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313 results on '"Génin, Emmanuelle"'

1. Human genetic structure in Northwest France provides new insights into West European historical demography

Author

Alves, Isabel, Giemza, Joanna, Blum, Michael G. B., Bernhardsson, Carolina, Chatel, Stéphanie, Karakachoff, Matilde, Saint Pierre, Aude, Herzig, Anthony F., Olaso, Robert, Monteil, Martial, Gallien, Véronique, Cabot, Elodie, Svensson, Emma, Bacq, Delphine, Baron, Estelle, Berthelier, Charlotte, Besse, Céline, Blanché, Hélène, Bocher, Ozvan, Boland, Anne, Bonnaud, Stéphanie, Charpentier, Eric, Dandine-Roulland, Claire, Férec, Claude, Fruchet, Christine, Lecointe, Simon, Le Floch, Edith, Ludwig, Thomas E., Marenne, Gaëlle, Meyer, Vincent, Quellery, Elisabeth, Racimo, Fernando, Rouault, Karen, Sandron, Florian, Schott, Jean-Jacques, Velo-Suarez, Lourdes, Violleau, Jade, Willerslev, Eske, Coativy, Yves, Jézéquel, Mael, Le Bris, Daniel, Nicolas, Clément, Pailler, Yvan, Goldberg, Marcel, Zins, Marie, Le Marec, Hervé, Jakobsson, Mattias, Darlu, Pierre, Génin, Emmanuelle, Deleuze, Jean-François, Redon, Richard, and Dina, Christian

Published
2024
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7. Secure Multilayer Perceptron Based On Homomorphic Encryption

Author

Bellafqira, Reda, Coatrieux, Gouenou, Genin, Emmanuelle, and Cozic, Michel

Subjects
Computer Science - Cryptography and Security
Abstract

In this work, we propose an outsourced Secure Multilayer Perceptron (SMLP) scheme where privacy and confidentiality of both the data and the model are ensured during the training and the classification phases. More clearly, this SMLP : i) can be trained by a cloud server based on data previously outsourced by a user in an homomorphically encrypted form; ii) its parameters are homomorphically encrypted giving thus no clues to the cloud; and iii) it can also be used for classifying new encrypted data sent by the user returning him the encrypted classification result encrypted. The originality of this scheme is threefold. To the best of our knowledge, it is the first multilayer perceptron (MLP) secured in its training phase over homomorphically encrypted data with no problem of convergence. And It does not require extra-communications between the server and the user. It is based on the Rectified Linear Unit (ReLU) activation function that we secure with no approximation contrarily to actual SMLP solutions. To do so, we take advantage of two semi-honest non-colluding servers. Experimental results carried out on a binary database encrypted with the Paillier cryptosystem demonstrate the overall performance of our scheme and its convergence.

Published
2018

10. The genetic history of France

Author

Saint Pierre, Aude, Giemza, Joanna, Alves, Isabel, Karakachoff, Matilde, Gaudin, Marinna, Amouyel, Philippe, Dartigues, Jean-François, Tzourio, Christophe, Monteil, Martial, Galan, Pilar, Hercberg, Serge, Mathieson, Iain, Redon, Richard, Génin, Emmanuelle, and Dina, Christian

Published
2020
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12. Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm

