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 primary cardiac electrical disorders, we apply multi-omics screening strategies to establish clinical and genetic risk stratification for developing cardiac arrhythmia and prevent sudden cardiac death (SCD).

RISTRAD project

We developed state-of-the-art projects in genomics and pathophysiology of cardiac arrhythmias to elucidate the genetic basis of primary cardiac arrhythmias such as the Brugada syndrome, the long and short QT syndrome, the catecholaminergic polymorphic ventricular tachycardia, the conduction defects (congenital or progressive atrio-ventricular blocks), sinus dysfunction, idiopathic ventricular fibrillation and more complex cardiac diseases as arrhythmogenic cardiomyopathy. The identification of new clinical and molecular markers from these ‘sensitized’ models of SCD are likely relevant to the broad problem of SCD.

REGIOCARD project

Our strategies based on whole genome screening allow us to open unique opportunities to interrogate the full spectrum genetic variations (rare, common and intermediate frequency variants; point mutation, small insertion deletion and copy number variations) from which ones have been so far unexplored such as the low-frequency (MAF<5%). Furthermore we particularly interested in investigating the role of variants in the non-coding region of the genome, seat of the gene regulation. We then developed research programs on cardiac epigenetics to functionally annotate the gene regulatory regions of the genome.
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NEXT_IRP_VERACITIES project

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.