Author: "Thierry, Frebourg" / Topic: male - Searchworks@Jio Institute Digital Library Search Results

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138 results on '"Thierry, Frebourg"'

1. Circulating <scp>DNA</scp> changes are predictive of disease progression after transarterial chemoembolization

Author: Ludivine Beaussire, Pierre Michel, Alice Gangloff, Thierry Frebourg, L. Schwarz, Odile Goria, Slim Ghomadi, Jean-Jacques Tuech, Vincent Verdier, Frédéric Di Fiore, Céline Savoye-Collet, Ghassan Riachi, David Sefrioui, Nasrin Sarafan-Vasseur, and Hélène Montialoux
Subjects: Male, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, Gastroenterology, Internal medicine, medicine, Humans, Prospective Studies, Chemoembolization, Therapeutic, Liquid biopsy, Telomerase, Aged, Aged, 80 and over, Receiver operating characteristic, medicine.diagnostic_test, business.industry, Liver Neoplasms, Disease progression, Magnetic resonance imaging, DNA, Neoplasm, Middle Aged, medicine.disease, Oncology, Cell-free fetal DNA, Hepatocellular carcinoma, Mutation, Disease Progression, Circulating DNA, Female, alpha-Fetoproteins, business, Cell-Free Nucleic Acids, Progressive disease
Abstract: Transarterial chemoembolization (TACE) is used to treat patients with unresectable hepatocellular carcinoma (HCC). We evaluated the clinical impact of a-fetoprotein (AFP) and circulating cell-free and tumor DNA (cfDNA and ctDNA) changes around the TACE procedure. Our prospective monocentric study enrolled consecutive patients treated with TACE, with samples collected at baseline (D - 1), Day 2 (D + 2) and 1 month (M + 1) after TACE. cfDNA was quantified by the fluorometric method, and ctDNA was quantified by digital polymerase chain reaction designed for two hotspot TERT mutations. Computerized tomography scans or magnetic resonance imaging were performed at M + 1 every 3 months following TACE and independently reviewed. The objective was to identify thresholds of cfDNA, ctDNA and AFP changes associated with progressive disease (PD) using receiver operating characteristic curves. Thirty-eight patients were included from March 2018 to March 2019. All markers significantly increased from D - 1 to D + 2 (P .005), and cfDNA and ctDNA significantly decreased from D + 2 to M + 1 (P .0001). The analysis of changes from D - 1 to M + 1 identified thresholds at +31.4% for cfDNA and 0% for ctDNA that were significantly associated with PD at M + 1 (44.4% [+31.4%] vs 3.8% [≤+31.4%] and 50.0% [0%] vs 5.0% [≤0%], respectively). No significant threshold was identified for AFP. Using a score combining cfDNA and ctDNA, the patients were classified into high- or low-risk PD groups at M + 1, with PD rates of 80.0% vs 4.3% (P = .001) and median progression-free survival times of 1.3 vs 10.3 months (P = .002). Our study suggests that cfDNA and ctDNA increases around the TACE procedure and are associated with therapeutic failure.
Published: 2021
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2. CEA, CA19-9, circulating DNA and circulating tumour cell kinetics in patients treated for metastatic colorectal cancer (mCRC)

Author: David Sefrioui, Ludivine Beaussire, André Gillibert, France Blanchard, Emmanuel Toure, Céline Bazille, Anne Perdrix, Frédéric Ziegler, Alice Gangloff, Mélanie Hassine, Caroline Elie, Anne-Laure Bignon, Aurélie Parzy, Philippe Gomez, Caroline Thill, Florian Clatot, Jean-Christophe Sabourin, Thierry Frebourg, Jacques Benichou, Karine Bouhier-Leporrier, Marie-Pierre Gallais, Nasrin Sarafan-Vasseur, Pierre Michel, Frédéric Di Fiore, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Unité de biostatistiques [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Département de Pathologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Laboratoire de biochimie générale [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre hospitalier universitaire de Rouen, Hepatogastroenterologie, chu Elbeuf Les Feugrais, Hepatogastroenterology, Caen University Hospital, Caen., Department of Hepatogastroenterology, Caen University Hospital, Departement Hepatogastroenterologie, Centre Francois Baclesse, Caen, Medical Oncology, centre Frédéric Joliot, Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), Service d'Hépato-Gastroentérologie [CHU Rouen], and Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN)
Subjects: Adult, Male, Cell kinetics, Oncology, Cancer Research, medicine.medical_specialty, Scoring system, endocrine system diseases, Colorectal cancer, medicine.medical_treatment, Article, Circulating Tumor DNA, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Humans, Antigens, Tumor-Associated, Carbohydrate, In patient, Prospective Studies, Neoplasm Metastasis, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Chemotherapy, business.industry, Middle Aged, Neoplastic Cells, Circulating, medicine.disease, Survival Analysis, digestive system diseases, Carcinoembryonic Antigen, Up-Regulation, 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Circulating DNA, Female, CA19-9, Colorectal Neoplasms, business, Progressive disease
Abstract: BACKGROUND: We previously reported that CEA kinetics are a marker of progressive disease (PD) in metastatic colorectal cancer (mCRC). This study was specifically designed to confirm CEA kinetics for predicting PD and to evaluate CA19-9, cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) kinetics. METHODS: Patients starting a chemotherapy (CT) with pre-treatment CEA > 5 ng/mL and/or CA19.9 > 30 UI/mL were prospectively included. Samples were collected from baseline to cycle 4 for CEA and CA19-9 and at baseline and the sixth week for other markers. CEA kinetics were calculated from the first to the third or fourth CT cycle. RESULTS: A total of 192 mCRC patients were included. CEA kinetics based on the previously identified >0.05 threshold was significantly associated with PD (p
Published: 2021
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3. Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Author: Marianne Begorre, Daniel Cailliez, Claire Beneteau, Pierre Chenal, Thierry Frebourg, Guillaume Benoist, François Lecoquierre, Raphaele Mangione, Florence Petit, Nicolas Gruchy, Louise Devisme, Sophie Patrier, Juliette Coursimault, Fanny Pelluard, Hubert Journel, Bénédicte Gérard, Marion Gérard, Pascale Saugier-Veber, Valérie Layet, Alain Liquier, Corinne Jeanne, Mirjam M. de Jong, Nadia Tillouche, Anne Bazin, Gaël Nicolas, Conny M. A. van Ravenswaaij-Arts, Anne-Claire Brehin, Wilfrid Finck, Sophie Coutant, Sophie Degre, Christine Francannet, Madeleine Joubert, Hélène Laurichesse Delmas, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire CERBA [Saint Ouen l'Aumône], Service d'Anatomie Pathologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Lausanne = University of Lausanne (UNIL), Service de Gynécologie-Obstétrique et Médecine de la Reproduction [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe Hospitalier du Havre, University of Groningen [Groningen], Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique prénatale [CHU Caen], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service de Génétique [CHU Caen], Clinical Cognitive Neuropsychiatry Research Program (CCNP), Université de Lausanne (UNIL), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Genotype, audal dysgenesis, Ectromelia, [SDV]Life Sciences [q-bio], REQUIREMENT, Malformation sequence, Biology, Sirenomelia, CAUDAL REGRESSION, Frameshift mutation, 03 medical and health sciences, Genetics, medicine, Humans, CDX2 Transcription Factor, Genetic Predisposition to Disease, CDX2, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Calcium-Binding Proteins, 030305 genetics & heredity, Wnt signaling pathway, Heterozygote advantage, DEFECTS, medicine.disease, caudal dysgenesis, de novo mutation, Pedigree, Phenotype, Amino Acid Substitution, GROWTH, Female, CDX2 de novo mutation, exome sequencing
Abstract: Full access; International audience; Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio‐based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2 . We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.
Published: 2020
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4. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author: James W. Wheless, Thierry Frebourg, Robert Olaso, Rosemarie Smith, Kelly Nori, François Lecoquierre, Delphine Héron, Roseline Caumes, Anne Boland, Ange-Line Bruel, Candy Kumps, Gaël Nicolas, Sarah Stewart, Sophie Rondeau, Diane Doummar, Marlène Rio, Giulia Barcia, Anne-Marie Guerrot, Gwenaël Le Guyader, Alexandra Afenjar, Sarah Vergult, Karine Poirier, Juliette Coursimault, Jennifer Morrison, Amy Kritzer, Anne-Sophie Alaix, Rebecca Hernan, Anne-Sophie Denommé-Pichon, Sabine Sigaudy, Christine Coubes, Pascale Saugier-Veber, Francisca Millan Zamora, Austin Larson, Michelle M. Morrow, Christine Poitou, Björn Menten, Mathilde Nizon, Thomas Smol, Elise Schaefer, Bénédicte Gérard, Charles Coutton, Salima El Chehadeh, Fanggeng Zou, Stéphanie Valence, Anita Shanmugham, Wendy K. Chung, Bert Callewaert, Christina Kresge, Arnold Munnich, Beth A. Pletcher, Laurence Faivre, Estelle Colin, Laurence Colleaux, Patricia G Wheeler, Annelies Dheedene, Frédéric Tran Mau-Them, Jean-François Deleuze, Claude Houdayer, Jeanne Amiel, Frédéric Bilan, Marine Tessarech, Bertrand Isidor, Guillaume Jouret, Cyril Mignot, Benjamin Cogné, Shuxi Liu, Boris Keren, Françoise Devillard, Catherine Schramm, Margaret Helm, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), GeneDx [Gaithersburg, MD, USA], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique médicale d’Alsace, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Sorbonne Université (SU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Columbia University Irving Medical Center (CUIMC), University of Colorado Anschutz [Aurora], University of Tennessee System, Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Université de Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maine Medical Center, Arnold Palmer Hospital, Boston Children's Hospital, National Center of Genetics, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: Male, Bioinformatics, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, MESH: Child, Intellectual disability, Missense mutation, MESH: Obesity, MESH: Genetic Variation, MESH: Nerve Tissue Proteins, Child, Genetics (clinical), MESH: Genetic Association Studies, MESH: Heterozygote, 0303 health sciences, MESH: Transcription Factors, MESH: Infant, 3. Good health, Phenotype, MESH: Feeding and Eating Disorders, MESH: Young Adult, Child, Preschool, MESH: Epilepsy, Learning disability, Female, medicine.symptom, Adult, Heterozygote, Adolescent, Language delay, Nerve Tissue Proteins, Biology, MESH: Phenotype, MESH: Language Development Disorders, Feeding and Eating Disorders, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Language Development Disorders, Obesity, Genetic Association Studies, 030304 developmental biology, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Genetic Variation, Infant, MESH: Adult, medicine.disease, Human genetics, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Autism, MESH: Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.
Published: 2022
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5. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Author: Seçil Aksoy, Michael O. Woods, Heinric Williams, Bruno Buecher, Finlay A. Macrae, Lotte N. Krogh, Jay Qiu, Wan K.W. Juhari, Jan T. Lowery, Anne-Marie Gerdes, Magnus von Knebel Doeberitz, Luigi Ricciardiello, Karsten Schulmann, Jose Luis Soto, Kristina Lagerstedt-Robinson, Kiwamu Akagi, Raj Ramesar, Uffe Birk Jensen, Angel Alonso, Robert Hüneburg, Olivier Caron, Michel Longy, Jan Lubinski, Kate Green, Annabel Goodwin, D. Gareth Evans, Julie Wods, Leigha Senter, Matthew F. Kalady, Mark Clendenning, Barbara A. Leggett, Ravindran Ankathil, Swati G. Patel, Julian Barwell, Katherine M. Tucker, Grant Lee, Pascaline Berthet, Dawn M. Nixon, Sonia S. Kupfer, Naohiro Tomita, Susan Parry, Trinidad Caldés, Robert W. Haile, Edenir Inêz Palmero, Karin Alvarez, Cassandra B. Nichols, Mark A. Jenkins, N. Jewel Samadder, Loic LeMarchand, John Burn, Francisco Lopez, Rodney J. Scott, Pierre Laurent-Puig, Julie Arnold, Christina Therkildsen, Hans K. Schackert, Pilar Garre, Reinhard Buettner, Adriana Della Valle, Patricia Esperon, Wolff Schmiegel, Karl Heinimann, Inge Bernstein, Matthias Kloor, Nicoline Hoogerbrugge, Rui Manuel Reis, Fränzel J.B. Van Duijnhoven, Christoph Engel, Mohd Nizam Zahary, Sylviane Olschwang, Sapna Syngal, Valérie Bonadona, Nicholas Pachter, Matilde Navarro, Albert de la Chapelle, Beate Betz, Jukka-Pekka Mecklin, Catherine Noguès, Elena M. Stoffel, Toni T. Seppälä, Chrystelle Colas, Anneke Lucassen, Allan D. Spigelman, Youenn Drouet, Elisa J. Cops, Uri Ladabaum, Steve Thibodeau, Jeffrey N. Weitzel, Fiona Lalloo, Patrick J. Morrison, Maurizio Genuardi, Kohji Tanakaya, Patrick M. Lynch, Frederik J. Hes, William D. Foulkes, Carmen Guillén-Ponce, Jenny von Salomé, Emilia Rogoża-Janiszewska, Andrew Latchford, John L. Hopper, Carrie Snyder, Verónica Barca-Tierno, Gabriela Möslein, Lauren M. Gima, Melissa C. Southey, Paul A. James, Marion Dhooge, Claudia Perne, Steven Gallinger, Heather Hampel, Amanda B. Spurdle, Ingrid Winship, Emmanuelle Fourme, Rish K. Pai, Daniela Turchetti, Marta Pineda, Jürgen Weitz, James Hill, Daniel D. Buchanan, Carlos A. Vaccaro, Noralane M. Lindor, Rachel Pearlman, Pål Møller, Christian P. Strassburg, Jane C. Figueiredo, Aída Falcón de Vargas, Silke Zachariae, Karolin Bucksch, Joanne Ngeow, Silke Redler, Henrik Okkels, Maija R.J. Kohonen-Corish, Hans F. A. Vasen, Verena Steinke-Lange, Roselyne Guimbaud, Deepak Vangala, Isabelle Coupier, Nils Rahner, Berrin Tunca, Sanne W. Bajwa-ten Broeke, Niels de Wind, Sophie Lejeune, José Gaston Guillem, Karin Wadt, Polly A. Newcomb, Elke Holinski-Feder, Florencia Neffa, Rodrigo Santa Cruz Guindalini, Paul E. Wise, Julian R. Sampson, Graham Casey, Lene Juel Rasmussen, Rolf H. Sijmons, Tadeusz Dębniak, Ann-Sofie Backman, Joji Utsunomiya, Melyssa Aronson, Aung Ko Win, Yves-Jean Bignon, Judy W. C. Ho, Robyn L. Ward, Mev Dominguez-Valentin, Karolina Malińska, Elizabeth E. Half, John-Paul Plazzer, Marjolijn J. L. Ligtenberg, Rachel Austin, Nicola K. Poplawski, Marcia Cruz-Correa, Nagahide Matsubara, Charlotte Kvist Lautrup, Thomas Hansen, Tatsuro Yamaguchi, Thomas John, David J. Amor, Ilana Solomon, Yun-Hee Choi, Meghan J. van Wanzeele, Rakefet Shtoyerman, Vanessa Huntley, Maartje Nielsen, Deborah Neklason, Kevin J. Monahan, Gülçin Tezcan, Stefan Aretz, Talya Boisjoli, Sophie Giraud, Thierry Frebourg, Christophe Rosty, Heike Görgens, Lone Sunde, Allyson Templeton, Jacob Nattermann, Mala Pande, Joan Brunet, Nancy Uhrhammer, James M. Church, Florencia Spirandelli, Laurent Briollais, James G. Dowty, Jeanette C. Reece, Rachel Susman, Fay Kastrinos, Kirsi Pylvänäinen, Gabriel Capellá, Helène Schuster, Min H. Chew, Markus Loeffler, Christine Lasset, Michael J. Hall, Capuccine Delnatte, Floor A. Duijkers, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Digital Precision Cancer Medicine (iCAN), ATG - Applied Tumor Genomics, HUS Abdominal Center, Clinical sciences, Medical Genetics, Win A.K., Dowty J.G., Reece J.C., Lee G., Templeton A.S., Plazzer J.-P., Buchanan D.D., Akagi K., Aksoy S., Alonso A., Alvarez K., Amor D.J., Ankathil R., Aretz S., Arnold J.L., Aronson M., Austin R., Backman A.-S., Bajwa-ten Broeke S.W., Barca-Tierno V., Barwell J., Bernstein I., Berthet P., Betz B., Bignon Y.-J., Boisjoli T., Bonadona V., Briollais L., Brunet J., Bucksch K., Buecher B., Buettner R., Burn J., Caldes T., Capella G., Caron O., Casey G., Chew M.H., Choi Y.-H., Church J., Clendenning M., Colas C., Cops E.J., Coupier I., Cruz-Correa M., de la Chapelle A., de Wind N., Debniak T., Della Valle A., Delnatte C., Dhooge M., Dominguez-Valentin M., Drouet Y., Duijkers F.A., Engel C., Esperon P., Evans D.G., Falcon de Vargas A., Figueiredo J.C., Foulkes W., Fourme E., Frebourg T., Gallinger S., Garre P., Genuardi M., Gerdes A.-M., Gima L.M., Giraud S., Goodwin A., Gorgens H., Green K., Guillem J., Guillen-Ponce C., Guimbaud R., Guindalini R.S.C., Half E.E., Hall M.J., Hampel H., Hansen T.V.O., Heinimann K., Hes F.J., Hill J., Ho J.W.C., Holinski-Feder E., Hoogerbrugge N., Huneburg R., Huntley V., James P.A., Jensen U.B., John T., Juhari W.K.W., Kalady M., Kastrinos F., Kloor M., Kohonen-Corish M.R., Krogh L.N., Kupfer S.S., Ladabaum U., Lagerstedt-Robinson K., Lalloo F., Lasset C., Latchford A., Laurent-Puig P., Lautrup C.K., Leggett B.A., Lejeune S., LeMarchand L., Ligtenberg M., Lindor N., Loeffler M., Longy M., Lopez F., Lowery J., Lubinski J., Lucassen A.M., Lynch P.M., Malinska K., Matsubara N., Mecklin J.-P., Moller P., Monahan K., Morrison P.J., Nattermann J., Navarro M., Neffa F., Neklason D., Newcomb P.A., Ngeow J., Nichols C., Nielsen M., Nixon D.M., Nogues C., Okkels H., Olschwang S., Pachter N., Pai R.K., Palmero E.I., Pande M., Parry S., Patel S.G., Pearlman R., Perne C., Pineda M., Poplawski N.K., Pylvanainen K., Qiu J., Rahner N., Ramesar R., Rasmussen L.J., Redler S., Reis R.M., Ricciardiello L., Rogoza-Janiszewska E., Rosty C., Samadder N.J., Sampson J.R., Schackert H.K., Schmiegel W., Schulmann K., Schuster H., Scott R., Senter L., Seppala T.T., Shtoyerman R., Sijmons R.H., Snyder C., Solomon I.B., Soto J.L., Southey M.C., Spigelman A., Spirandelli F., Spurdle A.B., Steinke-Lange V., Stoffel E.M., Strassburg C.P., Sunde L., Susman R., Syngal S., Tanakaya K., Tezcan G., Therkildsen C., Thibodeau S., Tomita N., Tucker K.M., Tunca B., Turchetti D., Uhrhammer N., Utsunomiya J., Vaccaro C., van Duijnhoven F.J.B., van Wanzeele M.J., Vangala D.B., Vasen H.F.A., von Knebel Doeberitz M., von Salome J., Wadt K.A.W., Ward R.L., Weitz J., Weitzel J.N., Williams H., Winship I., Wise P.E., Wods J., Woods M.O., Yamaguchi T., Zachariae S., Zahary M.N., Hopper J.L., Haile R.W., Macrae F.A., Moslein G., and Jenkins M.A.
Subjects: 0301 basic medicine, Proband, Oncology, Male, Heredity, DNA mismatch repair, [SDV]Life Sciences [q-bio], SUSCEPTIBILITY, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Residence Characteristics, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PMS2, ComputingMilieux_MISCELLANEOUS, MLH1, Age Factors, Middle Aged, Penetrance, Lynch syndrome, 3. Good health, Pedigree, Phenotype, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, Adult, medicine.medical_specialty, PENETRANCE, congenital, hereditary, and neonatal diseases and abnormalities, GENES, 3122 Cancers, colorectal cancer, BREAST, Risk Assessment, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Retrospective Studies, business.industry, MUTATIONS, Cancer, medicine.disease, digestive system diseases, MSH2, MSH6, MODEL, INDIVIDUALS, 030104 developmental biology, Lynch Syndrome, Gene-Environment Interaction, business
Abstract: Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.
Published: 2021
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6. Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium

Author: Thierry Frebourg, Gwendoline Lienard, Stéphanie Baert-Desurmont, Camille Tlemsani, Nadim Hamzaoui, Lisa Golmard, Michel Bahuau, Gaëlle Bougeard, Edwige Kasper, Vincent Goussot, Stéphane Pinson, Elodie Lacaze, Marie-Pascale Beaumont, Emmanuelle Barouk Simonet, Sandrine Manase, Christine Toulas, Sophie Lejeune, Nancy Uhrhammer, Flavie Boulouard, Jacques Mauillon, Véronica Cusin, Stéphanie Vasseur, Marion Dhooge, Marie-Pierre Buisine, Claude Houdayer, Virginie Bubien, Florence Coulet, and Jean-Marc Rey
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Heterozygote, Colorectal cancer, Colonoscopy, Breast Neoplasms, 030105 genetics & heredity, 03 medical and health sciences, Deoxyribonuclease (Pyrimidine Dimer), Breast cancer, MUTYH, Neoplastic Syndromes, Hereditary, Internal medicine, Genetics, medicine, Biomarkers, Tumor, Humans, Basal cell carcinoma, Genetics (clinical), Germ-Line Mutation, Aged, Ovarian Neoplasms, medicine.diagnostic_test, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Melanoma, Cancer, Middle Aged, medicine.disease, Pedigree, 030104 developmental biology, Adenomatous Polyposis Coli, Female, Sarcoma, business, Colorectal Neoplasms
Abstract: Biallelic pathogenic variants in the NTHL1 (Nth Like DNA Glycosylase 1) gene cause a recently identified autosomal recessive hereditary cancer syndrome predisposing to adenomatous polyposis and colorectal cancer. Half of biallelic carriers also display multiple colonic or extra-colonic primary tumors, mainly breast, endometrium, urothelium and brain tumors. Published data designate NTHL1 as an important contributor to hereditary cancers but also underline the scarcity of available informations. Thanks to the French oncogenetic consortium (Groupe Genetique et Cancer), we collected NTHL1 variants from 7765 patients attending for hereditary colorectal cancer or polyposis (n =3936) or other hereditary cancers (n =3829). Here, we describe ten patients with pathogenic biallelic NTHL1 germline variants i.e. the second largest NTHL1 series. All carriers were from the "colorectal cancer or polyposis" series. All 9 biallelic carriers who underwent colonoscopy presented adenomatous polyps. For digestive cancers, average age at diagnosis was 56.2 and we reported colorectal, duodenal, caecal and pancreatic cancers. Extra-digestive malignancies included sarcoma, basal cell carcinoma, breast cancer, urothelial carcinoma and melanoma. Although tumor risks remain to be precisely defined, these novel data support NTHL1 inclusion in diagnostic panel testing. Colonic surveillance should be conducted based on MUTYH recommendations while extra-colonic surveillance has to be defined. This article is protected by copyright. All rights reserved.
Published: 2020

7. Clinical and molecular description of 19 patients with GATAD2B-Associated Neurodevelopmental Disorder (GAND)

Author: Gaël Nicolas, Yline Capri, Alban Ziegler, Christiane Zweier, Bénédicte Duban-Bedu, Roberta Polli, Neda Mazaheri, Alessandra Murgia, Cindy Colson, Pascale Saugier-Veber, Reza Maroofian, Laurence Perrin, François Lecoquierre, Stephan Waldmüller, Benjamin Cogné, Angelika Rieß, A.S. Lebre, M. Brasseur-Daudruy, Bert Callewaert, Antje Wiesener, Anne-Marie Guerrot, Thierry Frebourg, Thomas Smol, Benjamin Durand, Rebecca Buchert-Lo, Veronka Horber, Tobias B. Haack, Patrick Edery, Gabriella Vera, Gaetan Lesca, Geoffroy Delplancq, Sandra Mercier, Christopher Carroll, Maria Blandfort, Khaoula Zaafrane-Khachnaoui, Hamid Galehdari, Emanuela Leonardi, Arthur Sorlin, Fabienne Giulianno, Isabelle Sabatier, Florence Petit, Licia Turolla, Nicolas Chatron, Amélie Piton, Janine Magg, Estelle Colin, Stéphane Bézieau, Dominique Bonneau, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'imagerie médicale [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Génétique Moléculaire, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Service de Génétique Clinique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Université de Montpellier (UM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Center for Medical Genetics [Ghent], Ghent University Hospital, Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Human Genetics, and Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain
Subjects: Male, Pediatrics, Developmental delay, [SDV]Life Sciences [q-bio], GATA Transcription Factors, GATAD2B, Developmental delay, Intellectual disability, Next-generation sequencing, GATAD2B, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, Pregnancy, Intellectual disability, Hypertelorism, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Sequence Deletion, 0303 health sciences, Brain, High-Throughput Nucleotide Sequencing, General Medicine, Magnetic Resonance Imaging, Hypotonia, 3. Good health, Phenotype, Child, Preschool, Muscle Hypotonia, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Speech Disorders, 03 medical and health sciences, Disease severity, Intellectual Disability, Genetics, medicine, Humans, 030304 developmental biology, business.industry, Macrocephaly, Infant, medicine.disease, Megalencephaly, Repressor Proteins, Neurodevelopmental Disorders, Face, Next-generation sequencing, business, 030217 neurology & neurosurgery
Abstract: De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management.
Published: 2020
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8. Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes

Author: Maud Blanluet, Jacqueline Bou, Jacques Mauillon, Sandrine Manase, Steeve Fourneaux, Stéphanie Baert-Desurmont, Olivier Quenez, Julie Tinat, Marion Gérard, François Lecoquierre, Emilie Bouvignies, Myriam Vezain, Régine Marlin, Mathias Schwartz, Raphaël Lanos, Thierry Frebourg, Isabelle Tournier, Pierre Macquere, Sophie Coutant, Stéphanie Vasseur, Gaëlle Bougeard, Françoise Charbonnier, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: Adult, Male, 0301 basic medicine, Sequence analysis, Alu element, Computational biology, 030105 genetics & heredity, Biology, Sensitivity and Specificity, Article, 03 medical and health sciences, Exon, MUTYH, Genetics, medicine, Humans, Genetic Testing, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Massive parallel sequencing, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Exons, Sequence Analysis, DNA, Middle Aged, medicine.disease, Introns, digestive system diseases, Lynch syndrome, 3. Good health, MSH6, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MSH2, Female, Colorectal Neoplasms
Abstract: We have developed and validated for the diagnosis of inherited colorectal cancer (CRC) a massive parallel sequencing strategy based on: (i) fast capture of exonic and intronic sequences from ten genes involved in Mendelian forms of CRC (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, STK11, SMAD4, BMPR1A and PTEN); (ii) sequencing on MiSeq and NextSeq 500 Illumina platforms; (iii) a bioinformatic pipeline that includes BWA-Picard-GATK (Broad Institute) and CASAVA (Illumina) in parallel for mapping and variant calling, Alamut Batch (Interactive BioSoftware) for annotation, CANOES for CNV detection and finally, chimeric reads analysis for the detection of other types of structural variants (SVs). Analysis of 1644 new index cases allowed the identification of 323 patients with class 4 or 5 variants, corresponding to a 20% disease-causing variant detection rate. This rate reached 37% in patients with Lynch syndrome, suspected on the basis of tumour analyses. Thanks to this strategy, we detected overlapping phenotypes (e.g., MUTYH biallelic mutations mimicking Lynch syndrome), mosaic alterations and complex SVs such as a genomic deletion involving the last BMPR1A exons and PTEN, an Alu insertion within MSH2 exon 8 and a mosaic deletion of STK11 exons 3–10. This strategy allows, in a single step, detection of all types of CRC gene alterations including SVs and provides a high disease-causing variant detection rate, thus optimizing the diagnosis of inherited CRC.
Published: 2018
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9. Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer’s Disease Patient

Author: Hélène Tubeuf, Kilan Le Guennec, Anne-Claire Richard, Jean-François Deleuze, Dominique Campion, Anne Boland, David Wallon, Didier Hannequin, Alexandra Martins, Olivier Quenez, Thierry Frebourg, Pascaline Gaildrat, Stéphane Rousseau, Gaël Nicolas, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre National de Génotypage (CNG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Male, 0301 basic medicine, Proband, [SDV]Life Sciences [q-bio], Biology, Compound heterozygosity, 03 medical and health sciences, Exon, 0302 clinical medicine, Gene Frequency, Alzheimer Disease, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Early-onset Alzheimer's disease, LDL-Receptor Related Proteins, ComputingMilieux_MISCELLANEOUS, Loss function, Exome sequencing, Genetics, General Neuroscience, Genetic Variation, Membrane Transport Proteins, General Medicine, Middle Aged, medicine.disease, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Case-Control Studies, RNA splicing, Female, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Minigene
Abstract: Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer's disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5' splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient.
Published: 2018
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10. Gestational choriocarcinoma associated with a germline TP53 mutation

