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32 results on '"Danielle Martinet"'

1. A single epidermal stem cell strategy for safe ex vivo gene therapy

Author: Stéphanie Droz‐Georget Lathion, Ariane Rochat, Graham Knott, Alessandra Recchia, Danielle Martinet, Sara Benmohammed, Nicolas Grasset, Andrea Zaffalon, Nathalie Besuchet Schmutz, Emmanuelle Savioz‐Dayer, Jacques Samuel Beckmann, Jacques Rougemont, Fulvio Mavilio, and Yann Barrandon
Subjects: cell therapy, regulatory affairs, stem cells, wound healing, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract There is a widespread agreement from patient and professional organisations alike that the safety of stem cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected stem cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous stem cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced epidermal stem cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with self‐inactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual stem cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced stem cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced stem cells transplanted onto immunodeficient mice regenerated a non‐blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole‐genome sequencing. The progeny of the selected stem cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long‐term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of by‐passing the heterogeneity of a transduced stem cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene‐editing technologies like zinc finger nucleases, TALENs and homologous recombination for next‐generation gene therapy.
Published: 2015
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2. Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

Author: Robin G Walters, Lachlan J M Coin, Aimo Ruokonen, Adam J de Smith, Julia S El-Sayed Moustafa, Sebastien Jacquemont, Paul Elliott, Tõnu Esko, Anna-Liisa Hartikainen, Jaana Laitinen, Katrin Männik, Danielle Martinet, David Meyre, Matthias Nauck, Claudia Schurmann, Rob Sladek, Gudmar Thorleifsson, Unnur Thorsteinsdóttir, Armand Valsesia, Gerard Waeber, Flore Zufferey, Beverley Balkau, François Pattou, Andres Metspalu, Henry Völzke, Peter Vollenweider, Kári Stefansson, Marjo-Riitta Järvelin, Jacques S Beckmann, Philippe Froguel, and Alexandra I F Blakemore
Subjects: Medicine, Science
Abstract: The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.
Published: 2013
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3. Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma.

Author: Armand Valsesia, Donata Rimoldi, Danielle Martinet, Mark Ibberson, Paola Benaglio, Manfredo Quadroni, Patrice Waridel, Muriel Gaillard, Mireille Pidoux, Blandine Rapin, Carlo Rivolta, Ioannis Xenarios, Andrew J G Simpson, Stylianos E Antonarakis, Jacques S Beckmann, C Victor Jongeneel, Christian Iseli, and Brian J Stevenson
Subjects: Medicine, Science
Abstract: Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression ('SCNA-genes') in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two large, independent melanoma SCNA datasets showed less than 10% overlap at the individual gene level, but network-guided analysis revealed 66% shared pathways, including all but three of the pathways identified in our data. Frequently altered pathways included WNT, cadherin signalling, angiogenesis and melanogenesis. Additionally, our results emphasize the potential of the EPHA3 and FRS2 gene products, involved in angiogenesis and migration, as possible therapeutic targets in melanoma. Our study demonstrates the utility of network-guided approaches, for both large and small datasets, to identify pathways recurrently perturbed in cancer.
Published: 2011
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4. Data from Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres

Author: Monika E. Hegi, Marc Levivier, Roger Stupp, Bernd Kaina, Marie-France Hamou, Claudio Pollo, Robert-Charles Janzer, Greg Jones, Danielle Martinet, Kristof van Dommelen, Annie-Claire Diserens, and Davide Sciuscio
Abstract: Purpose: Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma.Experimental Design: Ten paired samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity.Results: In glioblastoma, MGMT-methylated alleles ranged from 10% to 90%. In contrast, methylated alleles were highly enriched (100% of clones) in respective GS, even when 2 MGMT alleles were present, with 1 exception (MGMT promoter methylation was associated with a nonpermissive chromatin status in accordance with very low MGMT transcript levels and undetectable MGMT activity.Conclusions: In MGMT-methylated glioblastoma, MGMT promoter methylation is highly enriched in GS that supposedly comprise glioma-initiating cells. Thus, even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy. Clin Cancer Res; 17(2); 255–66. ©2010 AACR.
Published: 2023
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5. Supplementary Data from Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres

