Floriane Simonet
University of Nantes
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Featured researches published by Floriane Simonet.
Nature Genetics | 2013
Connie R. Bezzina; Julien Barc; Yuka Mizusawa; Carol Ann Remme; Jean-Baptiste Gourraud; Floriane Simonet; Arie O. Verkerk; Peter J. Schwartz; Lia Crotti; Federica Dagradi; Pascale Guicheney; Véronique Fressart; Antoine Leenhardt; Charles Antzelevitch; Susan Bartkowiak; Martin Borggrefe; Rainer Schimpf; Eric Schulze-Bahr; Sven Zumhagen; Elijah R. Behr; Rachel Bastiaenen; Jacob Tfelt-Hansen; Morten S. Olesen; Stefan Kääb; Britt M. Beckmann; Peter Weeke; Hiroshi Watanabe; Naoto Endo; Tohru Minamino; Minoru Horie
Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
Human Molecular Genetics | 2015
Solena Le Scouarnec; Matilde Karakachoff; Jean-Baptiste Gourraud; Pierre Lindenbaum; Stéphanie Bonnaud; Vincent Portero; Laetitia Duboscq-Bidot; Xavier Daumy; Floriane Simonet; Raluca Teusan; Estelle Baron; Jade Violleau; Elodie Persyn; Lise Bellanger; Julien Barc; Stéphanie Chatel; Raphaël P. Martins; Philippe Mabo; Frederic Sacher; Michel Haïssaguerre; Florence Kyndt; Sébastien Schmitt; Stéphane Bézieau; Hervé Le Marec; Christian Dina; Jean-Jacques Schott; Vincent Probst; Richard Redon
The Brugada syndrome (BrS) is a rare heritable cardiac arrhythmia disorder associated with ventricular fibrillation and sudden cardiac death. Mutations in the SCN5A gene have been causally related to BrS in 20-30% of cases. Twenty other genes have been described as involved in BrS, but their overall contribution to disease prevalence is still unclear. This study aims to estimate the burden of rare coding variation in arrhythmia-susceptibility genes among a large group of patients with BrS. We have developed a custom kit to capture and sequence the coding regions of 45 previously reported arrhythmia-susceptibility genes and applied this kit to 167 index cases presenting with a Brugada pattern on the electrocardiogram as well as 167 individuals aged over 65-year old and showing no history of cardiac arrhythmia. By applying burden tests, a significant enrichment in rare coding variation (with a minor allele frequency below 0.1%) was observed only for SCN5A, with rare coding variants carried by 20.4% of cases with BrS versus 2.4% of control individuals (P = 1.4 × 10(-7)). No significant enrichment was observed for any other arrhythmia-susceptibility gene, including SCN10A and CACNA1C. These results indicate that, except for SCN5A, rare coding variation in previously reported arrhythmia-susceptibility genes do not contribute significantly to the occurrence of BrS in a population with European ancestry. Extreme caution should thus be taken when interpreting genetic variation in molecular diagnostic setting, since rare coding variants were observed in a similar extent among cases versus controls, for most previously reported BrS-susceptibility genes.
Nature Genetics | 2015
Christian Dina; Nabila Bouatia-Naji; Nathan R. Tucker; Francesca N. Delling; Katelynn Toomer; Ronen Durst; Maelle Perrocheau; Leticia Fernandez-Friera; Jorge Solis; Thierry Le Tourneau; Ming-Huei Chen; Vincent Probst; Yohan Bossé; Philippe Pibarot; Diana Zelenika; Mark Lathrop; Serge Hercberg; R. Roussel; Emelia J. Benjamin; Fabrice Bonnet; Su Hao Lo; Elena Dolmatova; Floriane Simonet; Simon Lecointe; Florence Kyndt; Richard Redon; Hervé Le Marec; Philippe Froguel; Patrick T. Ellinor; Patrick Bruneval
Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1−/− mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.
European Journal of Human Genetics | 2015
Matilde Karakachoff; Nicolas Duforet-Frebourg; Floriane Simonet; Solena Le Scouarnec; Nadine Pellen; Simon Lecointe; Eric Charpentier; Françoise Gros; Stéphane Cauchi; Philippe Froguel; Nane Copin; Beverley Balkau; Pierre Ducimetière; E. Eschwege; François Alhenc-Gelas; A. Girault; Frédéric Fumeron; Michel Marre; R. Roussel; Fabrice Bonnet; S Cauchi; Joël Cogneau; Celine Born; Emile Caces; Martine Cailleau; Olivier Lantieri; J.G. Moreau; F. Rakotozafy; Jean Tichet; Thierry Le Tourneau
The difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendée Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses.
Nature Genetics | 2013
Connie R. Bezzina; Julien Barc; Yuka Mizusawa; Carol Ann Remme; Jean Baptiste Gourraud; Floriane Simonet; Arie O. Verkerk; Peter J. Schwartz; Lia Crotti; Federica Dagradi; Pascale Guicheney; Véronique Fressart; Antoine Leenhardt; Charles Antzelevitch; Susan Bartkowiak; Eric Schulze-Bahr; Sven Zumhagen; Elijah R. Behr; Rachel Bastiaenen; Jacob Tfelt-Hansen; Morten S. Olesen; Stefan Kääb; Britt M. Beckmann; Peter Weeke; Hiroshi Watanabe; Naoto Endo; Tohru Minamino; Minoru Horie; Seiko Ohno; Kanae Hasegawa
Heart Rhythm | 2014
V. Portero; S. Le Scouarnec; Zeineb Es-Salah-Lamoureux; S. Burel; Jean-Baptiste Gourraud; Stéphanie Bonnaud; Pierre Lindenbaum; Floriane Simonet; J. Violleau; J. Sandoval-Tortosa; Carol Scott; Stéphanie Chatel; G. Loussouarn; Thomas O’Hara; Philippe Mabo; Christian Dina; H. Le Marec; Jean-Jacques Schott; Vincent Probst; Isabelle Baró; Céline Marionneau; Flavien Charpentier; Richard Redon
Archives of Cardiovascular Diseases Supplements | 2015
Dylan Therasse; Floriane Simonet; Christian Dina; Aurélie Thollet; Philippe Mabo; Frederic Sacher; Dominique Babuty; Philippe Maury; Jean-Jacques Schott; Hervé Le Marec; Richard Redon; Vincent Probst; Jean-Baptiste Gourraud
. European Mathematical Genetics Meeting (EMGM) | 2015
Elodie Persyn; Matilde Karakachoff; Floriane Simonet; Jean-Jacques Schott; Richard Redon; Lise Bellanger; Christian Dina
International Biometric Conference | 2014
Lise Bellanger; Elodie Persyn; Floriane Simonet; Richard Redon; Jean-Jacques Schott; Solena Le Scouarnec; Matilde Karakachoff; Christian Dina