Author: Sophie Patrier-Sallebert, Anne-Claire Brehin, Gaëlle Bougeard, Capucine Delnatte, Sophie Sadot-Lebouvier, Sylvie Odent, Eric Vuillemin, Gwendoline Side-Pfennig, Francisco Llamas Gutierrez, A. Lamy, François Golfier, Elodie Colasse, Thierry Frebourg, Jean-Christophe Sabourin, Christine Kandel-Aznar, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), CRLCC René Gauducheau, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Chirurgie Gynécologique et Oncologique – Obstétrique [CHU Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Gestational trophoblastic disease, Lung Neoplasms, Biology, Germline, Malignant transformation, Gestational choriocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, Chorionic Gonadotropin, beta Subunit, Human, Li-Fraumeni syndrome, TP53, Choriocarcinoma, Allele, Pneumonectomy, Lung, neoplasms, ComputingMilieux_MISCELLANEOUS, Germ-Line Mutation, reproductive and urinary physiology, Genetics (clinical), medicine.disease, female genital diseases and pregnancy complications, 3. Good health, 030104 developmental biology, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Oncology, Li–Fraumeni syndrome, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, Female, Methotrexate, Tumor Suppressor Protein p53, medicine.drug
Abstract: Choriocarcinoma is a highly malignant neoplasm resulting from the malignant transformation of proliferating trophoblastic cells and the molecular mechanisms leading to this transformation remain to be characterized. We report here the first case of a female germline TP53 mutation carrier who developed, as a first tumour, a lung choriocarcinoma, 6 months after a normal delivery. Molecular analyses established the gestational origin of the choriocarcinoma and showed, within the tumour, the presence of the germline mutant TP53 allele and loss of the wild-type allele. Resistance to methotrexate chemotherapy led to perform a surgical resection of the tumour. In agreement with the permissive role of TP53 mutations to oncogenic events, this report strongly suggests that TP53 mutations may promote malignant transformation of proliferating trophoblastic cells. Therefore, female TP53 mutation carriers may have an increased risk of developing gestational choriocarcinoma and might benefit from β-hCG level monitoring after pregnancy.
Published: 2017
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11. A Simple, Universal, and Cost-Efficient Digital PCR Method for the Targeted Analysis of Copy Number Variations

Author: Ludivine Beaussire, Nathalie Le Meur, Géraldine Joly-Helas, Anne-Claire Brehin, Anne Boland, Gaël Nicolas, Dominique Campion, Jean-François Deleuze, Pascal Chambon, Anne Rovelet-Lecrux, Kévin Cassinari, Mathieu Castelain, Thierry Frebourg, Nasrin Sarafan-Vasseur, Olivier Quenez, Nicolas Gruchy, Pascale Saugier-Veber, Anne-Marie Guerrot, Alice Goldenberg, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Umea Plant Science Center (UPSC), Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences (SLU)-Swedish University of Agricultural Sciences (SLU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de cytogénétique prénatale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), and The authors are grateful to Matthieu Dujardin, Coralie Tiercin, Stéphane Le Mignot, Donovan Liot, Anne-Claire Richard, Stéphane Rousseau, Françoise Charbonnier, and Myriam Vezain for technical support.
Subjects: Male, 0301 basic medicine, DNA Copy Number Variations, Computer science, Clinical Biochemistry, Oligonucleotides, Computational biology, Polymerase Chain Reaction, Genome, 03 medical and health sciences, 0302 clinical medicine, Humans, Genomic medicine, Digital polymerase chain reaction, Copy-number variation, Locked nucleic acid, Selection (genetic algorithm), [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Genome, Human, Hydrolysis, Biochemistry (medical), Reproducibility of Results, DNA, Amplicon, 3. Good health, 030104 developmental biology, Human genome, 030217 neurology & neurosurgery
Abstract: BACKGROUND Rare copy number variations (CNVs) are a major cause of genetic diseases. Simple targeted methods are required for their confirmation and segregation analysis. We developed a simple and universal CNV assay based on digital PCR (dPCR) and universal locked nucleic acid (LNA) hydrolysis probes. METHODS We analyzed the mapping of the 90 LNA hydrolysis probes from the Roche Universal ProbeLibrary (UPL). For each CNV, selection of the optimal primers and LNA probe was almost automated; probes were reused across assays and each dPCR assay included the CNV amplicon and a reference amplicon. We assessed the assay performance on 93 small and large CNVs and performed a comparative cost-efficiency analysis. RESULTS UPL-LNA probes presented nearly 20000000 occurrences on the human genome and were homogeneously distributed with a mean interval of 156 bp. The assay accurately detected all the 93 CNVs, except one ( CONCLUSIONS The universal dPCR CNV assay is simple, robust, and cost-efficient because it combines a straightforward design allowed by universal probes and end point PCR, the advantages of a relative quantification of the target to the reference within the same reaction, and the high flexibility of the LNA hydrolysis probes. This method should be a useful tool for genomic medicine, which requires simple methods for the interpretation and segregation analysis of genomic variations.
Published: 2019
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12. Skipping Nonsense to Maintain Function: The Paradigm of

Author: Laëtitia, Meulemans, Romy L S, Mesman, Sandrine M, Caputo, Sophie, Krieger, Marine, Guillaud-Bataille, Virginie, Caux-Moncoutier, Mélanie, Léone, Nadia, Boutry-Kryza, Johanna, Sokolowska, Françoise, Révillion, Capucine, Delnatte, Hélène, Tubeuf, Omar, Soukarieh, Françoise, Bonnet-Dorion, Virginie, Guibert, Myriam, Bronner, Violaine, Bourdon, Sarab, Lizard, Paul, Vilquin, Maud, Privat, Aurélie, Drouet, Charlotte, Grout, Fabienne M G R, Calléja, Lisa, Golmard, Harry, Vrieling, Dominique, Stoppa-Lyonnet, Claude, Houdayer, Thierry, Frebourg, Maaike P G, Vreeswijk, Alexandra, Martins, and Pascaline, Gaildrat
Subjects: Adult, Aged, 80 and over, BRCA2 Protein, Male, Exons, Middle Aged, Polymorphism, Single Nucleotide, Recombinant Proteins, Pedigree, Alternative Splicing, Mice, Loss of Function Mutation, Cell Line, Tumor, Animals, Hereditary Breast and Ovarian Cancer Syndrome, Humans, Female, Genetic Predisposition to Disease, Embryonic Stem Cells, Aged
Abstract: Germline nonsense and canonical splice site variants identified in disease-causing genes are generally considered as loss-of-function (LoF) alleles and classified as pathogenic. However, a fraction of such variants could maintain function through their impact on RNA splicing. To test this hypothesis, we used the alternatively spliced
Published: 2019

13. Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer’s Disease

Author: Anne Boland, Gaël Nicolas, Camille Charbonnier, Sébastien S. Hébert, Annie Laquerrière, Kévin Cassinari, Emmanuelle Boscher, Dominique Campion, Olivier Martinaud, Jean-François Deleuze, Thomas Husson, David Wallon, Olivier Quenez, Mark Lathrop, Anne Rovelet-Lecrux, Florent Marguet, Thierry Frebourg, CHU de Québec–Université Laval, Université Laval [Québec] (ULaval), Faculté de médecine de l'Université Laval [Québec] (ULaval), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Department of Pathology, Rouen University Hospital, Service de neurologie [Rouen], CHU Rouen, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Département de Pathologie [CHU Rouen]
Subjects: Adult, Male, 0301 basic medicine, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Blotting, Western, miR-138, Locus (genetics), Biology, Real-Time Polymerase Chain Reaction, Gene dosage, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Risk Factors, Exome Sequencing, PSEN2, Gene duplication, mental disorders, PSEN1, medicine, Humans, Genetic Predisposition to Disease, Early-onset Alzheimer's disease, Copy-number variation, Age of Onset, Cells, Cultured, Exome sequencing, Aged, Genetics, Copy number variants, microRNA, General Neuroscience, early-onset Alzheimer’s disease, General Medicine, Middle Aged, medicine.disease, 3. Good health, MicroRNAs, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Case-Control Studies, Female, Geriatrics and Gerontology, Multiplex Polymerase Chain Reaction, 030217 neurology & neurosurgery
Abstract: International audience; Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP, PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1. This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD.
Published: 2019
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14. Hypersociability associated with developmental delay, macrocephaly and facial dysmorphism points to CHD3 mutations

Author: François Lecoquierre, Anne Boland, Valérie Drouin-Garraud, Gaël Nicolas, Thierry Frebourg, Juliette Coursimault, Jean-François Deleuze, J. Lechevallier, Anne-Claire Brehin, and Pascale Saugier-Veber
Subjects: Male, Hypersociability, Pediatrics, medicine.medical_specialty, Developmental Disabilities, Craniofacial Abnormalities, Young Adult, Intellectual disability, Genetics, medicine, Humans, Global developmental delay, Hypertelorism, Social Behavior, Genetics (clinical), business.industry, DNA Helicases, Macrocephaly, Syndrome, General Medicine, medicine.disease, Megalencephaly, Developmental disorder, Autism spectrum disorder, Mutation, Speech delay, medicine.symptom, business, Mi-2 Nucleosome Remodeling and Deacetylase Complex
Abstract: CHD3-related syndrome, also known as Snijders Blok-Campeau syndrome, is a rare developmental disorder described in 2018, caused by de novo pathogenic variants in the CHD3 gene. This syndrome is characterized by global developmental delay, speech delay, intellectual disability, hypotonia and behavioral disorders including autism spectrum disorder (ASD). Typical dysmorphic features include macrocephaly, hypertelorism, enophthalmia, sparse eyebrows, bulging forehead, midface hypoplasia, prominent nose and pointed chin. To our knowledge, there have been no other clinical descriptions of patients since the initial publication. We report the clinical description of a 21-year-old patient harboring a pathogenic de novo variant in CHD3. We reviewed the clinical features of the 35 previously reported patients. Main features were severe intellectual disability, dysmorphic facies, macrocephaly, cryptorchidism, pectus carinatum, severe ophthalmologic abnormalities and behavioral disorders including ASD, and a frank happy demeanor. Hypersociability, which was a noticeable clinical feature in our case, despite ASD, is an uncommon behavioral feature in syndromic intellectual disabilities. Our report supports hypersociability as a suggestive feature of CHD3-related syndrome along with developmental delay, macrocephaly and a dysmorphic facies.
Published: 2021
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15. Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability

Author: Gabriela Bindea, Arash Rafii, Pauline Maby, David Tougeron, Richard Sesboüé, Florence Le Pessot, Mihaela Angelova, Pierre Laurent-Puig, Maria Fischer, Jean-Christophe Sabourin, Maristella Sasso, Bernhard Mlecnik, Tessa Fredriksen, Anna C. Obenauf, Lucie Lafontaine, Franck Pagès, Jacques Mauillon, Jean-Baptiste Latouche, Amélie M. Bilocq, Pierre Michel, Mohamad Hamieh, Thierry Frebourg, Zlatko Trajanoski, Helen K. Angell, Viia Valge-Archer, Jérôme Galon, Jean-Jacques Tuech, Patrick Bruneval, Sarah E. Church, Anne Berger, Michael R. Speicher, Amos Kirilovsky, Inovarion, Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Innsbruck Medical University [Austria] (IMU), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medical University Graz, Université de Rouen Normandie (UNIROUEN), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Immunopathologie humaine, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie digestive [CHU Rouen], CHU Rouen, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Service de génétique [Rouen], Weill Cornell Medical College in Qatar (WCMC-Q), Weill Cornell Medicine [Qatar], Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency (UMR 1203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-CHU Montpellier, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Groupe de recherches expérimentales sur l'acte musical (GREAM), Université de Strasbourg (UNISTRA), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), AstraZeneca [Cambridge, UK], Génétique du cancer et des maladies neuropsychiatriques (GMFC), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastroentérologie [Rouen], École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de chirurgie digestive [Rouen], Service d'Anatomie et Cytologie Pathologique [Rouen], and Groupe de recherches expérimentales sur l'acte musical - [LabEx] (GREAM)
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Immunology, Biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Predictive Value of Tests, T-Lymphocyte Subsets, Chromosome instability, medicine, Humans, Cytotoxic T cell, Immunology and Allergy, Pathology, Molecular, Frameshift Mutation, Cells, Cultured, Survival analysis, Aged, Aged, 80 and over, Immunoassay, Microsatellite instability, Immunotherapy, Th1 Cells, Cytotoxicity Tests, Immunologic, Prognosis, medicine.disease, Survival Analysis, 3. Good health, 030104 developmental biology, Infectious Diseases, Immunoediting, 030220 oncology & carcinogenesis, Cancer research, Female, Microsatellite Instability, Colorectal Neoplasms, Transcriptome, Immunologic Memory, Microsatellite Repeats
Abstract: International audience; Microsatellite instability in colorectal cancer predicts favorable outcomes. However, the mechanistic relationship between microsatellite instability, tumor-infiltrating immune cells, Immunoscore, and their impact on patient survival remains to be elucidated. We found significant differences in mutational patterns, chromosomal instability, and gene expression that correlated with patient microsatellite instability status. A prominent immune gene expression was observed in microsatellite-instable (MSI) tumors, as well as in a subgroup of microsatellite-stable (MSS) tumors. MSI tumors had increased frameshift mutations, showed genetic evidence of immunoediting, had higher densities of Th1, effector-memory T cells, in situ proliferating T cells, and inhibitory PD1-PDL1 cells, had high Immunoscores, and were infiltrated with mutation-specific cytotoxic T cells. Multivariate analysis revealed that Immunoscore was superior to microsatellite instability in predicting patients' disease-specific recurrence and survival. These findings indicate that assessment of the immune status via Immunoscore provides a potent indicator of tumor recurrence beyond microsatellite-instability staging that could be an important guide for immunotherapy strategies.
Published: 2016
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16. Postmortem Diagnosis of Heart-hand Syndrome Associated With a 7p22.1p22.3 Deletion in a 16-week-old Fetus

Author: Thierry Frebourg, Sophie Patrier, Jean-Christophe Sabourin, Aude Tessier, Nathalie LeMeur, and Patrick Callier
Subjects: Male fetus, Genetic Markers, Heart Defects, Congenital, Male, rac1 GTP-Binding Protein, Pathology, medicine.medical_specialty, Limb defects, HEART-HAND SYNDROME, Heart Septal Defects, Atrial, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Abnormalities, Multiple, Upper Extremity Deformities, Congenital, Fetal Death, Postmortem Diagnosis, Fetus, Pelvic kidney, 030219 obstetrics & reproductive medicine, business.industry, Chromosome, General Medicine, medicine.disease, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Gestation, business, Chromosomes, Human, Pair 7, Gene Deletion, Lower Extremity Deformities, Congenital
Abstract: We report a male fetus with a 6.8 Mb deletion on chromosome 7p22.1p22.3 at 16 weeks of gestation. The fetus presented a heart-hand syndrome with great artery malposition, bilateral radial ray deficiency, a single pelvic kidney, and growth retardation. This deletion involves a minimal deleted region for cardiac malformation and the RAC1 gene, previously described in limb anomalies in mice. This fetus is the third human case with limb defects and RAC1 deletion.
Published: 2018

17. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease

Author: Dominique Campion, Colin Smith, Manon S. Oud, Safa Al Sarraj, Stefan H. Lelieveld, Gaël Nicolas, Anne-Claire Richard, Florent Marguet, Christian Gilissen, Thierry Frebourg, Alexander Hoischen, Joris A. Veltman, Rocio Acuna-Hidalgo, Didier Hannequin, Stéphane Rousseau, Patrick F. Chinnery, Olivier Quenez, Olaf Ansorge, Christopher Morris, Annie Laquerrière, Michael J. Keogh, Johannes Attems, David Wallon, Marloes Steehouwer, Chinnery, Patrick [0000-0002-7065-6617], Apollo - University of Cambridge Repository, PORCHET, Nathalie, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Radboud University Medical Center [Nijmegen], Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Department of Human Genetics [Nijmegen], Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Building Research Establishment (BRE/Edinburgh), University of Edinburgh, John Radcliffe Hospital [Oxford University Hospital], King‘s College London, Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Service de neurologie [Rouen], Mitochondrial Research Group, University of Northumbria at Newcastle [United Kingdom], and Department of Pathology, Rouen University Hospital
Subjects: 0301 basic medicine, Post‐zygotic, Adult, Male, Epidemiology, Somatic cell, [SDV]Life Sciences [q-bio], SORL1, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology, medicine.disease_cause, Deep sequencing, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Developmental Neuroscience, Alzheimer Disease, PSEN2, medicine, PSEN1, Humans, Genetic Predisposition to Disease, Prion‐like, Allele, Prion-like, Aged, Genes, Dominant, Genetics, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Mosaicism, Post-zygotic, Health Policy, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Amplicon, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, 030104 developmental biology, Alzheimer, Female, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery
Abstract: Introduction A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP , PSEN1 , or PSEN2 . We hypothesized that negatively screened patients may harbor somatic variants in these genes. Methods We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, Results We identified and confirmed nine somatic variants (allele fractions: 0.2%–10.8%): two APP , five SORL1 , one NCSTN , and one MARK4 variant by independent amplicon-based deep sequencing. Discussion Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases.
Published: 2018
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18. Clinical value of chip-based digital-PCR platform for the detection of circulating DNA in metastatic colorectal cancer

Author: David Sefrioui, Nasrin Sarafan-Vasseur, Ludivine Beaussire, Marina Baretti, Alice Gangloff, France Blanchard, Florian Clatot, Jean-Christophe Sabourin, Richard Sesboüé, Thierry Frebourg, Pierre Michel, Frédéric Di Fiore, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Groupe d'étude des proliférations lymphoïdes (GPL), and Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Colorectal cancer, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, Polymerase Chain Reaction, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Biomarkers, Tumor, medicine, Humans, Mutational status, Digital polymerase chain reaction, Neoplasm Metastasis, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Hepatology, business.industry, Gastroenterology, Cancer, DNA, Neoplasm, Middle Aged, Prognosis, medicine.disease, Molecular biology, 3. Good health, Survival Rate, Genes, ras, chemistry, Quartile, 030220 oncology & carcinogenesis, Mutation, Clinical value, Circulating DNA, Female, Colorectal Neoplasms, business, DNA
Abstract: The detection of circulating DNA is considered a promising strategy in cancer patients. Digital PCR has emerged as a sensitive method able to quantify both circulating free and tumour DNA.The aim of this study was to prospectively evaluate the clinical value of a chip-based digital PCR for the detection of circulating DNA.Digital PCR was used in 34 metastatic colorectal cancer patients to detect and quantify circulating free and tumour DNA based on K-ras mutational status. Clinical outcomes were analyzed according to circulating DNA measurements.Digital PCR yielded a detection rate of 69% for circulating tumour DNA. The median concentrations of circulating free and tumour DNA were 20 and 6.8 ng/mL, respectively, with significant correlation between both biomarkers (p0.001). Median overall survival was 4.8 months in patients with high circulating free DNA (75% quartile) versus not reached in patients with a low level (25% quartile) (p=0.029). Moreover, median overall survival was significantly decreased in patients with detectable circulating tumour DNA compared to those without (respectively 11.8 months versus not reached, p=0.04).Chip-based digital PCR is a simple and non-invasive method allowing the efficient detection of circulating DNA. Our results highlight that levels of these circulating markers may have a potential prognostic value.
Published: 2015
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19. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort

Author: G Leverger, Thierry Frebourg, Rosine Guimbaud, Laurence Brugières, Alex Duval, Florence Coulet, Noémie Lavoine, Gaëlle Bougeard, Dominique Leroux, J.-P. Fricker, Olivier Caron, Michèle Mathieu-Dramard, Sophie Lejeune, Franck Bourdeaut, Qing Wang, G Sebille, S Baert-Dusermont, O Cohen-Hagenauer, Felipe Andreiuolo, G Jedraszak, Natacha Entz-Werle, Jacques Grill, G. Couillault, Marie-Pierre Buisine, Chrystelle Colas, Odile Cabaret, Julie Tinat, C. Charpy, Martine Muleris, Sahra Bodo, Léa Guerrini-Rousseau, Unité fonctionnelle d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), inconnu, Inconnu, Hôpital de Hautepierre [Strasbourg], Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Toulouse [Toulouse], Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Biology, Young Adult, Germline mutation, Neoplastic Syndromes, Hereditary, Genetics, medicine, PMS2, Humans, Child, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Adaptor Proteins, Signal Transducing, Mismatch Repair Endonuclease PMS2, Adenosine Triphosphatases, Brain Neoplasms, Mortality rate, Neurooncology, Infant, Nuclear Proteins, medicine.disease, Lynch syndrome, 3. Good health, DNA-Binding Proteins, MSH6, DNA Repair Enzymes, MutS Homolog 2 Protein, Treatment Outcome, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MSH2, Child, Preschool, Mutation, Immunology, Female, Age of onset, Colorectal Neoplasms, MutL Protein Homolog 1
Abstract: Background Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. Methods Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. Results 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2–33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26–213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations ( MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). Conclusions In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.
Published: 2015
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20. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease

Author: Didier Hannequin, A-C Richard, Emmanuelle Génin, Anne Boland, Delphine Bacq, Benjamin Grenier-Boley, Céline Bellenguez, Luc Letenneur, Olivier Quenez, Hans Markus Munter, J.F. Deleuze, J-C Lambert, Thierry Frebourg, Camille Charbonnier, Dominique Campion, Stéphane Rousseau, Vincent Meyer, Mark Lathrop, Gaël Nicolas, P. Amouyel, Robert Olaso, Guillaume Bourque, Richard Redon, J. F. Dartigues, J-G Garnier, David Wallon, Anne Rovelet-Lecrux, and K Le Guennec
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, SORL1, Bioinformatics, Amyloid beta-Protein Precursor, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Gene Frequency, Alzheimer Disease, Risk Factors, Internal medicine, Odds Ratio, medicine, Humans, Exome, Genetic Predisposition to Disease, Early-onset Alzheimer's disease, Risk factor, Family history, Molecular Biology, Allele frequency, Alleles, LDL-Receptor Related Proteins, Amyloid beta-Peptides, business.industry, Genetic Variation, Membrane Transport Proteins, Odds ratio, Middle Aged, medicine.disease, Minor allele frequency, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Female, France, business, 030217 neurology & neurosurgery
Abstract: The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.
Published: 2015
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21. Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation

Author: Rosine Guimbaud, Odile Cabaret, Julie Leclerc, Thierry Frebourg, Lucie Delattre, Tonio Lovecchio, Gilles Morin, Sophie Lejeune, Nelly Burnichon, Myriam Bronner, Emilie Ait Yahya, Pierre Laurent-Puig, Marie-Pierre Buisine, Nicole Porchet, Stéphanie Baert-Desurmont, Philippe Jonveaux, Jacques Mauillon, and Cathy Flament
Subjects: 0301 basic medicine, Adult, Male, Heterozygote, Alu element, Biology, MLH1, Polymorphism, Single Nucleotide, Epigenesis, Genetic, 03 medical and health sciences, symbols.namesake, Alu Elements, Gene duplication, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Promoter Regions, Genetic, Gene, Genetics (clinical), Alleles, Genetics, Intron, High-Throughput Nucleotide Sequencing, DNA Methylation, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Lynch syndrome, Introns, Pedigree, 030104 developmental biology, Haplotypes, Mutation, Mendelian inheritance, symbols, Female, MutL Protein Homolog 1
Abstract: Constitutional epimutations are an alternative to genetic mutations in the etiology of genetic diseases. Some of these epimutations, termed secondary, correspond to the epigenetic effects of cis-acting genetic defects transmitted to the offspring following a Mendelian inheritance pattern. In Lynch syndrome, a few families with such apparently heritable MLH1 epimutations have been reported so far. We designed a long-range polymerase chain reaction next-generation sequencing strategy to screen MLH1 entire gene and applied it to 4 French families with heritable epimutations and 10 additional patients with no proven transmission of their epimutations. This strategy successfully detected the insertion of an Alu element in MLH1 coding sequence in one family. Two previously unreported MLH1 variants were also identified in other epimutation carriers: a nucleotide substitution within intron 1 and a single-nucleotide deletion in the 5′-UTR. Detection of a partial MLH1 duplication in another family required multiplex ligation-dependent probe amplification technology. We demonstrated the segregation of these variants with MLH1 methylation and studied the functional consequences of these defects on transcription. This is the largest cohort of patients with MLH1 secondary epimutations associated with a broad spectrum of genetic defects. This study provides further insight into the complexity of molecular mechanisms leading to secondary epimutations.
Published: 2017

22. Deep intronic hotspot variant explaining rhabdoid tumor predisposition syndrome in two patients with atypical teratoid and rhabdoid tumor

Author: Pascale Varlet, Laurence Brugières, Thierry Frebourg, Annie Laquerrière, Gaëlle Pierron, Stéphanie Puget, Olivier Delattre, Julien Masliah-Planchon, Franck Bourdeaut, Damien Bodet, Christelle Dufour, Arnault Tauziède-Espariat, Emmanuèle Lechapt-Zalcman, Pascale Schneider, CH Belfort-Montbéliard, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unit of Somatic Genomics, Department of Genetics, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and TAN, Yossan-Var
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Short Report, Biology, Bioinformatics, Germline, Rhabdoid Tumor Predisposition Syndrome, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Molecular genetics, Genetics, medicine, Humans, SMARCB1, Cells, Cultured, Germ-Line Mutation, Rhabdoid Tumor, Genetics (clinical), Teratoma, Cytogenetics, Infant, SMARCB1 Protein, Introns, Human genetics, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Medical genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: About one third of patients with rhabdoid tumors (RT) harbor a heterozygous germline variant in SMARCB1. Molecular diagnosis therefore keeps a crucial place in the diagnosis of RT, and genetic counseling should be systematically recommended. However, immunohistochemistry has progressively replaced molecular tools to assess the status of SMARCB1 in tumors; the necessity of analyzing SMARCB1 status in the tumor may thus be less considered by neuropathologists and pediatric neuro-oncologists. In the present manuscript as aforementioned, we report on two patients with bifocal RT in the first month of life and in whom no germline variant was initially found in the SMARCB1 coding sequence. Careful analysis of SMARCB1 status in the tumors revealed that only one of the two inactivating hits was found in the coding sequence. By sequencing the tumor cells RNA, we were able to detect an insertion with an abnormal sequence, due to the same intronic variant of SMARCB1, which led to the exonisation of the first intron. This cryptic variant was absent in the germline DNA of both patients. Of note, we previously reported one patient with the same deep intronic variant in the germline in a soft tissue RT. To our mind, this additional report on two patients clearly demonstrates that this intronic variant is a new hotspot that should now be systematically added to the germline screening of SMARCB1. We therefore recommend searching for and cautiously interpreting germline analysis if SMARCB1 has not been extensively studied in the tumor.
Published: 2017
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23. Lung Adenocarcinoma as Part of the Li-Fraumeni Syndrome Spectrum: Preliminary Data of the LIFSCREEN Randomized Clinical Trial

Author: Thierry Frebourg, Stéphanie Foulon, Olivier Caron, Patrick R. Benusiglio, and Laurence Brugières
Subjects: 0301 basic medicine, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Adolescent, Whole body imaging, Adenocarcinoma of Lung, Sensitivity and Specificity, law.invention, Li-Fraumeni Syndrome, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Germline mutation, Randomized controlled trial, law, Internal medicine, Research Letter, Medicine, Humans, Whole Body Imaging, Child, Germ-Line Mutation, Aged, medicine.diagnostic_test, business.industry, Cancer, Magnetic resonance imaging, Middle Aged, medicine.disease, Interim analysis, Magnetic Resonance Imaging, 030104 developmental biology, Li–Fraumeni syndrome, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Tumor Suppressor Protein p53, business
Abstract: This interim analysis of an ongoing randomized clinical trial presents preliminary findings regarding use of whole-body magnetic resonance imaging for cancer surveillance of TP53 mutation carriers.
Published: 2017

24. 17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression

Author: Emmanuelle Génin, Céline Bellenguez, Vincent Meyer, I. Le Ber, Thérèse Rivasseau Jonveaux, Paola Caroppo, Olivier Quenez, Thierry Frebourg, Luc Letenneur, Robert Olaso, Doris Lechner, D. Wallon, Dominique Campion, Lucie Guyant-Maréchal, Ognian Kalev, Philippe Amouyel, Anne-Claire Richard, Camille Charbonnier, Olivier Martinaud, L. Traykov, Shima Mehrabian, Jean-François Deleuze, Gaël Nicolas, Anne Rovelet-Lecrux, Mark Lathrop, Hans Markus Munter, Gabor G. Kovacs, Florence Pasquier, Stéphane Rousseau, Marie-Thérèse Bihoreau, Adeline Rollin-Sillaire, Stéphane Epelbaum, Guillaume Bourque, Anne Boland, Richard Redon, Jean-François Dartigues, Jean-Charles Lambert, Thomas Ströbel, Didier Hannequin, Peristera Paschou, K Le Guennec, John Alexander, Benjamin Grenier-Boley, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Unité de recherche de l'institut du thorax (ITX-lab)
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, DNA Copy Number Variations, Amyloid, [SDV]Life Sciences [q-bio], Gene Dosage, Neuroimaging, tau Proteins, Gene dosage, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Gene Duplication, Gene duplication, medicine, Humans, Dementia, Copy-number variation, Molecular Biology, Aged, Brain, Neurofibrillary Tangles, Neurofibrillary tangle, Middle Aged, medicine.disease, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Tauopathies, Case-Control Studies, Biomarker (medicine), Female, Tauopathy, Psychology, Neuroscience, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17
Abstract: International audience; To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.
Published: 2017
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25. Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests

Author: Sophie Grandjouan, Pascaline Berthet, Rosette Lidereau, E. Nogue, M. C. Picot, C. Bara, S. Giraud, Frédérique Nowak, J. Blin, Catherine Noguès, Bruno Buecher, D. Khayat, B. Bressac de Paillerets, Florent Soubrier, Virginie Galibert, Thierry Frebourg, Sylviane Olschwang, Hagay Sobol, D. Stoppa Lyonnet, Pascal Pujol, Philippe Jonveaux, Catherine Dugast, Christine Lasset, Claude Houdayer, Rosine Guimbaud, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Proband, Cancer Research, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Genes, BRCA2, Genes, BRCA1, Genetic Carrier Screening, DNA Mismatch Repair, 0302 clinical medicine, Referral and Consultation, Ovarian Neoplasms, Genetics, 0303 health sciences, medicine.diagnostic_test, 030305 genetics & heredity, Nuclear Proteins, Lynch syndrome, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, Oncology, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, France, MutL Protein Homolog 1, medicine.medical_specialty, Genetic counseling, Breast Neoplasms, Genetic Counseling, Cancer Care Facilities, 03 medical and health sciences, Breast cancer, Neoplastic Syndromes, Hereditary, Internal medicine, medicine, Humans, Genetic Testing, Adaptor Proteins, Signal Transducing, Genetic testing, Family Health, business.industry, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Mutation, Laboratories, business
Abstract: Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.
Published: 2013
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26. TREM2 R47H Variant as a Risk Factor for Early-Onset Alzheimer's Disease