Author

Desal, Hubert, Bourcier, Romain, Daumas-Duport, Benjamin, Isidor, Bertrand, Connault, Jérôme, Lebranchu, Pierre, Le Tourneau, Thierry, Viarouge, Marie Pierre, Papagiannaki, Chrisanthi, Piotin, Michel, Redjem, Hocine, Mazighi, Mikael, Desilles, Jean Philippe, Naggara, Olivier, Trystram, Denis, Edjlali-Goujon, Myriam, Rodriguez, Christine, Ben Hassen, Waghi, Saleme, Suzanna, Mounayer, Charbel, Levrier, Olivier, Aguettaz, Pierre, Combaz, Xavier, Pasco, Anne, Berthier, Emeline, Bintner, Marc, Molho, Marc, Gauthier, Pascale, Chivot, Cyril, Costalat, Vincent, Darganzil, Cyril, Bonafé, Alain, Januel, Anne Christine, Michelozzi, Caterina, Cognard, Christophe, Bonneville, Fabrice, Tall, Philippe, Darcourt, Jean, Biondi, Alessandra, Iosif, Cristina, Pomero, Elisa, Ferre, Jean Christophe, Gauvrit, Jean Yves, Eugene, François, Raoult, Hélène, Gentric, Jean Christophe, Ognard, Julien, Anxionnat, René, Bracard, Serge, Derelle, Anne Laure, Tonnelet, Romain, Spelle, Laurent, Ikka, Léon, Fahed, Robert, Rouchaud, Aymeric, Ozanne, Augustin, Caroff, Jildaz, Ben Achour, Nidal, Moret, Jacques, Chabert, Emmanuel, Berge, Jérôme, Marnat, Gaultier, Barreau, Xavier, Gariel, Florent, Clarencon, Frédéric, Aggour, Mohammed, Ricolfi, Frédéric, Chavent, Adrien, Thouant, Pierre, Lebidinsky, Pablo, Lemogne, Brivael, Herbreteau, Denis, Bibi, Richard, Pierot, Laurent, Soize, Sébastien, Labeyrie, Marc Antoine, Vandendries, Christophe, Houdart, Emmanuel, Kazemi, Appoline, Leclerc, Xavier, Pruvo, Jean Pierre, Gallas, Sophie, Velasco, Stéphane, Le Scouarnec, Solena, Bonnaud, Stéphanie, Karakachoff, Matilde, Bourcereau, Emmanuelle, Heurtebise-Chrétien, Sandrine, Menguy, Céline, Dina, Christian, Simonet, Floriane, Moles, Alexis, Lenoble, Cédric, Lindenbaum, Pierre, Chatel, Stéphanie, Génin, Emmanuelle, Deleuze, Jean-François, Schott, Jean-Jacques, Le Marec, Hervé, Loirand, Gervaise, and Redon, Richard

Published
2018
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15. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability

Author

Aubart, Melodie, Gazal, Steven, Arnaud, Pauline, Benarroch, Louise, Gross, Marie-Sylvie, Buratti, Julien, Boland, Anne, Meyer, Vincent, Zouali, Habib, Hanna, Nadine, Milleron, Olivier, Stheneur, Chantal, Bourgeron, Thomas, Desguerre, Isabelle, Jacob, Marie-Paule, Gouya, Laurent, Génin, Emmanuelle, Deleuze, Jean-François, Jondeau, Guillaume, and Boileau, Catherine

Published
2018
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17. WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects

Author

Karam, Adella, primary, Delvallée, Clarisse, additional, Estrada-Cuzcano, Alejandro, additional, Geoffroy, Véronique, additional, Lamouche, Jean-Baptiste, additional, Leuvrey, Anne-Sophie, additional, Nourisson, Elsa, additional, Tarabeux, Julien, additional, Stoetzel, Corinne, additional, Scheidecker, Sophie, additional, Porter, Louise Frances, additional, Génin, Emmanuelle, additional, Redon, Richard, additional, Sandron, Florian, additional, Boland, Anne, additional, Deleuze, Jean-François, additional, Le May, Nicolas, additional, Dollfus, Hélène, additional, and Muller, Jean, additional

Published
2023
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20. Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish

Author

Odelin, Gaelle, Faucherre, Adèle, Marchese, Damien, Pinard, Amélie, Jaouadi, Hager, Le Scouarnec, Solena, Deleuze, Jean-François, Génin, Emmanuelle, Lindenbaum, Pierre, Redon, Richard, Schott, Jean-Jacques, Chiarelli, Raphaël, Achouri, Younes, Faure, Emilie, Herbane, Marine, Théron, Alexis, Avierinos, Jean-François, Jopling, Chris, Collod-Béroud, Gwenaëlle, Rezsohazy, René, Zaffran, Stéphane, UCL - SST/LIBST - Louvain Institute of Biomolecular Science and Technology, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut du Thorax [Nantes], Département de Cardiologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 'Association Française contre les Myopathies' [NMH-Decrypt Project],the 'Fondation pour la Recherche Médicale'[DPC20111123002], the 'Institut National de la Santé et de laRecherche Médicale' and 'la Fondation Leducq' to S.Z. This workwas supported by the 'Fonds de la recherche Scientifique FNRS'[Crédit de recherche (CDR) J.0157.21] and the 'Fonds spéciaux derecherche' (FSR, UCLouvain) to R.R. A.P. received PhD fellowshipsfrom the 'Association Française du syndrome de Marfan et apparentés'.A.F. and C.J. are members of the Laboratory of ExcellenceIon Channel Science and Therapeutics supported by a grant fromthe ANR. Work in the C.J lab is supported by a grant from the 'laFondation Leducq', ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), and ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Organogenesis, General Biochemistry, General Physics and Astronomy, Genetics and Molecular Biology, General Chemistry, Development, Heart development, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5–1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1 −1His knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1 −/− mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.

Published
2023
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21. Correction: The genetic history of France

Author

Saint Pierre, Aude, Giemza, Joanna, Alves, Isabel, Karakachoff, Matilde, Gaudin, Marinna, Amouyel, Philippe, Dartigues, Jean-François, Tzourio, Christophe, Monteil, Martial, Galan, Pilar, Hercberg, Serge, Mathieson, Iain, Redon, Richard, Génin, Emmanuelle, and Dina, Christian

Published
2020
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23. Short Tandem Repeats in the era of next-generation sequencing: from historical loci to population databases

Author

Uguen, Kevin, Michaud, Jacques L., and Génin, Emmanuelle

Abstract

In this study, we explore the landscape of short tandem repeats (STRs) within the human genome through the lens of evolving technologies to detect genomic variations. STRs, which encompass approximately 3% of our genomic DNA, are crucial for understanding human genetic diversity, disease mechanisms, and evolutionary biology. The advent of high-throughput sequencing methods has revolutionized our ability to accurately map and analyze STRs, highlighting their significance in genetic disorders, forensic science, and population genetics. We review the current available methodologies for STR analysis, the challenges in interpreting STR variations across different populations, and the implications of STRs in medical genetics. Our findings underscore the urgent need for comprehensive STR databases that reflect the genetic diversity of global populations, facilitating the interpretation of STR data in clinical diagnostics, genetic research, and forensic applications. This work sets the stage for future studies aimed at harnessing STR variations to elucidate complex genetic traits and diseases, reinforcing the importance of integrating STRs into genetic research and clinical practice.

Published
2024
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24. Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score

Author

Bocher, Ozvan, primary, Ludwig, Thomas E., additional, Oglobinsky, Marie-Sophie, additional, Marenne, Gaëlle, additional, Deleuze, Jean-François, additional, Suryakant, Suryakant, additional, Odeberg, Jacob, additional, Morange, Pierre-Emmanuel, additional, Trégouët, David-Alexandre, additional, Perdry, Hervé, additional, and Génin, Emmanuelle, additional

Published
2022
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25. Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy

Author

Cartault, François, Munier, Patrick, Benko, Edgar, Desguerre, Isabelle, Hanein, Sylvain, Boddaert, Nathalie, Bandiera, Simonetta, Vellayoudom, Jeanine, Krejbich-Trotot, Pascale, Bintner, Marc, Hoarau, Jean-Jacques, Girard, Muriel, Génin, Emmanuelle, de Lonlay, Pascale, Fourmaintraux, Alain, Naville, Magali, Rodriguez, Diana, Feingold, Josué, Renouil, Michel, Munnich, Arnold, Westhof, Eric, Fähling, Michael, Lyonnet, Stanislas, and Henrion-Caude, Alexandra

