforce collaborations between them and will foster tighter connections between the two National Reference Centres for Inherited Cardiac Arrhythmias, based in Nantes (partner 1) and Paris (partner 2), which both develop large DNA collections dedicated to inherited cardiac arrhythmias. The J-wave syndromes could well be involved in a substantial proportion of still-unexplained SCD events: a better understanding of their etiology and pathophysiology will help in defining new prevention strategies against SCD in individuals with structurally normal hearts. Identifying new major and modifier determinants of SCD “represents an exciting next major step, ultimately enabling improved diagnosis, risk stratification, and treatment strategies”.