Author: Stéphane Rousseau, Dominique Campion, Thierry Frebourg, David Wallon, Cyril Pottier, Adeline Rollin-Sillaire, Anne-Claire Richard, Didier Hannequin, and Anne Rovelet-Lecrux
Subjects: Adult, Male, Disease, Biology, Exon, Alzheimer Disease, Risk Factors, Genetic variation, medicine, Humans, Early-onset Alzheimer's disease, Receptors, Immunologic, Risk factor, Aged, Genetics, Membrane Glycoproteins, TREM2, General Neuroscience, Genetic Variation, General Medicine, Middle Aged, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Immunology, Female, Geriatrics and Gerontology, Alzheimer's disease, Age of onset
Abstract: The rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD). In this study we examined the association between TREM2 exon 2 variants and early-onset AD in a sample of Caucasian subjects of French origin including 726 patients with age of onset ≤65 years and 783 controls. Only the rs75932628-T variant (predicted to cause an R47H substitution) conferred a significant risk for early-onset AD (OR, 4.07; 95% CI, 1.3 to 16.9; p = 0.009). These results confirm the association between this variant and AD and underline its involvement in early-onset cases.
Published: 2013
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27. Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds

Author: Stéphane Rousseau, Gaël Nicolas, Olivier Quenez, Maria Szaruga, Kilan Le Guennec, David Wallon, Frédérique Fluchère, Thierry Frebourg, Sarah Veugelen, Anne Rovelet-Lecrux, Dominique Campion, Bart De Strooper, and Lucía Chávez-Gutiérrez
Subjects: 0301 basic medicine, Male, Models, Molecular, Amyloid, Biology, Presenilin, lcsh:RC321-571, 03 medical and health sciences, Exon, 0302 clinical medicine, Endopeptidase activity, Alzheimer Disease, PSEN1, medicine, Presenilin-1, Humans, Exome, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Sequence Deletion, Genetics, Early-onset, Aβ43, Exons, Middle Aged, medicine.disease, Molecular biology, Phenotype, 030104 developmental biology, Neurology, Hydrophilic loop, Paraparesis, Spastic, Alzheimer's disease, Cognition Disorders, 030217 neurology & neurosurgery
Abstract: Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the γ-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete digestion of long Aβ peptides and enhances the production of Aβ43, which has been shown to be potently amyloidogenic and neurotoxic in vivo.
Published: 2017

28. Identification of Somatic Mutations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type by Massive Parallel Sequencing

Author: Sydney Dubois, B. Vergier, Jean-Philippe Merlio, Thierry Frebourg, Anne Benedicte Duval, Anne Pham-Ledard, Hervé Tilly, Fabrice Jardin, L. Verneuil, Philippe Courville, Bernard Lenormand, Philippe Bertrand, Elodie Bohers, Pascal Joly, Sylvain Mareschal, Pierre-Julien Viailly, Isabelle Tournier, Maxime Fontanilles, Catherine Maingonnat, Philippe Ruminy, Marie Beylot-Barry, Emilie Andrieu, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département d'oncologie médicale [Rouen], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Service de dermatologie [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département de Pathologie [CHU Rouen], Service de Dermatologie [CHU Caen], CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN)
Subjects: 0301 basic medicine, Male, Skin Neoplasms, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Dermatology, Biology, Biochemistry, Cutaneous lymphoma, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, medicine, CIITA, Primary Cutaneous Diffuse Large B-Cell Lymphoma, Humans, Copy-number variation, Molecular Biology, Exome sequencing, Genetic Association Studies, Aged, Aged, 80 and over, Leg, Massive parallel sequencing, Primary central nervous system lymphoma, High-Throughput Nucleotide Sequencing, Cell Biology, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Myeloid Differentiation Factor 88, Cancer research, Female, Lymphoma, Large B-Cell, Diffuse, Diffuse large B-cell lymphoma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; To determine whether the mutational profile of primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) is unique by comparison with other diffuse large B-cell lymphoma subtypes, we analyzed a total cohort of 20 PCLBCL-LT patients by using next-generation sequencing with a lymphoma panel designed for diffuse large B-cell lymphoma. We also analyzed 12 pairs of tumor and control DNA samples by whole-exome sequencing, which led us to perform resequencing of three selected genes not included in the lymphoma panel: TBL1XR1, KLHL6, and IKZF3. Our study clearly identifies an original mutational landscape of PCLBCL-LT with a very restricted set of highly recurrent mutations (>40%) involving MYD88 (p.L265P variant), PIM1, and CD79B. Other genes involved in B-cell signaling, NF-κB activation, or DNA modeling were found altered, notably TBL1XR1 (33%), MYC (26%) CREBBP (26%), and IRF4 (21%) or HIST1H1E (41%). MYD88L265P variant was associated with copy number variations or copy neutral loss of heterozygosity in 60% of patients. The most frequent genetic losses involved CDKN2A/2B, TNFAIP3/A20, PRDM1, TCF3, and CIITA. Together, these results show that PCLBCL-LT exhibits a unique mutational landscape, combining highly recurrent hotspot mutations in genes involved in NF-kB and B-cell signaling pathways, which provides a rationale for using selective inhibitors of the B-cell receptor.
Published: 2017
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29. Contribution to Alzheimer's disease risk of rare variants in TREM_2, SORL_1, and ABCA_7 in 1779 cases and 1273 controls

Author: Céline Bellenguez, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez, Kilan Le Guennec, Gaël Nicolas, Ganesh Chauhan, David Wallon, Stéphane Rousseau, Anne Claire Richard, Anne Boland, Guillaume Bourque, Hans Markus Munter, Robert Olaso, Vincent Meyer, Adeline Rollin-Sillaire, Florence Pasquier, Luc Letenneur, Richard Redon, Jean-François Dartigues, Christophe Tzourio, Thierry Frebourg, Mark Lathrop, Jean-François Deleuze, Didier Hannequin, Emmanuelle Genin, Philippe Amouyel, Stéphanie Debette, Jean-Charles Lambert, Dominique Campion, Olivier Martinaud, Aline Zarea, Stéphanie Bombois, Marie-Anne Mackowiak, Vincent Deramecourt, Agnès Michon, Isabelle Le Ber, Bruno Dubois, Olivier Godefroy, Frédérique Etcharry-Bouyx, Valérie Chauviré, Ludivine Chamard, Eric Berger, Eloi Magnin, Jean-Francois Dartigues, Sophie Auriacombe, François Tison, Vincent de la Sayette, Dominique Castan, Elsa Dionet, Francois Sellal, Olivier Rouaud, Christel Thauvin, Olivier Moreaud, Mathilde Sauvée, Maïté Formaglio, Hélène Mollion, Isabelle Roullet-Solignac, Alain Vighetto, Bernard Croisile, Mira Didic, Olivier Félician, Lejla Koric, Mathieu Ceccaldi, Audrey Gabelle, Cecilia Marelli, Pierre Labauge, Thérèse Jonveaux, Martine Vercelletto, Claire Boutoleau-Bretonnière, Giovanni Castelnovo, Claire Paquet, Julien Dumurgier, Jacques Hugon, Foucauld De Boisgueheneuc, Serge Belliard, Serge Bakchine, Marie Sarazin, Marie-Odile Barrellon, Bernard Laurent, Frédéric Blanc, Jérémie Pariente, Snejana Jurici, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Excellence Laboratory LabEx DISTALZ, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, Metacohorts Consortium, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), McGill University and Genome Quebec Innovation Centre, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie [Lille], Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Institut National de la Santé et de la Recherche Médicale (Inserm)-Université de Bordeaux, Université de Bordeaux (UB), INSERM, Team Psycoépidémiologie du Vieillissement et des Maladies Chroniques - Population Health Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Epidémiologie, santé publique et développement, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR99-ISPED, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université de Lille, Troubles cognitifs vasculaires et dégénératifs, Université de Lille, Sciences et Technologies, Réseau International des Instituts Pasteur (RIIP), Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CNR MAJ collaborators, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), European Project: 305299,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,AGEDBRAINSYSBIO(2013), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Male, Adult, Aging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, SORL1, Apolipoprotein E4, Genome-wide association study, Biology, ABCA7, 03 medical and health sciences, Young Adult, Immunologic, Alzheimer Disease, Genetic variation, Receptors, medicine, 80 and over, TREM2, Humans, Genetic Predisposition to Disease, Receptors, Immunologic, Genetic Association Studies, LDL-Receptor Related Proteins, Aged, Aged, 80 and over, Genetics, Membrane Glycoproteins, Whole Genome Sequencing, General Neuroscience, Genetic Variation, Membrane Transport Proteins, Heritability, Middle Aged, Alzheimer's disease, medicine.disease, Minor allele frequency, 030104 developmental biology, biology.protein, ATP-Binding Cassette Transporters, Female, Neurology (clinical), Geriatrics and Gerontology, Developmental Biology, Genome-Wide Association Study
Abstract: International audience; We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk~and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10$^{-6}$ was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a~clearer insight into the classes of rare variants involved. Despite different effect sizes and~varying~cumulative minor allele frequencies, the rare protein-truncating and missense-predicted~damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE $\varepsilon$4.
Published: 2017
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30. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients

Author: Anne-Marie Guerrot, Joelle Roume, Thierry Frebourg, Patricia Faure, Pascale Saugier-Veber, Sylvain Renolleau, Séverine Audebert-Bellanger, Gilles Morin, Isabelle Desguerre, Renaud Touraine, Ghislaine Plessis, Séverine Drunat, Marjolaine Willems, Sarah Grotto, Hubert Journel, Eric Verspyck, Brigitte Simon-Bouy, Jean-Marie Cuisset, Anne-Gaëlle Grebille, Stéphane Marret, Vincent Flurin, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Maladies Neuromusculaires de l'Enfant, Hôpital Roger Salengro [Lille], Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de neurologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHI Poissy-Saint-Germain, Centre Hospitalier de Versailles André Mignot (CHV), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Service de gynécologie et obstétrique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Team 4 NeoVasc - Region Team ERI 28 INSERM (Neovasc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Heart Defects, Congenital, Male, 0301 basic medicine, Weakness, Pediatrics, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], SMN1, Spinal Muscular Atrophies of Childhood, Ultrasonography, Prenatal, 03 medical and health sciences, Life Expectancy, 0302 clinical medicine, medicine, Humans, Increased nuchal translucency, ComputingMilieux_MISCELLANEOUS, Arthrogryposis, Respiratory Distress Syndrome, Newborn, Pregnancy, Reflex, Abnormal, business.industry, Homozygote, Infant, Newborn, Muscle weakness, Spinal muscular atrophy, medicine.disease, SMA, Survival of Motor Neuron 1 Protein, Cranial Nerve Diseases, Hypotonia, 3. Good health, Survival of Motor Neuron 2 Protein, 030104 developmental biology, Autonomic Nervous System Diseases, Neurology, Muscle Hypotonia, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Background Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. Objective The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. Methods SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. Results Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Conclusion Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.
Published: 2016
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31. Clinical and Molecular Findings in 39 Patients with KBG Syndrome Caused by Deletion or Mutation of ANKRD11

Author: Aurélia Jacquette, Alice Goldenberg, Thierry Frebourg, Julien Thevenon, David Geneviève, Anne-Marie Guerrot, Andrée Delahaye-Duriez, Yline Capri, Bruno Leheup, François Lecoquierre, Florence Riccardi, Tiffany Busa, Laurent Villard, Pierre Cacciagli, Vincent Gatinois, Julien Mancini, Chantal Missirian, Lionel Van Maldergem, Massimiliano Rossi, Laurence Perrin, Catherine Vincent-Delorme, Pascale Saugier-Veber, Philippe Khau Van Kien, Gwenaël Nadeau, Annick Toutain, Alain Verloes, Sandrine Marlin, Rolph Pfundt, Elise Schaefer, Arthur Sorlin, Vincent Michaud, Christel Thauvin-Robinet, Philippe Parent, Cyril Mignot, Charles Coutton, Nicole Philip, Véronique Satre, Aude Tessier, Service de génétique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Human Genetics, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Verdier, Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CHU Trousseau [APHP], Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), École Supérieure des Géomètres et Topographes ( ESGT CNAM ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Laboratoire de Géodésie et de Géomatique ( L2G ESGT CNAM ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Service de Cytogénétique, Centre hospitalier de Valence, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Centre Interdisciplinaire de Nanoscience de Marseille ( CINaM ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique [Tours], Hôpital Bretonneau-CHRU Tours, Service de Génétique, Hôpital de Hautepierre [Strasbourg], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Paoli Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] ( BiosTIC ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ) -Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radboud University Medical Center [Nijmegen], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Bordeaux Pellegrin [Bordeaux], Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut Paoli-Calmettes, Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] (BiosTIC ), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gall, Valérie, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)
Subjects: Male, 0301 basic medicine, 030105 genetics & heredity, medicine.disease_cause, Bioinformatics, Intellectual disability, Child, Genetics (clinical), Genetics, Comparative Genomic Hybridization, Mutation, Middle Aged, KBG syndrome, Phenotype, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Chromosome Deletion, medicine.symptom, Haploinsufficiency, Adult, Adolescent, Biology, Malignancy, Short stature, ANKRD11, Young Adult, 03 medical and health sciences, Intellectual Disability, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Precocious puberty, Abnormalities, Multiple, long-term prognosis, Alleles, Genetic Association Studies, Aged, Retrospective Studies, Bone Diseases, Developmental, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Tooth Abnormalities, 16q24.3 deletion, Point mutation, Facies, Infant, medicine.disease, haploinsufficiency, Repressor Proteins, Amino Acid Substitution, Autism, Chromosomes, Human, Pair 16
Abstract: Item does not contain fulltext KBG syndrome, due to ANKRD11 alteration is characterized by developmental delay, short stature, dysmorphic facial features, and skeletal anomalies. We report a clinical and molecular study of 39 patients affected by KBG syndrome. Among them, 19 were diagnosed after the detection of a 16q24.3 deletion encompassing the ANKRD11 gene by array CGH. In the 20 remaining patients, the clinical suspicion was confirmed by the identification of an ANKRD11 mutation by direct sequencing. We present arguments to modulate the previously reported diagnostic criteria. Macrodontia should no longer be considered a mandatory feature. KBG syndrome is compatible with autonomous life in adulthood. Autism is less frequent than previously reported. We also describe new clinical findings with a potential impact on the follow-up of patients, such as precocious puberty and a case of malignancy. Most deletions remove the 5'end or the entire coding region but never extend toward 16q telomere suggesting that distal 16q deletion could be lethal. Although ANKRD11 appears to be a major gene associated with intellectual disability, KBG syndrome remains under-diagnosed. NGS-based approaches for sequencing will improve the detection of point mutations in this gene. Broad knowledge of the clinical phenotype is essential for a correct interpretation of the molecular results. (c) 2016 Wiley Periodicals, Inc.
Published: 2016
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32. Germline