Published
2012

27. Histological and genetic characterization and follow-up of 130 patients with chronic triple-negative thrombocytosis

Author

Lemoine, Sandrine, primary, Mornet, Clelia, additional, Quintin-Roue, Isabelle, additional, Rousselet, Marie-Christine, additional, Cottin, Laurane, additional, Georgeais, Aurélie, additional, Dubouis, Ludovic, additional, Boyer, Françoise, additional, Orvain, Corentin, additional, Caillon, Clara, additional, Renard, Maxime, additional, Le Brun, Valoris, additional, Le Clech, Lenaig, additional, Ianotto, Jean-Christophe, additional, Génin, Emmanuelle, additional, Burroni, Barbara, additional, Ugo, Valérie, additional, Paz, Damien Luque, additional, and Lippert, Eric, additional

Published
2022
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30. The Interplay between the Unfolded Protein Response, Inflammation and Infection in Cystic Fibrosis

Author

Trouvé, Pascal, Férec, Claude, Génin, Emmanuelle, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and PODEUR, Sophie

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, QH301-705.5, [SDV]Life Sciences [q-bio], Review, unfolded protein response, Infections, Models, Biological, infection, [SDV] Life Sciences [q-bio], cystic fibrosis, inflammation, Animals, Humans, Biology (General), Protein Processing, Post-Translational
Abstract

International audience; In cystic fibrosis (CF), p.Phe508del is the most frequent mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The p.Phe508del-CFTR protein is retained in the ER and rapidly degraded. This retention likely triggers an atypical Unfolded Protein Response (UPR) involving ATF6, which reduces the expression of p.Phe508del-CFTR. There are still some debates on the role of the UPR in CF: could it be triggered by the accumulation of misfolded CFTR proteins in the endoplasmic reticulum as was proposed for the most common CFTR mutation p.Phe508del? Or, is it the consequence of inflammation and infection that occur in the disease? In this review, we summarize recent findings on UPR in CF and show how infection, inflammation and UPR act together in CF. We propose to rethink their respective role in CF and to consider them as a whole.

Published
2021
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31. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021
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33. CFTR Cooperative Cis-Regulatory Elements in Intestinal Cells

Author

Collobert, Mégane, Bocher, Ozvan, Le Nabec, Anaïs, Génin, Emmanuelle, Férec, Claude, and Moisan, Stéphanie

Subjects
cis-ruption disorders, lcsh:Chemistry, congenital, hereditary, and neonatal diseases and abnormalities, lcsh:Biology (General), lcsh:QD1-999, transcription factors, regulation, CFTR, 3D structure, lcsh:QH301-705.5, Article
Abstract

About 8% of the human genome is covered with candidate cis-regulatory elements (cCREs). Disruptions of CREs, described as “cis-ruptions” have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range cystic fibrosis transmembrane conductance regulator (CFTR) regulatory elements were identified, but the regulatory mechanisms of the CFTR gene have yet to be fully elucidated. The aim of this work is to improve our knowledge of the CFTR gene regulation, and to identity factors that could impact the CFTR gene expression, and potentially account for the variability of the clinical presentation of cystic fibrosis as well as CFTR-related disorders. Here, we apply the robust GWAS3D score to determine which of the CFTR introns could be involved in gene regulation. This approach highlights four particular CFTR introns of interest. Using reporter gene constructs in intestinal cells, we show that two new introns display strong cooperative effects in intestinal cells. Chromatin immunoprecipitation analyses further demonstrate fixation of transcription factors network. These results provide new insights into our understanding of the CFTR gene regulation and allow us to suggest a 3D CFTR locus structure in intestinal cells. A better understand of regulation mechanisms of the CFTR gene could elucidate cases of patients where the phenotype is not yet explained by the genotype. This would thus help in better diagnosis and therefore better management. These cis-acting regions may be a therapeutic challenge that could lead to the development of specific molecules capable of modulating gene expression in the future.