Author: Monika E. Hegi, Marc Levivier, Roger Stupp, Bernd Kaina, Marie-France Hamou, Claudio Pollo, Robert-Charles Janzer, Greg Jones, Danielle Martinet, Kristof van Dommelen, Annie-Claire Diserens, and Davide Sciuscio
Abstract: Supplementary Figures S1-S6; Supplementary Table S1.
Published: 2023
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6. Xq28 duplication includingMECP2in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Author: Sophie Rondeau, Charles Coutton, Pierre-Simon Jouk, Lydie Burglen, Alice Goldenberg, Bérénice Doray, Nathalie Marle, Séverine Drunat, Pascal Chambon, P. Callier, Thierry Bienvenu, F. Devillard, M.-L. Moutard, Danielle Martinet, Bernard Aral, Pascale Saugier-Veber, Nathalie Perreton, Marie-Claude Addor, Marguerite Miguet, Martine Doco-Fenzy, N. Le Meur, Anne-Marie Guerrot, J.-L. Alessandri, C. Thauvin-Robinet, R. Touraine, Anne-Claude Tabet, Anne-Laure Mosca-Boidron, S. El Chehadeh, D. Devys, Sébastien Lebon, Alexandra Afenjar, Sandra Chantot-Bastaraud, Laurence Faivre, Emilie Landais, Cathy Philippe, Klaus Dieterich, Valérie Kremer, Julien Thevenon, Véronique Satre, V. des Portes, Francine Mugneret, Willie Reardon, and Fabienne Prieur
Subjects: 0301 basic medicine, Genetics, Pediatrics, medicine.medical_specialty, Genetic counseling, MECP2 duplication syndrome, 030105 genetics & heredity, Biology, medicine.disease, X-inactivation, 3. Good health, Xq28, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene duplication, medicine, Asymptomatic carrier, Skewed X-inactivation, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.
Published: 2017
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7. SCRIB and PUF60 Are Primary Drivers of the Multisystemic Phenotypes of the 8q24.3 Copy-Number Variant

Author: Jacques S. Beckmann, Christelle Golzio, Nicholas Katsanis, Andrew Dauber, Małgorzata J.M. Nowaczyk, Susan Zeesman, Joel N. Hirschhorn, Francine M. Jodelka, Jill A. Rosenfeld, Danielle Martinet, Bruno Leheup, Cécile Guenot, Michelle L. Hastings, Susanne Kjaergaard, Sébastien Jacquemont, Janice Zunich, Maria Kibaek, UL, NGERE, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Harvard Medical School [Boston] (HMS), Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Center for Human Disease Modeling, Duke University [Durham], Service de Génétique Médicale [CHUV Lausanne], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Service de Génétique Clinique [CHUV Lausanne], Department of Cell Biology and Anatomy [Chicago Medical School · Rosalind Franklin University], Chicago Medical School [Rosalind Franklin University], Rosalind Franklin University-Rosalind Franklin University, Department of Pediatrics [Odense University Hospital], Odense University Hospital, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), McMaster University [Hamilton, Ontario], PerkinElmer, Inc., Indiana University School of Medicine, Indiana University System-Indiana University System, and Dept of Genetics, Harvard Medical School
Subjects: Male, Microcephaly, Developmental Disabilities, [SDV]Life Sciences [q-bio], medicine.disease_cause, 0302 clinical medicine, Genetics(clinical), Copy-number variation, Child, Zebrafish, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Chromosome Mapping, RNA-Binding Proteins, Phenotype, [SDV] Life Sciences [q-bio], Child, Preschool, Gene Knockdown Techniques, RNA splicing, Female, RNA Splicing Factors, Erratum, Chromosomes, Human, Pair 8, SCRIB, Adolescent, DNA Copy Number Variations, Biology, Article, 03 medical and health sciences, Intellectual Disability, medicine, Animals, Humans, Allele, Alleles, 030304 developmental biology, Tumor Suppressor Proteins, Membrane Proteins, medicine.disease, Human genetics, Genetic architecture, Repressor Proteins, Gene Deletion, 030217 neurology & neurosurgery, HeLa Cells
Abstract: International audience; Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.
Published: 2013
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8. Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5

