Team I

© Stéphane Bellanger - 2018 - Ile de Nantes

Objectives and strategy

Since 2009, the team has developed new strategies for genetic epidemiology based on massive sequencing and high throughput genotyping technologies and applied them to cardiac diseases.

The working hypothesis is that predisposition to these pathologies results from a combination of rare genetic variations triggering the risk and genetic polymorphisms impacting the penetrance and/or severity of the disease. Through the recruitment of large families and large cohorts of patients, we have implemented these approaches on pathologies associated with an increased risk of sudden cardiac death as well as valvular disorders.
Following the identification of the first gene of predisposition to mitral valvular dystrophy, we have developed a new line of research aimed at understanding the pathophysiological mechanisms leading to mitral degeneration.

The scientific objective of the team is to elucidate the missing heritability of diseases affecting the cardiovascular system, based on the pradigm "rare variation / common disease". Our activity concerns not only arrhythmias and cardiac valvular disorders, but also new pathologies of interest such as dyslipidemias and intracranials aneurysms.

Research programs


1. Genetic epidemiology (C. Dina et R. Redon)

This program aims to develop new tools in order to elucidate the missing heritability in chronic pathologies, in particular by the construction of reference panels representative of the French population, who will serve as control groups in the context of biomedical genetics programs.

2. Rare variants and polymorphisms predisposing patients to electric cardiac anomalies (J. Barc)

Our hypothesis is that cardiac arrhythmias such as Brugada syndrome are pertinent models for understanding the mechanisms leading to ventricular fibrillation. The identification of the genetic predispositions to sudden death in high risk individuals will make it possible to understand these mechanisms. Projet RISTRAD - MSCA-IF

3. Valvular disorders: imaging, genetics and pathophysiology (S. Le Scouarnec and J. Mérot)

Our recent results have highlighted a strong genetic component in mitral valve prolapse and calcified aortic stenosis, which supports the concept that valvular degeneration is not only due to aging. We plan to further study the genetic basis of valve degeneration through a program of integrated research combining state of the art valvular imaging, high throughput genetic testing and functional investigations.

4. Genetics of vascular diseases (JJ. Schott)

The goal of this program is to share our expertise in human genetics with the clinicians and physiologists working at the Institute. We work primarily on two pathologies, where enough clinical and scientific expertise is available within the Institute to ensure our international competitiveness: intracranial aneurysm and dyslipidemia.

Recent publications

Bourcier R, Le Scouarnec S, Bonnaud S, Karakachoff M, Bourcereau E, Heurtebise-Chrétien S, Menguy C, Dina C, Simonet F, Moles A, Lenoble C, Lindenbaum P, Chatel S, Isidor B, Génin E, Deleuze J-F, Schott J-J, Le Marec H, ICAN Study Group, Loirand G, Desal H, Redon R.
Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm.
Am J Hum Genet 2018;102:133–141.

Le Tourneau T, Le Scouarnec S, Cueff C, Bernstein D, Aalberts JJJ, Lecointe S, Mérot J, Bernstein JA, Oomen T, Dina C, Karakachoff M, Desal H, Al Habash O, Delling FN, Capoulade R, Suurmeijer AJH, Milan D, Norris RA, Markwald R, Aikawa E, Slaugenhaupt SA, Jeunemaitre X, Hagège A, Roussel J-C, Trochu J-N, Levine RA, Kyndt F, Probst V, Le Marec H, Schott JJ.
New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study.
Eur Heart J 2018;39:1269–1277.

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.
Progressive Atrial Conduction Defects Associated With Bone Malformation Caused by a Connexin-45 Mutation.
J Am Coll Cardiol 2017;70:358–370.

Huchet F, Kyndt F, Barc J, Thollet A, Charpentier F, Redon R, Schott JJ, le Marec H, Probst V, Gourraud JB.
Familial Catecholamine-Induced QT Prolongation in Unexplained Sudden Cardiac Death.
J Am Coll Cardiol. 2017 Mar 28;69(12):1642-1643.

Dina C, Bouatia-Naji N, Tucker N, Delling FN, Toomer K, [...], Milan DJ*, Slaugenhaupt SA*, Levine RA*, Schott JJ*, Hagege AA*, Mvp-France, Jeunemaitre X*. Leducq Transatlantic MITRAL Network.
Genetic association analyses highlight biological pathways underlying mitral valve prolapse.
Nat Genet.
2015 Oct;47(10):1206-11.

Le Scouarnec S, Karakachoff M, Gourraud JB, 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 JJ, Probst V, Redon R. 
Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. 
Hum Mol Genet. 2015 May 15;24(10):2757-63

Bezzina CR*, Barc J*, Mizusawa Y*, Remme CA*, Gourraud JB*, Simonet F, Verkerk AO, Schwartz PJ, Crotti L, Dagradi F, Guicheney P, Fressart V, Leenhardt A, Antzelevitch C, Bartkowiak S, Borggrefe M, Schimpf R, Schulze-Bahr E, Zumhagen S, Behr ER, Bastiaenen R, Tfelt-Hansen J, Olesen MS, Kääb S, Beckmann BM, Weeke P, Watanabe H, Endo N, Minamino T, Horie M, Ohno S, Hasegawa K, Makita N, Nogami A, Shimizu W, Aiba T, Froguel P, Balkau B, Lantieri O, Torchio M, Wiese C, Weber D, Wolswinkel R, Coronel R, Boukens BJ, Bézieau S, Charpentier E, Chatel S, Despres A, Gros F, Kyndt F, Lecointe S, Lindenbaum P, Portero V, Violleau J, Gessler M, Tan HL, Roden DM, Christoffels VM, Le Marec H, Wilde AA*, Probst V*, Schott JJ*, Dina C* & Redon R*. 
Common variants at the SCN5A/SCN10A and HEY2 loci predispose to Brugada syndrome, a rare disease with high risk of sudden cardiac death.
Nat Genet. 2013 Sep;45(9):1044-9