Published
2021

38. Combining full-length gene assay and SpliceAI to interpret the splicing impact of all possible SPINK1coding variants

Author

Wu, Hao, Lin, Jin-Huan, Tang, Xin-Ying, Marenne, Gaëlle, Zou, Wen-Bin, Schutz, Sacha, Masson, Emmanuelle, Génin, Emmanuelle, Fichou, Yann, Le Gac, Gerald, Férec, Claude, Liao, Zhuan, and Chen, Jian-Min

Abstract

Background: Single-nucleotide variants (SNVs) within gene coding sequences can significantly impact pre-mRNA splicing, bearing profound implications for pathogenic mechanisms and precision medicine. In this study, we aim to harness the well-established full-length gene splicing assay (FLGSA) in conjunction with SpliceAI to prospectively interpret the splicing effects of all potential coding SNVs within the four-exon SPINK1gene, a gene associated with chronic pancreatitis. Results: Our study began with a retrospective analysis of 27 SPINK1coding SNVs previously assessed using FLGSA, proceeded with a prospective analysis of 35 new FLGSA-tested SPINK1coding SNVs, followed by data extrapolation, and ended with further validation. In total, we analyzed 67 SPINK1coding SNVs, which account for 9.3% of the 720 possible coding SNVs. Among these 67 FLGSA-analyzed SNVs, 12 were found to impact splicing. Through detailed comparison of FLGSA results and SpliceAI predictions, we inferred that the remaining 653 untested coding SNVs in the SPINK1gene are unlikely to significantly affect splicing. Of the 12 splice-altering events, nine produced both normally spliced and aberrantly spliced transcripts, while the remaining three only generated aberrantly spliced transcripts. These splice-impacting SNVs were found solely in exons 1 and 2, notably at the first and/or last coding nucleotides of these exons. Among the 12 splice-altering events, 11 were missense variants (2.17% of 506 potential missense variants), and one was synonymous (0.61% of 164 potential synonymous variants). Notably, adjusting the SpliceAI cut-off to 0.30 instead of the conventional 0.20 would improve specificity without reducing sensitivity. Conclusions: By integrating FLGSA with SpliceAI, we have determined that less than 2% (1.67%) of all possible coding SNVs in SPINK1significantly influence splicing outcomes. Our findings emphasize the critical importance of conducting splicing analysis within the broader genomic sequence context of the study gene and highlight the inherent uncertainties associated with intermediate SpliceAI scores (0.20 to 0.80). This study contributes to the field by being the first to prospectively interpret all potential coding SNVs in a disease-associated gene with a high degree of accuracy, representing a meaningful attempt at shifting from retrospective to prospective variant analysis in the era of exome and genome sequencing.

Published
2024
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39. A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome

Author

Delvallée, Clarisse, Nicaise, Samuel, Antin, Manuela, Leuvrey, Anne-Sophie, Nourisson, Elsa, Leitch, Carmen C, Kellaris, Georgios, Stoetzel, Corinne, Geoffroy, Véronique, Scheidecker, Sophie, Keren, Boris, Depienne, Christel, Klar, Joakim, Dahl, Niklas, Deleuze, Jean-François, Génin, Emmanuelle, Redon, Richard, Demurger, Florence, Devriendt, Koenraad, Mathieu-Dramard, Michèle, Poitou-Bernert, Christine, Odent, Sylvie, Katsanis, Nicholas, Mandel, Jean-Louis, Davis, Erica E, Dollfus, Hélène, Muller, Jean, Delvallée, Clarisse, Nicaise, Samuel, Antin, Manuela, Leuvrey, Anne-Sophie, Nourisson, Elsa, Leitch, Carmen C, Kellaris, Georgios, Stoetzel, Corinne, Geoffroy, Véronique, Scheidecker, Sophie, Keren, Boris, Depienne, Christel, Klar, Joakim, Dahl, Niklas, Deleuze, Jean-François, Génin, Emmanuelle, Redon, Richard, Demurger, Florence, Devriendt, Koenraad, Mathieu-Dramard, Michèle, Poitou-Bernert, Christine, Odent, Sylvie, Katsanis, Nicholas, Mandel, Jean-Louis, Davis, Erica E, Dollfus, Hélène, and Muller, Jean

Abstract

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.