Author: D. Hull, Diana Ballhausen, Luisa Bonafé, Danielle Martinet, Peter Kannu, and Ana Belinda Campos-Xavier
Subjects: Adult, Male, Biology, Gene dosage, Germline, 03 medical and health sciences, Exon, Quantitative Trait, Heritable, 0302 clinical medicine, Glypicans, Chromosome Duplication, Genetics, medicine, Humans, Gene, Genetics (clinical), 030304 developmental biology, Comparative Genomic Hybridization, 0303 health sciences, Chromosomes, Human, Pair 13, Polydactyly, Facies, Infant, Chromosome, General Medicine, medicine.disease, MicroRNAs, Phenotype, Female, RNA, Long Noncoding, Human genome, Haploinsufficiency, 030217 neurology & neurosurgery
Abstract: Genomic rearrangements at chromosome 13q31.3q32.1 have been associated with digital anomalies, dysmorphic features, and variable degree of mental disability. Microdeletions leading to haploinsufficiency of miR17∼92, a cluster of micro RNA genes closely linked to GPC5 in both mouse and human genomes, has recently been associated with digital anomalies in the Feingold like syndrome. Here, we report on a boy with familial dominant post-axial polydactyly (PAP) type A, overgrowth, significant facial dysmorphisms and autistic traits who carries the smallest germline microduplication known so far in that region. The microduplication encompasses the whole miR17∼92 cluster and the first 5 exons of GPC5. This report supports the newly recognized role of miR17∼92 gene dosage in digital developmental anomalies, and suggests a possible role of GPC5 in growth regulation and in cognitive development.
Published: 2013
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9. Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial

Author: Mathilde C.M. Kouwenhoven, Karima Mokhtari, René-Olivier Mirimanoff, Marie-France Hamou, Christian Hartmann, Danielle Martinet, Pieter Wesseling, Roger Stupp, A. von Deimling, M. J. van den Bent, Michael Weller, N Besuchet Schmutz, Wanyu L. Lambiv, Robert-Charles Janzer, Thierry Gorlia, Annie-Claire Diserens, Monika E. Hegi, Pierre Bady, Warren P. Mason, Pathology, CCA - Disease profiling, University of Zurich, Hegi, M E, Neurology, Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group, European Organisation for, Research, and Treatment of Cancer Brain, Tumour
Subjects: Male, Oncology, Pathology, medicine.medical_treatment, 2804 Cellular and Molecular Neuroscience, Central Pathology Review, 0302 clinical medicine, Brain Neoplasms, Chemoradiotherapy, Middle Aged, Prognosis, Translational research Tissue engineering and pathology [ONCOL 3], 3. Good health, Dacarbazine, ErbB Receptors, Treatment Outcome, 2728 Neurology (clinical), 030220 oncology & carcinogenesis, Female, medicine.drug, Adult, medicine.medical_specialty, IDH1, Adolescent, Oligodendroglioma, 610 Medicine & health, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, Temozolomide, medicine, Humans, Clinical significance, Aged, Brain Neoplasms/genetics, Brain Neoplasms/pathology, Clinical Trials, Phase III as Topic, DNA Methylation, Dacarbazine/analogs & derivatives, Dacarbazine/therapeutic use, Glioblastoma/genetics, Glioblastoma/pathology, Mutation, Oligodendroglioma/genetics, Oligodendroglioma/pathology, Receptor, Epidermal Growth Factor/genetics, Receptor, Epidermal Growth Factor/metabolism, Survival Analysis, Chemotherapy, business.industry, medicine.disease, 10040 Clinic for Neurology, nervous system diseases, 2734 Pathology and Forensic Medicine, Clinical trial, Component (group theory), Neurology (clinical), Glioblastoma, business, 030217 neurology & neurosurgery
Abstract: Item does not contain fulltext Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy. 01 juni 2012
Published: 2012
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10. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author: Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), 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), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, 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 ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Heterozygote, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Biology, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Order, Genetics, medicine, Humans, Copy-number variation, Clinical genetics, Obesity, Young adult, Child, Genetics (clinical), 030304 developmental biology, Child Development Disorders, Pervasive/diagnosis, Child Development Disorders, Pervasive/genetics, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities/diagnosis, Developmental Disabilities/genetics, Female, Intelligence Tests, Phenotype, Syndrome, 2. Zero hunger, Psychiatry, 0303 health sciences, Intelligence quotient, Neuropsychology, Complex traits, medicine.disease, Comorbidity, 3. Good health, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Medical genetics, Human medicine, Copy-Number Variation, 030217 neurology & neurosurgery
Abstract: Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.
Published: 2012
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11. The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

