Genetics of cardiac arrhythmia disorders and sudden death

Julien Barc and Vincent Probst

The primary objective of our group is to improve healthcare by combining basic research and clinical activity into translational research programs. Taking advantage of large pedigrees and one of the largest worldwide cohorts of patients suffering from inherited cardiac electrical disorders (Brugada syndrome, the long and short QT syndrome, the catecholaminergic polymorphic ventricular tachycardia, conduction defects, sinus dysfunction, idiopathic ventricular fibrillation and arrhythmogenic cardiomyopathy) we apply multi-omics screening strategies to establish clinical and genetic risk stratification for developing cardiac arrhythmia and prevent sudden cardiac death (SCD). The identification of new clinical and molecular markers from these ‘sensitized’ models of SCD are likely relevant to the broad problem of SCD.
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REGIOCARD project

Our strategy based on whole genome screening allows us to open unique opportunities to interrogate the full spectrum genetic variations. Furthermore we are particularly interested in investigating the role of variants in the non-coding regions of the genome, seat of the gene regulation. We then developed the REGIOCARD program on cardiac epigenetics to functionally annotate the human cardiac regulatory regions.
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LEARN project

The translational research project LEARN combines multi-omics approach and phenotype characterization to decipher the molecular mechanism leading to a new syndrome associating cardiac electrical disorders and developmental defects. Large deletions, identified in 6 families, located in a gene desert area suggest the crucial role of a regulatory region. Based on human cardiomyocytes derived from iPSC and mouse model deleted for this regulatory region, we will investigate the role, targeted genes, the transcriptomic, electrophysiological consequences of this deleted regulatory element.

European Joint Programme on Rare Diseases: LQTS-NEXT

LQTS-NEXT will focus on the Long QT Syndrome (LQTS) as a model to test the hypotheses that (1) additional genetic factors as well as non-genetic parameters (clinical, ECG) conspire with the mutation to modulate disease severity, and (2) the incorporation of such additional genetic and non-genetic parameters in a risk prediction algorithm will provide a refined, personalized, assessment of risk. Furthermore, LQTS-NEXT will apply cutting edge genomic and bioinformatics approaches to identify the genetic defect underlying LQTS in patients that have remained mutation-negative after extensive gene panel testing of LQTS associated genes.

International research partnership GAINES

Our research takes place in a context of international collaborations allowing young scientists to interact with the world leaders in the field, follow training to acquire new skills and develop their network.

Publications

RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome. Belbachir N, Portero V, Al Sayed ZR, Gourraud J-B, Dilasser F, Jesel L, Guo H, Wu H, Gaborit N, Guilluy C, Girardeau A, Bonnaud S, Simonet F, Karakachoff M, Pattier S, Scott C, Burel S, Marionneau C, Chariau C, Gaignerie A, David L, Genin E, Deleuze J-F, Dina C, Sauzeau V, Loirand G, Baró I, Schott J-J, Probst V, Wu JC, Redon R, Charpentier F, Le Scouarnec S. Eur Heart J. 2019;doi:10.1093/eurheartj/ehz308.

Progressive Atrial Conduction Defects Associated With Bone Malformation Caused by a Connexin-45 Mutation. Seki* A, Ishikawa* T, Daumy* X, Mishima H, Barc J, Sasaki R, Nishii K, Saito K, Urano M, Ohno S, Otsuki S, Kimoto H, Baruteau A-E, Thollet A, Fouchard S, Bonnaud S, Parent P, Shibata Y, Perrin J-P, Le Marec H, Hagiwara N, Mercier S, Horie M, Probst V, Yoshiura* K-I, Redon* R, Schott* J-J, Makita* N. J Am Coll Cardiol 2017;70:358–370.

Familial Catecholamine-Induced QT Prolongation in Unexplained Sudden Cardiac Death. Huchet* F, Kyndt* F, Barc* J, Thollet A, Charpentier F, Redon R, Schott JJ, le Marec H, Probst V, Gourraud JB. J Am Coll Cardiol 2017;69:1642–1643.

Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. Le Scouarnec* S, Karakachoff* M, Gourraud* J-B, Lindenbaum P, Bonnaud S, Portero V, Duboscq-Bidot L, Daumy X, Simonet F, Teusan R, Baron E, Violleau J, Persyn E, Bellanger L, Barc J, Chatel S, Martins R, Mabo P, Sacher F, Haïssaguerre M, Kyndt F, Schmitt S, Bézieau S, Le Marec H, Dina C, Schott J-J, Probst V, Redon R. Hum Mol Genet 2015;24:2757–2763.