Published
2021
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42. Moment estimators of relatedness from low-depth whole-genome sequencing data.

Author

Herzig, Anthony F., Ciullo, M., FranceGenRef Consortium, Deleuze, Jean-François, Génin, Emmanuelle, Redon, Richard, Adjou, Chantal, Chatel, Stéphanie, Férec, Claude, Goldberg, Marcel, Halbout, Philippe-Antoine, Le Marec, Hervé, L'Helgouach, David, Rouault, Karen, Schott, Jean-Jacques, Vogelsperger, Anne, Zins, Marie, Bacq, Delphine, Blanchet, Hélène, and Boland, Anne

Subjects
NUCLEOTIDE sequencing, KINSHIP, BROTHERLINESS, GENOTYPES
Abstract

Background: Estimating relatedness is an important step for many genetic study designs. A variety of methods for estimating coefficients of pairwise relatedness from genotype data have been proposed. Both the kinship coefficient φ and the fraternity coefficient ψ for all pairs of individuals are of interest. However, when dealing with low-depth sequencing or imputation data, individual level genotypes cannot be confidently called. To ignore such uncertainty is known to result in biased estimates. Accordingly, methods have recently been developed to estimate kinship from uncertain genotypes. Results: We present new method-of-moment estimators of both the coefficients φ and ψ calculated directly from genotype likelihoods. We have simulated low-depth genetic data for a sample of individuals with extensive relatedness by using the complex pedigree of the known genetic isolates of Cilento in South Italy. Through this simulation, we explore the behaviour of our estimators, demonstrate their properties, and show advantages over alternative methods. A demonstration of our method is given for a sample of 150 French individuals with down-sampled sequencing data. Conclusions: We find that our method can provide accurate relatedness estimates whilst holding advantages over existing methods in terms of robustness, independence from external software, and required computation time. The method presented in this paper is referred to as LowKi (Low-depth Kinship) and has been made available in an R package (https://github.com/genostats/LowKi). [ABSTRACT FROM AUTHOR]

Published
2022
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47. A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet‐Biedl syndrome

Author

Delvallée, Clarisse, primary, Nicaise, Samuel, additional, Antin, Manuela, additional, Leuvrey, Anne‐Sophie, additional, Nourisson, Elsa, additional, Leitch, Carmen C., additional, Kellaris, Georgios, additional, Stoetzel, Corinne, additional, Geoffroy, Véronique, additional, Scheidecker, Sophie, additional, Keren, Boris, additional, Depienne, Christel, additional, Klar, Joakim, additional, Dahl, Niklas, additional, Deleuze, Jean‐François, additional, Génin, Emmanuelle, additional, Redon, Richard, additional, Demurger, Florence, additional, Devriendt, Koenraad, additional, Mathieu‐Dramard, Michèle, additional, Poitou‐Bernert, Christine, additional, Odent, Sylvie, additional, Katsanis, Nicholas, additional, Mandel, Jean‐Louis, additional, Davis, Erica E., additional, Dollfus, Hélène, additional, and Muller, Jean, additional

Published
2020
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50. CNV assessment using the Illumina Infinium 1M platform: Agreement according to algorithm and source of DNA

Author

Marenne, Gaëlle, Chanock, Stephen, Rothman, Nathaniel, Rodríguez-Santiago, Benjamín, Rico, Daniel, Pita, Guillermo, Pérez-Jurado, Luis, Valencia, Alfonso, Jacobs, Kevin, Pisano, David G., Díaz-Uriarte, Ramón, Earl, Julie, García-Closas, Montserrat, Silverman, Debra, Kogevinas, Manolis, Génin, Emmanuelle, Real, Francisco X, and Malats, Núria

Published
2009
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