Author: Katya Nardou, Nicole Gross, Aurélie Coulon, Jacques S. Beckmann, Danielle Martinet, Niggli Fk, Marjorie Flahaut, Jean-Marc Joseph, Annick Mühlethaler-Mottet, Roland Meier, University of Zurich, and Flahaut, M
Subjects: Male, Cancer Research, Fluorescent Antibody Technique, Small hairpin RNA, Neuroblastoma, Transactivation, 0302 clinical medicine, RNA interference, 1306 Cancer Research, In Situ Hybridization, Fluorescence, beta Catenin, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Wnt signaling pathway, LRP5, 3. Good health, Gene Expression Regulation, Neoplastic, Caspases, 030220 oncology & carcinogenesis, Female, RNA Interference, Signal Transduction, FZD1, ATP Binding Cassette Transporter, Subfamily B, Cell Survival, Blotting, Western, Active Transport, Cell Nucleus, 610 Medicine & health, Biology, Cell Line, 03 medical and health sciences, 1311 Genetics, Cell Line, Tumor, 1312 Molecular Biology, Genetics, Humans, Gene silencing, ATP Binding Cassette Transporter, Subfamily B, Member 1, Molecular Biology, 030304 developmental biology, Cell Nucleus, Gene Expression Profiling, Frizzled Receptors, Wnt Proteins, 10036 Medical Clinic, Doxorubicin, Drug Resistance, Neoplasm, Cancer research
Abstract: The development of chemoresistance represents a major obstacle in the successful treatment of cancers such as neuroblastoma (NB), a particularly aggressive childhood solid tumour. The mechanisms underlying the chemoresistant phenotype in NB were addressed by gene expression profiling of two doxorubicin (DoxR)-resistant vs sensitive parental cell lines. Not surprisingly, the MDR1 gene was included in the identified upregulated genes, although the highest overexpressed transcript in both cell lines was the frizzled-1 Wnt receptor (FZD1) gene, an essential component of the Wnt/beta-catenin pathway. FZD1 upregulation in resistant variants was shown to mediate sustained activation of the Wnt/beta-catenin pathway as revealed by nuclear beta-catenin translocation and target genes transactivation. Interestingly, specific micro-adapted short hairpin RNA (shRNAmir)-mediated FZD1 silencing induced parallel strong decrease in the expression of MDR1, another beta-catenin target gene, revealing a complex, Wnt/beta-catenin-mediated implication of FZD1 in chemoresistance. The significant restoration of drug sensitivity in FZD1-silenced cells confirmed the FZD1-associated chemoresistance. RNA samples from 21 patient tumours (diagnosis and postchemotherapy), showed a highly significant FZD1 and/or MDR1 overexpression after treatment, underlining a role for FZD1-mediated Wnt/beta-catenin pathway in clinical chemoresistance. Our data represent the first implication of the Wnt/beta-catenin pathway in NB chemoresistance and identify potential new targets to treat aggressive and resistant NB.
Published: 2009
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12. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome

Author: Bregje W.M. van Bon, Tiia Reimand, Berten Ceulemans, Barbara Delle Chiaie, Christine Oley, Anne Destree, Ernie M.H.F. Bongers, Danielle Martinet, Dom McMullan, Rolph Pfund, Bert B.A. de Vries, Jenneke van den Ende, Louise Brueton, Connie Schrander-Stumpel, Corrado Romano, Marco Fichera, Alexander P.A. Stegmann, Edwin Reyniers, Geert Mortier, Suzanna G.M. Frints, Isabelle Maystadt, Katrin Männik, Nathalie Van der Aa, Ants Kurg, Geert Vandeweyer, Björn Menten, Alessandra Ferrarini, R. Frank Kooy, Sébastien Jacquemont, and Liesbeth Rooms
Subjects: Male, Williams Syndrome, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Language delay, Population, Chromosome Disorders, Speech Disorders, Genomic disorders and inherited multi-system disorders [IGMD 3], Communication disorder, Intellectual Disability, Gene duplication, Genetics, medicine, Humans, Abnormalities, Multiple, Diaphragmatic hernia, Child, education, Genetics (clinical), Family Health, education.field_of_study, business.industry, Infant, Syndrome, General Medicine, medicine.disease, Hypotonia, Phenotype, Child, Preschool, Face, Speech delay, Autism, Female, Human medicine, Chromosome Deletion, medicine.symptom, business, Chromosomes, Human, Pair 7
Abstract: Contains fulltext : 80644.pdf (Publisher’s version ) (Closed access) Interstitial deletions of 7q11.23 cause Williams-Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams-Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000-1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI. Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.
Published: 2009
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13. A new CRB1 rat mutation links Müller glial cells to retinal telangiectasia

Author: Patricia Crisanti, Carlo Rivolta, Marilyn Dernigoghossian, Rosanna Pescini-Gobert, Charlotte Andrieu-Soler, Alejandro Maass, Jean-Claude Jeanny, Min Zhao, Laura Kowalczuk, Marie-Christine Naud, Michèle Savoldelli, Wilfred F. J. van IJcken, Danielle Martinet, Francisco Halili, Francine Behar-Cohen, Jan Wijnholds, María Paz Cortés, Mohamed El Sanharawi, Marianne Berdugo, Brigitte Goldenberg, Netherlands Institute for Neuroscience (NIN), and Cell biology
Subjects: Retinal degeneration, Neurons/ultrastructure, Retinal Degeneration/genetics, Telangiectasis/complications, adherens junction, Photoreceptor cell, chemistry.chemical_compound, Visual Pathways/pathology, genetics, Fluorescein Angiography, Cells, Cultured, Macular telangiectasia, Neurons, Genetics, medicine.diagnostic_test, General Neuroscience, Age Factors, Articles, Glial Fibrillary Acidic Protein/metabolism, Retinal Vessels/pathology, Cell biology, Platelet Endothelial Cell Adhesion Molecule-1, Retinal telangiectasia, medicine.anatomical_structure, Ependymoglial Cells/pathology, Muller glia, Retinal Degeneration/etiology, Signal Transduction, Antigens, CD31/metabolism, Mutation/genetics, Eye Proteins/metabolism, Ependymoglial Cells, microcirculation, Visual Pathways/ultrastructure, Biology, Eye Proteins/genetics, retinal blood vessels, Rats, Mutant Strains, SDG 3 - Good Health and Well-being, Glial Fibrillary Acidic Protein, Electroretinography, medicine, Animals, Retinal Degeneration/pathology, Visual Pathways, Telangiectasis, Eye Proteins, Retinal Vessels/ultrastructure, Telangiectasis/genetics, Signal Transduction/physiology, Neurons/pathology, disease model, Retinal Vessels, Retinal, medicine.disease, Actin cytoskeleton, Rats, Disease Models, Animal, Animals, Newborn, nervous system, chemistry, Ependymoglial Cells/ultrastructure, Mutation, retinal degeneration, Ependymoglial Cells/metabolism
Abstract: We have identified and characterized a spontaneous Brown Norway from Janvier rat strain (BN-J) presenting a progressive retinal degeneration associated with early retinal telangiectasia, neuronal alterations, and loss of retinal Müller glial cells resembling human macular telangiectasia type 2 (MacTel 2), which is a retinal disease of unknown cause. Genetic analyses showed that the BN-J phenotype results from an autosomal recessive indel novel mutation in theCrb1gene, causing dislocalization of the protein from the retinal Müller glia (RMG)/photoreceptor cell junction. The transcriptomic analyses of primary RMG cultures allowed identification of the dysregulated pathways in BN-J rats compared with wild-type BN rats. Among those pathways, TGF-β and Kit Receptor Signaling, MAPK Cascade, Growth Factors and Inflammatory Pathways, G-Protein Signaling Pathways, Regulation of Actin Cytoskeleton, and Cardiovascular Signaling were found. Potential molecular targets linking RMG/photoreceptor interaction with the development of retinal telangiectasia are identified. This model can help us to better understand the physiopathologic mechanisms of MacTel 2 and other retinal diseases associated with telangiectasia.
Published: 2015
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14. A single epidermal stem cell strategy for safe ex vivo gene therapy