Author: Fanélie, Jouenne, Isaure, Chauvot de Beauchene, Emeline, Bollaert, Marie-Françoise, Avril, Olivier, Caron, Olivier, Ingster, Axel, Lecesne, Patrick, Benusiglio, Philippe, Terrier, Vincent, Caumette, Daniel, Pissaloux, Arnaud, de la Fouchardière, Odile, Cabaret, Birama, N'Diaye, Amélie, Velghe, Gaelle, Bougeard, Graham J, Mann, Serge, Koscielny, Jennifer H, Barrett, Mark, Harland, Julia, Newton-Bishop, Nelleke, Gruis, Remco, Van Doorn, Marion, Gauthier-Villars, Gaelle, Pierron, Dominique, Stoppa-Lyonnet, Isabelle, Coupier, Rosine, Guimbaud, Capucine, Delnatte, Jean-Yves, Scoazec, Alexander M, Eggermont, Jean, Feunteun, Luba, Tchertanov, Jean-Baptiste, Demoulin, Thierry, Frebourg, and Brigitte, Bressac-de Paillerets
Subjects: Male, Heterozygote, Receptor, Platelet-Derived Growth Factor alpha, Genes, p16, Sarcoma, Soft Tissue Neoplasms, Pedigree, Genetic Determinism, Exome Sequencing, Cyclin-Dependent Kinase Inhibitor p18, Humans, Female, Genetic Predisposition to Disease, Cyclin-Dependent Kinase Inhibitor p16, Germ-Line Mutation
Abstract: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology.We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation inGermline mutations in
Published: 2016

33. Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma

Author: Sydney Dubois, Vincent Camus, Philippe Bertrand, Elodie Bohers, Jean Michel Picquenot, Pierre-Julien Viailly, Fabrice Jardin, Marie Cornic, Philippe Ruminy, Thierry Frebourg, Aspasia Stamatoullas, Christian Bastard, Liana Veresezan, Nasrin Sarafan-Vasseur, Sylvain Mareschal, Catherine Maingonnat, Pierre Vera, Hervé Tilly, Valérie Tallon-Simon, Stéphanie Becker, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), service d'anatomo-pathologie, Service de médecine nucléaire [Rouen], CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU), and Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
Subjects: 0301 basic medicine, Male, Receptors, Cytoplasmic and Nuclear, medicine.disease_cause, 0302 clinical medicine, Recurrence, immune system diseases, Neoplasms, Positron Emission Tomography Computed Tomography, hemic and lymphatic diseases, Mutation, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Hematology, DNA, Neoplasm, Articles, Middle Aged, Prognosis, Combined Modality Therapy, Hodgkin Disease, 3. Good health, Tumor Burden, Treatment Outcome, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, Adult, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Karyopherins, 03 medical and health sciences, Young Adult, Germline mutation, Cell Line, Tumor, Biopsy, medicine, Biomarkers, Tumor, Humans, Codon, Survival analysis, Neoplasm Staging, Retrospective Studies, medicine.disease, Minimal residual disease, Survival Analysis, Lymphoma, 030104 developmental biology, Amino Acid Substitution, Cancer research
Abstract: International audience; Classical Hodgkin lymphoma is one of the most common lymphomas and shares clinical and genetic features with primary mediastinal B-cell lymphoma. In this retrospective study, we analyzed the recurrent hotspot mutation of the exportin 1 (XPO1, p.E571K) gene, previously identified in primary mediastinal B-cell lymphoma, in biopsies and plasma circulating cell-free DNA from patients with classical Hodgkin lymphoma using a highly sensitive digital PCR technique. A total of 94 patients were included in the present study. This widely expressed XPO1 E571K mutation is present in one quarter of classical Hodgkin lymphoma patients (24.2%). Mutated and wild-type classical Hodgkin lymphomas were similar regarding the main clinical features. Patients with a detectable XPO1 mutation at the end of treatment displayed a tendency toward shorter progression-free survival, as compared to patients with undetectable mutation in plasma cell-free DNA (2-year progression-free survival: 57.1%, 95% confidence interval: 30.1-100% versus 2-year progression-free survival: 90.5%, 95% confidence interval: 78.8-100%, respectively, P=0.0601). To conclude, the detection of the XPO1 E571K mutation in biopsy and plasma cell-free DNA by digital PCR may be used as a novel biomarker in classical Hodgkin lymphoma for both diagnosis and minimal residual disease, and pinpoints a crucial role of XPO1 in classical Hodgkin lymphoma pathogenesis. The detection of somatic mutation in the plasma cell-free DNA of patients represents a major technological advance in the context of liquid biopsies and noninvasive management of classical Hodgkin lymphoma.
Published: 2016
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34. Identification of partial SLC20A2 deletions in primary brain calcification using whole-exome sequencing

Author: Marc Vérin, Anne-Claire Richard, Olivier Quenez, Anne Rovelet-Lecrux, Dominique Campion, Stéphanie David, João Ricardo Mendes de Oliveira, Joana Ferreira, Gaël Nicolas, Isabelle Le Ber, Anne Boland, Jean-François Deleuze, Thierry Frebourg, Snejana Jurici, Didier Hannequin, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Service de neurologie [Rennes], Université de Rennes (UR), Comportement et noyaux gris centraux = Behavior and Basal Ganglia [Rennes], Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR), Centre Hospitalier Saint Jean de Perpignan, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universidade Federal de Pernambuco [Recife] (UFPE), DEA20140630628, FRM, Fondation pour la Recherche Médicale, Jonchère, Laurent, Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR)
Subjects: 0301 basic medicine, Male, Sequence analysis, Short Report, PDGFRB, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Genetics, Humans, Exome, Copy-number variation, Genotyping, Genetics (clinical), Exome sequencing, Aged, Brain Diseases, Sodium-Phosphate Cotransporter Proteins, Type III, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Calcinosis, Sequence Analysis, DNA, Syndrome, Amplicon, Middle Aged, 030104 developmental biology, Female, Xenotropic and Polytropic Retrovirus Receptor, 030217 neurology & neurosurgery, Algorithms, Gene Deletion
Abstract: International audience; Primary brain calcification (PBC) is a dominantly inherited calcifying disorder of the brain. SLC20A2 loss-of-function variants account for the majority of families. Only one genomic deletion encompassing SLC20A2 and six other genes has been reported. We performed whole-exome sequencing (WES) in 24 unrelated French patients with PBC, negatively screened for sequence variant in the known genes SLC20A2, PDGFB, PDGFRB and XPR1. We used the CANOES tool to detect copy number variations (CNVs). We detected two deletions of exon 2 of SLC20A2 in two unrelated patients, which segregated with PBC in one family. We then reanalyzed the same series using a QMPSF assay including one amplicon in each exon of SLC20A2 and detected two supplemental partial deletions in two patients: one deletion of exon 4 and one deletion of exons 4 and 5. These deletions were missed by the first screening step of CANOES but could finally be detected after readjustment of bioinformatic parameters and use of a genotyping step of CANOES. This study reports the first partial deletions of SLC20A2 and strengthens its position as the major PBC-causative gene. It is possible to detect short CNVs from WES data, although the sensitivity of such tools should be evaluated in comparison with other methods. © 2016 Macmillan Publishers Limited, part of Springer Nature.
Published: 2016
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35. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Author: Frédéric Blanc, Adeline Rollin-Sillaire, O. Moreaud, Mark Lathrop, Mathieu Ceccaldi, Anne-Claire Richard, Catherine Thomas-Antérion, Olivier Quenez, Camille Charbonnier, Anne Rovelet-Lecrux, Vincent Meyer, Dominique Campion, Didier Hannequin, Bernard Croisile, Robert Olaso, Claire Paquet, Hans Markus Munter, Ludivine Chamard, Mathilde Sauvée, Anne Boland, Marie Sarazin, Lucie Guyant-Maréchal, Sophie Coutant, Florence Pasquier, Kilan Le Guennec, François Sellal, David Wallon, Guillaume Bourque, Claire Boutoleau-Bretonnière, Stéphane Rousseau, Alexandre Montpetit, Delphine Bacq, Jean-François Deleuze, Jérémie Pariente, Audrey Gabelle, Thierry Frebourg, Isabelle Le Ber, Daniel Auld, Jean-Guillaume Garnier, Olivier Martinaud, Gaël Nicolas, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Mémoire de Ressources et Recherche - CMRR [Haute-Normandie], Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Rouen], Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), McGill University and Genome Quebec Innovation Centre, Centre d'Innovation (Génome Québec), Génome Québec, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche -CMRR [Lille-Bailleul], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Neurologique Pierre Wertheimer, Service de Neurologie, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Laboratoire d'Etude des Mécanismes Cognitifs (EMC), Université Lumière - Lyon 2 (UL2), Laboratoire d'Histologie et de Biologie du Vieillissement, Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire [AP-HP Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Mémoire de Ressources et de Recherche [Grenoble] (CMRR), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire de Psychologie et NeuroCognition (LPNC ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie, Hôpital pasteur [Colmar], Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Département de Gériatrie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS)-Hôpital de jour St François [Strasbourg], Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Imagerie cérébrale et handicaps neurologiques, Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Lumière - Lyon 2 (UL2)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Psychologie et NeuroCognition (LPNC), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institute for Research and Innovation in Biomedicine ( IRIB ), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes ( LITIS ), Université Le Havre Normandie ( ULH ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Centre National de Séquençage (Genoscope) ( CNS ), Centre d'Innovation ( Génome Québec ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Troubles cognitifs dégénératifs et vasculaires ( DN2M ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -INSERM, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Hôpital Roger Salengro, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôpital Nord Laënnec, Laboratoire d'Etude des Mécanismes Cognitifs ( EMC ), Université Lumière - Lyon 2 ( UL2 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ), Centre Mémoire de Ressources et de Recherche [Grenoble] ( CMRR ), Centre Hospitalier Universitaire [Grenoble] ( CHU ), Laboratoire de Psychologie et NeuroCognition ( LPNC ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Institut de Neurosciences des Systèmes ( INS ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie ( ICube ), Institut National des Sciences Appliquées - Strasbourg ( INSA Strasbourg ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg ( ENGEES ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Matériaux et nanosciences d'Alsace, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: 0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Biology, Bioinformatics, Article, 03 medical and health sciences, Amyloid beta-Protein Precursor, 0302 clinical medicine, Alzheimer Disease, PSEN2, Presenilin-2, Genetics, medicine, PSEN1, Presenilin-1, Dementia, Humans, Exome, Genetic Testing, Family history, Genetics (clinical), Exome sequencing, [SCCO.NEUR]Cognitive science/Neuroscience, Middle Aged, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, Case-Control Studies, [ SCCO.NEUR ] Cognitive science/Neuroscience, Mutation, Female, Alzheimer's disease, Age of onset, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract: International audience; Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.
Published: 2016
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36. Amyloid-β Protein Precursor Gene Expression in Alzheimer's Disease and Other Conditions

Author: Anne Rovelet Lecrux, Thierry Frebourg, David Maltête, Stephanie Bombois, Cyril Pottier, Didier Hannequin, David Wallon, Dominique Campion, and Snejana Jurici
Subjects: Adult, Male, medicine.medical_specialty, Down syndrome, BACE1-AS, Amyloid beta-Protein Precursor, Alzheimer Disease, Internal medicine, Presenilin-2, Gene duplication, Gene expression, Presenilin-1, medicine, Amyloid precursor protein, Humans, RNA, Messenger, Age of Onset, Aged, biology, business.industry, General Neuroscience, P3 peptide, General Medicine, Middle Aged, medicine.disease, Biochemistry of Alzheimer's disease, Stroke, Psychiatry and Mental health, Clinical Psychology, Endocrinology, Gene Expression Regulation, Mutation, biology.protein, Female, Down Syndrome, Geriatrics and Gerontology, business, Amyloid precursor protein secretase
Abstract: Several lines of evidence suggest that AβPP gene expression could influence risk for Alzheimer's disease (AD). Using a highly sensitive multiplex fluorescent RT-PCR assay, we compared peripheral blood cells expression of AβPP mRNA among sporadic AD patients (n = 133), autosomal dominant early-onset AD cases (ADEOAD, n = 21), Down syndrome patients (n = 21), AD patients with AβPP duplication (n = 9), patients with recent ischemic stroke (n = 25), and healthy controls (n = 58). Compared to healthy controls (median = 0.98), AβPP expression was not increased in sporadic AD patients (median = 1.01, p = 0.42) nor in ADEOAD patients (median = 0.96, p = 0.26). Down syndrome patients as well as patients with AβPP duplication had significantly increased levels of AβPP mRNA compared to controls (median = 1.48 and median = 1.36, p < 0.0001 and p = 0.0007, respectively). A weaker but significant increase in relative amount of AβPP transcripts in patients who suffered from recent stroke was observed (median = 1.14, p = 0.0007). Our results do not support a pathogenic role of AβPP overexpression in sporadic AD although a small subset of patients displays AβPP overexpression in the same range as Down syndrome patients.
Published: 2012
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37. Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus

Author: Michael K. E. Schäfer, Laura Keglowich, Elisabeth Bouché, Mariola Marx, Muriel Bozon, Nathalie Drouot, Valérie Castellani, Thierry Frebourg, Pascale Saugier-Veber, Simone Diestel, Marie Minz, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: Male, L1, DNA Mutational Analysis, Mutant, MESH: Neurons, medicine.disease_cause, 0302 clinical medicine, Missense mutation, MESH: Genetic Variation, MESH: DNA Mutational Analysis, Genetics (clinical), Neurons, 0303 health sciences, Mutation, MESH: Middle Aged, MESH: Hydrocephalus, Cerebral Aqueduct, Genetic Diseases, X-Linked, ER retention, Exons, Middle Aged, Pedigree, Female, Hydrocephalus, Adult, MESH: Mutation, MESH: Pedigree, Neural Cell Adhesion Molecule L1, Biology, Cell Line, 03 medical and health sciences, Cellular and Molecular Neuroscience, Calnexin, MESH: Genetic Diseases, X-Linked, Genetics, medicine, Humans, MESH: Cerebral Aqueduct, 030304 developmental biology, MESH: Humans, Endoplasmic reticulum, Genetic Variation, MESH: Adult, MESH: Neural Cell Adhesion Molecule L1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Molecular biology, MESH: Male, MESH: Cell Line, Neural cell adhesion molecule, MESH: Exons, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Mutations in the gene encoding the neural cell adhesion molecule L1CAM cause several neurological disorders collectively referred to as L1 syndrome. We report here a family case of X-linked hydrocephalus in which an obligate female carrier has two exonic L1CAM missense mutations in trans substituting amino acids in the first (p.W635C) or second (p.V768I) fibronectin-type III domains. We performed various biochemical and cell biological in vitro assays to evaluate the pathogenicity of these variants. Mutant L1-W635C protein accumulates in the endoplasmic reticulum (ER), is not transported into axons, and fails to promote L1CAM-mediated cell-cell adhesion as well as neurite growth. Immunoprecipitation experiments show that L1-W635C associates with the molecular ER chaperone calnexin and is modified by poly-ubiquitination. The mutant L1-V768I protein localizes at the cell surface, is not retained in the ER, and promotes neurite growth similar to wild-type L1CAM. However, the p.V768I mutation impairs L1CAM-mediated cell-cell adhesion albeit less severe than L1-W635C. These data indicate that p.W635C is a novel loss-of-function L1 syndrome mutation. The p.V768I mutation may represent a non-pathogenic variant or a variant associated with low penetrance. The poly-ubiquitination of L1-W635C and its association with the ER chaperone calnexin provide further insights into the molecular mechanisms underlying defective cell surface trafficking of L1CAM in L1 syndrome.
Published: 2012
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38. Development of a Nonfluorescent Multiplex Semiquantitative Polymerase Chain Reaction to Confirm Rearrangements Detected by Array-Comparative Genomic Hybridization

Author: Vincent Huin, Mario Tosi, Pascale Saugier-Veber, Thierry Frebourg, Nathalie Le Meur, Nathalie Drouot, and Pascal Chambon
Subjects: Male, Comparative Genomic Hybridization, Genome, Human, Chemistry, Gene Dosage, Genetic Variation, Reproducibility of Results, General Medicine, Repeatability, Polymerase Chain Reaction, Molecular biology, Gene dosage, law.invention, law, Multiplex polymerase chain reaction, Humans, Female, Multiplex, Human genome, Copy-number variation, Genetics (clinical), Polymerase chain reaction, Comparative genomic hybridization
Abstract: Copy number variations in the human genome are commonly detected using genome-wide high-resolution screening methods such as array-comparative genomic hybridization. To confirm these copy number variations, we have used an assay based on a semiquantitative multiplex polymerase chain reaction (PCR) of short unlabeled fragments and performed on the microfluidic Bio-Rad Experion system. We have compared the performance of this semiquantitative multiplex PCR of short unlabeled fragments assay with that of the semiquantitative multiplex PCR of short fluorescent fragments assay and have shown that its repeatability and reproducibility are very satisfying, with a relative standard deviation lower than 6.5%. We conclude that this robust and sensitive technology provides reliable data for the confirmation of rearrangements detected by array-comparative genomic hybridization.
Published: 2011
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39. Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers

Author: Olivier Caron, Estelle Houivet, Thierry Frebourg, Stéphanie Baert-Desurmont, Françoise Charbonnier, Jacques Benichou, Marie-Pierre Buisine, Solene Houlle, Julie Tinat, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacoepidemiologie et évaluation de l'impact des produits de santé sur les populations, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), LAboratoire de biologie moléculaire, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Peer, Hal, and Université Bordeaux Segalen - Bordeaux 2-Université de Rouen Normandie (UNIROUEN)
Subjects: Male, congenital, hereditary, and neonatal diseases and abnormalities, Letter, Population, Penetrance, Single-nucleotide polymorphism, Biology, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, education, neoplasms, Genetics (clinical), MMR genes, 030304 developmental biology, 0303 health sciences, education.field_of_study, Genetic heterogeneity, Epistasis, Genetic, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Lynch syndrome, 3. Good health, MSH6, MSH2, 030220 oncology & carcinogenesis, Mutation, Modifier factors, Female, Allelic heterogeneity, France, Colorectal Neoplasms
Abstract: Several studies have reported that, in Lynch syndrome resulting from mutations of the mismatch repair (MMR) genes, a CA repeat ≤17 within the IGF1 promoter, SNPs within the xenobiotic metabolizing enzyme gene CYP1A1 and SNPs on 8q23.3 and 11q23.1 modify colorectal cancer (CRC) risk in MMR mutation carriers. We analysed the impact of these polymorphisms on CRC risk in 748 French MMR mutation carriers derived from 359 families. We also analysed the effect of the Novel 1 SNP (18q21), which has recently been shown to increase CRC risk in the general population. We observed a significant difference in the CRC-free survival time between males and females, between MSH2 and MSH6 mutation carriers and between MLH1 and MSH6, indicating that this series is representative of Lynch syndrome. In contrast, the univariate log-rank test, as well as multivariate Cox model analysis controlling for familial aggregation and mutated MMR gene, year of birth and gender showed that the polymorphic alleles tested were not associated with a significant CRC risk increase, neither on the entire sample nor among males and females. This discrepancy with previous reports might be explained both by the genetic heterogeneity between the different populations analysed and the allelic heterogeneity of the MMR mutations. We conclude that genotyping of these polymorphisms is not useful to evaluate CRC risk in MMR mutation carriers and to optimize their clinical follow-up.
Published: 2011
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40. Type I hyperprolinemia: genotype/phenotype correlations

Author: Valérie Drouin-Garraud, Simona Orcesi, Audrey Guilmatre, Caroline Espil-Taris, Lionel Van Maldergem, Luisa Bonafé, Dominique Campion, David Valle, Thierry Frebourg, Vassili Valayannopoulos, Eric Le Galloudec, Patricia Blanchet, Cyril Mignot, Vincent des Portes, Bernard Echenne, Christine Ioos, Claudia Izzi, Hélène Maurey, Gabriella Di Rosa, Solenn Legallic, Jodi D. Hoffman, Alexandra Afenjar, Alice Goldenberg, Gary Steel, Alecia Willis, Agathe Roubertie, Agnès Guët, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Department of Medical and Surgical Pediatrics, University Hospital, Department of Genetics, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Neuro-Metabolism, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Regional Hospital, Tufts Medical Center, Università degli Studi di Brescia = University of Brescia (UniBs), Fondation 'Neurological Institute C. Mondino ', Université de Lausanne = University of Lausanne (UNIL), Beauvais Hospital, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Raymond-Poincaré Hospital, CHU Pitié-Salpêtrière [AP-HP], Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac [CHU Montpellier], Service de neuropédiatrie, CHU Hôpital, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Università degli Studi di Brescia [Brescia], Université de Lausanne (UNIL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Gui de Chauliac, and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Adult, Male, Adolescent, Proline, Mutation, Missense, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Proline dehydrogenase, Genotype, Proline Oxidase, Genetics, medicine, Humans, Missense mutation, Allele, Child, Amino Acid Metabolism, Inborn Errors, Alleles, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, Proline oxidase, [SCCO.NEUR]Cognitive science/Neuroscience, Haplotype, Infant, Life Sciences, medicine.disease, Molecular biology, 3. Good health, Case-Control Studies, Child, Preschool, Hyperprolinemia, PRODH, type I hyperprolinemia, 22q11, POX enzymatic activity, Female, 030217 neurology & neurosurgery
Abstract: International audience; Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. 8/14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for 6 novel mutations and 2 haplotypes. The c.1331G>A, p.G444D allele has a drastic effect whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia.
Published: 2010
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41. Myoclonus dystonia plus syndrome due to a novel 7q21 microdeletion

Author: Emmanuelle Apartis, Thierry Frebourg, Pascale Saugier-Veber, Emmanuel Roze, Virginie Czernecki, Diane Doummar, Lydie Burglen, Nathalie Drouot, and Marie-Anne Barthez
Subjects: Male, Myoclonus, Microcephaly, Adolescent, Myoclonic Jerk, Neurological disorder, Polymerase Chain Reaction, Short stature, SGCE, Pregnancy, Genetics, medicine, Humans, Child, Genetics (clinical), Dystonia, business.industry, Infant, Newborn, Syndrome, medicine.disease, Developmental disorder, Female, Chromosome Deletion, medicine.symptom, business, Chromosomes, Human, Pair 7
Abstract: Myoclonus dystonia (M-D) is a rare genetic movement disorder characterized by a combination of myoclonic jerks and dystonia. It is usually due to mutations in the SGCE gene. We report on a patient with a typical M-D syndrome, but also short stature, microcephaly, and mental retardation. Molecular analysis showed no mutations within the SGCE gene but a microdeletion encompassing the SGCE gene in chromosome region 7q21. Array-CGH analysis showed that the deletion spanned approximately 1.88 Mb. We suggest that M-D plus patients with mental retardation, microcephaly, dysmorphism, or short stature, all frequently associated disorders, should be screened for 7q21 microdeletion. By examining previously published cases of mental retardation associated with pure 7q21 deletions, we identified two distinct regions of respectively 455 and 496 kb that are critical for mental retardation and growth retardation. Among the genes located within these regions, LOC253012, also known as HEPACAM2, is a good candidate for both mental retardation and microcephaly.
Published: 2010
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42. Professionals Assess the Acceptability of Preimplantation Genetic Diagnosis and Prenatal Diagnosis for Managing Inherited Predisposition to Cancer

Author: Francis Puech, Claire Julian-Reynier, Didier Lémery, Dominique Stoppa-Lyonnet, Françoise Chabal, Thierry Frebourg, and Catherine Noguès
Subjects: Male, Cancer Research, medicine.medical_specialty, Attitude of Health Personnel, Cross-sectional study, Prenatal diagnosis, Preimplantation genetic diagnosis, Inherited Predisposition, Pregnancy, Neoplasms, Prenatal Diagnosis, Surveys and Questionnaires, medicine, Humans, Genetic Predisposition to Disease, Preimplantation Diagnosis, Gynecology, Obstetrics, business.industry, Cancer, Middle Aged, medicine.disease, Penetrance, Cross-Sectional Studies, Oncology, Female, France, business, Developed country
Abstract: Purpose Preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) practices for inherited predisposition to cancer are heterogeneous in industrialized countries. In France, permission to perform PGD/PND must be obtained from registered Multidisciplinary Prenatal Diagnosis Teams (MPDTs). The aim of this study was to determine French professionals' attitudes about the acceptability of PGD and PND for inherited predisposition to cancer. Methods A cross-sectional survey was performed, involving self-administered questionnaires mailed to all registered cancer geneticists (CGs; n = 123) and MPDTs (n = 47) in France. Results The response rates of CGs and MPDTs were 62% and 64%, respectively; 59% and 50% of the CGs had at least discussed PGD and PND, respectively, with their consultees during the previous year. When severe cancer is liable to occur in childhood with a high penetrance and no effective methods of prevention/treatment exist, high rates of acceptability of PGD/PND were recorded (> 80%). When cancer is liable to occur before the age of 50 years but not in childhood and some form of prevention/treatment is available that preserves quality of life, PGD was rated as acceptable by one MPDT (3.3%) and 10 CGs (13.2%), and PND was rated acceptable by nine CGs (11.8%). Most respondents agreed that the acceptability of PND/PGD depends on patients' family history of cancer and their reproductive history. Conclusion With the most severe forms of inherited cancer, no differences were observed between the acceptability to practitioners of PND and PGD, but with late-onset syndromes, there is still much uncertainty. Guidelines would help to standardize the practices of professionals handling these reproductive issues.
Published: 2009
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43. Detection of somatic quantitative genetic alterations by multiplex polymerase chain reaction for the prediction of outcome in diffuse large B-cell lymphomas

Author: G Buchonnet, Christian Bastard, Mario Tosi, Hervé Tilly, Françoise Parmentier, Fabrice Jardin, Sabine Quief, Jean-Pierre Kerckaert, Philippe Ruminy, Jean-Michel Picquenot, Céline Villenet, and Thierry Frebourg
Subjects: Adult, Male, Adolescent, Gene Dosage, Biology, Polymerase Chain Reaction, Gene dosage, law.invention, Antibodies, Monoclonal, Murine-Derived, Nucleic acid thermodynamics, law, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Proto-Oncogenes, Gene duplication, Multiplex polymerase chain reaction, medicine, Humans, Genes, Tumor Suppressor, neoplasms, Polymerase chain reaction, Aged, Aged, 80 and over, Chromosome Aberrations, Gene Amplification, Hematopoietic Stem Cell Transplantation, Antibodies, Monoclonal, Nucleic Acid Hybridization, Hematology, Middle Aged, Prognosis, medicine.disease, BCL6, Combined Modality Therapy, Molecular biology, Neoplasm Proteins, Treatment Outcome, Female, Lymphoma, Large B-Cell, Diffuse, Rituximab, Diffuse large B-cell lymphoma, Gene Deletion, Comparative genomic hybridization
Abstract: Background Genomic gains and losses play a crucial role in the development of diffuse large B-cell lymphomas. High resolution array comparative genomic hybridization provides a comprehensive view of these genomic imbalances but is not routinely applicable. We developed a polymerase chain reaction assay to provide information regarding gains or losses of relevant genes and prognosis in diffuse large B-cell lymphomas.Design and Methods Two polymerase chain reaction assays (multiplex polymerase chain reaction of short fluorescent fragments, QMPSF) were designed to detect gains or losses of c-REL, BCL6, SIM1, PTPRK, MYC, CDKN2A, MDM2, CDKN1B, TP53 and BCL2. Array comparative genomic hybridization was simultaneously performed to evaluate the sensitivity and predictive value of the QMPSF assay. The biological and clinical relevance of this assay were assessed.Results The predictive value of the QMPSF assay for detecting abnormal DNA copy numbers ranged between 88–97%, giving an overall concordance rate of 92% with comparative genomic hybridization results. In 77 cases of diffuse large B-cell lymphomas, gains of MYC, CDKN1B, c-REL and BCL2 were detected in 12%, 40%, 27% and 29%, respectively. TP53 and CDKN2A deletions were observed in 22% and 36% respectively. BCL2 and CDKN2A allelic status correlated with protein expression. TP53 mutations were associated with allelic deletions in 45% of cases. The prognostic value of a single QMPSF assay including TP53, MYC, CDKN2A, SIM1 and CDKN1B was predictive of the outcome independently of the germinal center B-cell like/non-germinal center B-cell like subtype or the International Prognostic Index.Conclusions QMPSF is a reliable and flexible method for detecting somatic quantitative genetic alterations in diffuse large B-cell lymphomas and could be integrated in future prognostic predictive models.
Published: 2008
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44. Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk

Author: Delphine Bonnet, Rosine Guimbaud, Pascaline Berthet, Anne-Françoise Cailleux, Marie-Pierre Buisine, Jacques Mauillon, Paul Gesta, David Malka, Stéphanie Baert-Desurmont, Estelle Cauchin, Estelle Houivet, Marine Lebrun, Caroline Abadie, Salima El Chehadeh, Isabelle Coupier, Lorena Ippolito, Julie Tinat, Philippe Jonveaux, Qing Wang, Marie Agnès Collonge-Rame, Françoise Desseigne, Sylvie Manouvrier, Jean-Christophe Saurin, Marion Gauthier-Villars, Jean-Marc Rey, Catherine Dugast, Laurence Brugières, Christine Toulas, Brigitte Bressac-de Paillerets, Pierre Laurent-Puig, Pascal Pujol, Sophie Giraud, Fabienne Prieur, Florence Polycarpe-Osaer, Jean Chiesa, Jacques Benichou, Dominique Leroux, Bruno Buecher, Ludovic Mansuy, Marie-Emmanuelle Morin-Meschin, Joanna Sokolowska, Marion Bougeard, Sophie Lejeune, Myriam Bronner, Jacqueline Duffour, Agnès Hardouin, Hakim Sebaoui, Valérie Bonadona, Julien Blot, Chrystelle Colas, Aziz Zaanan, Olivier Caron, Françoise Charbonnier, François Duhoux, Thierry Frebourg, Laurence Faivre, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Cancéropole Nord-Ouest, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Eugène Marquis (CRLCC), Oncologie thoracique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Léon Bérard [Lyon], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Institut Curie Paris, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique Clinique [CHRU Nïmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Onco-génétique, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de génétique [Cliniques Universitaires Saint-Luc, Bruxelles], Cliniques Universitaires Saint-Luc [Bruxelles], Génétique biologique histologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hépatologie et de Gastroentérologie [Lyon], Unité de recherche clinique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU), and UL, NGERE
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Genotyping Techniques, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene Frequency, Risk Factors, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Prospective cohort study, Alleles, Genetics (clinical), Chromosomes, Human, Pair 15, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Lynch syndrome, 3. Good health, SNP genotyping, [SDV] Life Sciences [q-bio], 030104 developmental biology, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 18, Colorectal Neoplasms, business, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract: International audience; To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's chi(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P
Published: 2016
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45. Heterogeneity ofNSD1alterations in 116 patients with Sotos syndrome

Author: Céline Bonnet, Valérie Cormier-Daire, Valérie Drouin-Garraud, Thierry Billette de Villemeur, Muriel Holder-Espinasse, Séverine Fehrenbach, Didier Lacombe, Dominique Bonneau, Nicolas Jeanne, Marie-France Portnoï, Joelle Roume, Valérie Malan, Marion Gérard, Christine Coubes, Lydie Burglen, Alexandra Afenjar, Delphine Héron, Clarisse Baumann, Thierry Frebourg, Albert David, and Pascale Saugier-Veber
Subjects: Adult, Male, Adolescent, Biology, Polymerase Chain Reaction, Genetic Heterogeneity, Gene duplication, Genetics, medicine, Humans, Abnormalities, Multiple, Child, Genetics (clinical), Sotos syndrome, Genetic heterogeneity, Point mutation, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Macrocephaly, Infant, Nuclear Proteins, Bone age, Histone-Lysine N-Methyltransferase, Syndrome, medicine.disease, Phenotype, Child, Preschool, Overgrowth syndrome, Histone Methyltransferases, Female, medicine.symptom
Abstract: Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features, learning difficulties, and macrocephaly with frequent pre- and postnatal overgrowth with advanced bone age. Here, we report on our experience in the molecular diagnostic of Sotos syndrome on 116 patients. Using direct sequencing and a quantitative multiplex PCR of short fluorescent fragments (QMPSF)-based assay allowing accurate detection of both total and partial NSD1 deletions, we identified NSD1 abnormalities in 104 patients corresponding to 102 Sotos families (90%). NSD1 point mutations were detected in 80% of the index cases, large deletions removing the NSD1 gene entirely in 14%, and intragenic NSD1 rearrangements in 6%. Among the 69 detected distinct point mutations, 48 were novel. The QMPSF assay detected an exonic duplication and a mosaic partial deletion. QMPSF mapping of the 15 large deletions revealed the heterogeneity of the deletions, which vary in size from 1 to 4.5 Mb. Clinical features of NSD1-positive Sotos patients revealed that the phenotype in patients with nontruncating mutations was less severe that in patients with truncating mutations. This study confirms the heterogeneity of NSD1 alterations in Sotos syndrome and therefore the need to complete sequencing analysis by screening for partial deletions and duplications to ensure an accurate molecular diagnosis of this syndrome.
Published: 2007
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46. Comparison of a quantitative PCR method with FISH for the assessment of the four aneuploidies commonly evaluated in CLL patients

Author: Thierry Frebourg, Françoise Parmentier, Hervé Tilly, G Raux, Dominique Vaur, Xavier Troussard, Christophe Fruchart, Stéphane Leprêtre, Christian Bastard, D Penther, D Nagib, and Mario Tosi
Subjects: Male, Cancer Research, Cost-Benefit Analysis, Chronic lymphocytic leukemia, Trisomy, In situ hybridization, Biology, Polymerase Chain Reaction, Multiplex polymerase chain reaction, medicine, Humans, Gene, In Situ Hybridization, Fluorescence, Aged, Chromosome 13, Aged, 80 and over, Genetics, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 11, Hematology, Middle Aged, Aneuploidy, Prognosis, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Molecular biology, Real-time polymerase chain reaction, Oncology, %22">Fish , Female, Chromosome Deletion, Chromosomes, Human, Pair 16
Abstract: Four chromosomal defects associated with outcome are commonly evaluated by fluorescent in situ hybridization (FISH) in chronic lymphocytic leukemia (CLL), namely deletions of the 13q13-q14, 11q22 and 17p13 regions and trisomy 12. In this study, we compared a quantitative PCR method – quantitative multiplex PCR of short fluorescent fragment (QMPSF) – with FISH for the detection of these acquired aneuploidies in a series of 110 patients with Binet stage A CLL. Genes located in the deleted or gained regions were selected as target genes and amplified using a method based on the simultaneous amplification of short fluorescent genomic fragments under quantitative conditions. A chromosomal imbalance involving one or several of the four loci was detected by either method in 72 patients (65%). A chromosome 13 deletion was present in 61 patients (54%), a 11q22 deletion in nine (8%), a trisomy 12 in nine and a 17p deletion in one. FISH and QMPSF results were identical for 103 out of 110 patients and discrepancies could be explained in most cases. This study demonstrates that a quantitative multiplex PCR represents a cost-effective method that could replace FISH in CLL patients. However, although QMPSF is perfectly adapted to the detection of primary defects, care should be taken when searching for clonal evolutions present in a small proportion of tumor cells.
Published: 2007
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47. Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Diagnostics

Author: Nickolas Papadopoulos, Päivi Peltomäki, Richard D. Kolodner, Tao Liu, Bert Vogelstein, Kenneth W. Kinzler, Britta Halvarsson, Mef Nilbert, Thierry Frebourg, Kristina Lagerstedt Robinson, Jana Vandrovcova, Mark Clendenning, and Annika Lindblom
Subjects: Male, Oncology, Cancer Research, DNA Mismatch Repair, 0302 clinical medicine, PMS2, Mismatch Repair Endonuclease PMS2, Adenosine Triphosphatases, Genetics, 0303 health sciences, Nuclear Proteins, Middle Aged, Immunohistochemistry, Lynch syndrome, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, MutS Homolog 2 Protein, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, MutL Protein Homolog 1, Adult, Proto-Oncogene Proteins B-raf, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Amsterdam criteria, Mutation, Missense, MLH1, Diagnosis, Differential, 03 medical and health sciences, Germline mutation, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, neoplasms, Germ-Line Mutation, Adaptor Proteins, Signal Transducing, Retrospective Studies, 030304 developmental biology, business.industry, Decision Trees, nutritional and metabolic diseases, Microsatellite instability, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, MSH6, DNA Repair Enzymes, MSH2, Carrier Proteins, business
Abstract: Background Preventive programs for individuals who have high lifetime risks of colorectal cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with hereditary colorectal cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), have an increased risk to develop colorectal cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC. Methods Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a clinic for patients at high risk for HNPCC were selected for screening to detect mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 based on family history, microsatellite instability (MSI), and immunohistochemical analysis of MMR protein expression. Tumors were also screened for BRAF V600E mutations; patients with the mutation were considered as non-HNPCC. Results Among the 112 patients who were selected for screening, 69 had germline MMR mutations (58 pathogenic and 11 of unknown biologic relevance). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 (88%) of patients in families who met Amsterdam criteria and in 13 of 22 (59%) of patients in families who did not. Among patients with MSI-negative tumors, pathogenic MMR mutations were found in 5 of 17 (29%) of families meeting Amsterdam criteria and in 1 of 30 (3%) of non-Amsterdam families with one patient younger than age 50 years. In three patients with MSI-negative tumors who had pathogenic mutations in MLH1 or MSH6, immunohistochemistry showed loss of the mutated protein. Conclusion Our findings suggest that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with IVISI-negative tumors. (Less)
Published: 2007
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48. A Simple Method for the Routine Detection of Somatic Quantitative Genetic Alterations in Colorectal Cancer

Author: Audrey Killian, Frédéric Di Fiore, Florence Le Pessot, France Blanchard, Aude Lamy, Grégory Raux, Jean–Michel Flaman, Bernard Paillot, Pierre Michel, Jean–Christophe Sabourin, Jean–Jacques Tuech, Francis Michot, Jean–Pierre Kerckaert, Richard Sesboüé, and Thierry Frebourg
Subjects: Male, Somatic cell, Biology, Polymerase Chain Reaction, Fluorescence, law.invention, Proto-Oncogene Proteins c-myc, Loss of heterozygosity, Predictive Value of Tests, law, Multiplex polymerase chain reaction, Humans, Multiplex, Gene, Polymerase chain reaction, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Hepatology, Gene Expression Profiling, Gene Amplification, Gastroenterology, Reproducibility of Results, Prognosis, Molecular biology, Gene Expression Regulation, Neoplastic, genomic DNA, Genes, DCC, Female, Tumor Suppressor Protein p53, Colorectal Neoplasms, Protein Kinases, Gene Deletion, Comparative genomic hybridization
Abstract: Background & Aims: Several quantitative genetic alterations have been suggested to have in colorectal cancer (CRC) either a prognostic or a therapeutic predictive value. Routine detection of these alterations is limited by the absence of simple methods. Methods: The somatic quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF) is based on the simultaneous amplification under quantitative conditions of several dye-labeled targets both from tumor and nonmalignant tissues. For each patient, the resulting QMPSF fluorescent profiles are superimposed, and quantitative changes are simply detected by an increase or decrease of the corresponding fluorescent peaks. Two assays were developed and applied to 57 CRC: a "bar code" exploring several loci with known prognostic value and a "kinogram" studying the copy number change of kinase genes, against which inhibitors have been developed. Results: The bar code revealed that the most frequent alterations were the gain of AURKA /20q13 (53%) and MYC /8q24 (39%) and heterozygous deletion of DCC /18q21.3 (39%) and TP53 /17p13 (23%). The kinogram detected a gene copy number increase for AURKA , PTK2 , MET , and EGFR in 53%, 37%, 33%, and 28% of the tumors, respectively. QMPSF results were validated by comparative genomic hybridization and multiplex real-time polymerase chain reaction on genomic DNA. Conclusions: The somatic QMPSF is a simple method able to detect simultaneously on a routine basis several quantitative changes in tumors. Its flexibility will allow the integration of clinically relevant genes. This high throughput method should be a valuable complementary tool of fluorescent in situ hybrization and comparative genomic hybridization.
Published: 2007
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49. Digital PCR for quantification of recurrent and potentially actionable somatic mutations in circulating free DNA from patients with diffuse large B-cell lymphoma

Author: Pierre-Julien Viailly, Philippe Ruminy, Catherine Maingonnat, Philippe Bertrand, Emilie Lemasle, Ludivine Beaussire, Sylvain Mareschal, Aspasia Stamatoullas, Christian Bastard, Hervé Tilly, Nasrin Sarafan-Vasseur, Fabrice Jardin, Thierry Frebourg, Marie Cornic, Sydney Dubois, Jean-Michel Picquenot, Vincent Camus, Elodie Bohers, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Génétique du cancer et des maladies neuropsychiatriques (GMFC), and Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Somatic cell, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Biology, Karyopherins, medicine.disease_cause, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Recurrence, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Biomarkers, Tumor, Humans, Digital polymerase chain reaction, Liquid biopsy, ComputingMilieux_MISCELLANEOUS, Aged, Neoplasm Staging, Aged, 80 and over, Mutation, Liquid Biopsy, High-Throughput Nucleotide Sequencing, Hematology, DNA, Neoplasm, Middle Aged, medicine.disease, 3. Good health, Lymphoma, 030104 developmental biology, Real-time polymerase chain reaction, Oncology, 030220 oncology & carcinogenesis, Positron-Emission Tomography, Myeloid Differentiation Factor 88, Cancer research, Female, Lymphoma, Large B-Cell, Diffuse, Diffuse large B-cell lymphoma
Abstract: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy harboring frequent targetable activating somatic mutations. Emerging evidence suggests that circulating cell-free DNA (cfDNA) can be used to detect somatic variants in DLBCL using Next-Generation Sequencing (NGS) experiments. In this proof-of-concept study, we chose to develop simple and valuable digital PCR (dPCR) assays for the detection of recurrent exportin-1 (XPO1) E571K, EZH2 Y641N, and MYD88 L265P mutations in DLBCL patients, thereby identifying patients most likely to potentially benefit from targeted therapies. We demonstrated that our dPCR assays were sufficiently sensitive to detect rare XPO1, EZH2, and MYD88 mutations in plasma cfDNA, with a sensitivity of 0.05%. cfDNA somatic mutation detection by dPCR seems to be a promising technique in the management of DLBCL, in addition to NGS experiments.
Published: 2015
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50. Clinical and pathologic features of Aicardi-Goutières syndrome due to an IFIH1 mutation: A pediatric case report

Author: Florent Marguet, Thierry Frebourg, Olivier Quenez, Annie Laquerrière, Catherine Vanhulle, Alice Goldenberg, Clémentine Dumant-Forest, Philippe Flahaut, Myriam Vezain, Isabelle Tournier, Françoise Charbonnier, Gaël Nicolas, Anne-Marie Guerrot, and Soumeya Bekri
Subjects: 0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Interferon-Induced Helicase, IFIH1, Adolescent, Encephalopathy, Neuropathology, Nervous System Malformations, 03 medical and health sciences, 0302 clinical medicine, Autoimmune Diseases of the Nervous System, Genetics, Medicine, Humans, Medical history, Chilblains, Exome, Genetics (clinical), Exome sequencing, Paraplegia, Brain Diseases, business.industry, Infant, Newborn, medicine.disease, 030104 developmental biology, Mutation, Etiology, Aicardi–Goutières syndrome, business, 030217 neurology & neurosurgery
Abstract: We describe the case of a young patient with calcifying encephalopathy, born to asymptomatic parents. An extensive hypothesis-driven etiological assessment was performed and failed to detect the precise etiology during many years. We therefore decided to perform whole exome sequencing of the child-unaffected parents trio. A de novo pathogenic variant in the IFIH1 gene which has recently been shown to cause autosomal dominant forms of Aicardi-Goutieres syndrome was identified. This child presented with a severe form with neonatal thrombocytopenia and hepatomegaly, the latter having been detected during late gestation. Although first milestones were uneventful, he progressively lost motor skills from the age of 12 months and developed severe spastic paraplegia. Brain imaging revealed white matter abnormalities and extensive calcifications. He also presented atypical skin lesions, different from chilblains. His medical history was marked by two episodes of acute pancreatitis. We provide herein the results of pathological examination including detailed description of the neuropathological hallmarks. To our knowledge, this the first detailed clinico-pathological description of a patient with an IFIH1 pathogenic variant.
Published: 2015

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138 results on '"Thierry, Frebourg"'

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