Author: Stephanie Lathion, Nicolas Grasset, Danielle Martinet, Sara Benmohammed, Alessandra Recchia, Yann Barrandon, Jacques Rougemont, Nathalie Besuchet Schmutz, Ariane Rochat, Jacques S. Beckmann, Emmanuelle Savioz-Dayer, Andrea Zaffalon, Graham Knott, Fulvio Mavilio, Laboratory of Cytogenetics, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, and École pratique des hautes études (EPHE)
Subjects: Adult, Male, Collagen Type VII, [SDV]Life Sciences [q-bio], Genetic enhancement, Cell therapy, Regulatory affairs, Stem cells, Wound healing, wound healing, Mice, SCID, Biology, Mice, Transduction, Genetic, Animals, Humans, Research Articles, regulatory affairs, Cells, Cultured, Transcription activator-like effector nuclease, Stem Cells, Infant, Newborn, Genetic Therapy, Zinc finger nuclease, Epidermolysis Bullosa Dystrophica, 3. Good health, Transplantation, Retroviridae, Immunology, Cancer research, Heterografts, Molecular Medicine, Female, cell therapy, Epidermis, Closeup, Stem cell, Ex vivo, Stem Cell Transplantation
Abstract: International audience; There is a widespread agreement from patient and professional organisations alike that the safety of stem cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected stem cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous stem cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced epidermal stem cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with self-inactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual stem cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced stem cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced stem cells transplanted onto immunodeficient mice regenerated a non-blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole-genome sequencing. The progeny of the selected stem cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long-term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of by-passing the heterogeneity of a transduced stem cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene-editing technologies like zinc finger nucleases, TALENs and homologous recombination for next-generation gene therapy.
Published: 2015
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15. A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology

Author: Eugenia Migliavacca, Christelle Golzio, Katrin Männik, Ian Blumenthal, Edwin C. Oh, Louise Harewood, Jack A. Kosmicki, Maria Nicla Loviglio, Giuliana Giannuzzi, Loyse Hippolyte, Anne M. Maillard, Ali Abdullah Alfaiz, Mieke M. van Haelst, Joris Andrieux, James F. Gusella, Mark J. Daly, Jacques S. Beckmann, Sébastien Jacquemont, Michael E. Talkowski, Nicholas Katsanis, Alexandre Reymond, Robert Witwicki, Gérard Didelot, Ilse van der Werf, Ali A. Alfaiz, Marianna Zazhytska, Jacqueline Chrast, Aurélien Macé, Sven Bergmann, Zoltan Kutalik, Vanessa Siffredi, Flore Zufferey, Danielle Martinet, Frédérique Bena, Anita Rauch, Sonia Bouquillon, Bruno Delobel, Odile Boute, Bénédicte Duban-Bedu, Cédric Le Caignec, Bertrand Isidor, Jean Chiesa, Boris Keren, Brigitte Gilbert-Dussardier, Renaud Touraine, Dominique Campion, Caroline Rooryck Thambo, Michèle Mathieu-Dramard, Ghislaine Plessis, Frank Kooy, Hilde Peeters, Katrin Ounap, Anneke T. Vulto-van Silfhout, Bert B. de Vries, Ellen van Binsbergen, Ann Nordgren, Mafalda Mucciolo, Alessandra Renieri, Evica Rajcan-Separovic, John A. Philipps, Richard J. Ellis, Other departments, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), University of Zurich, and Katsanis, Nicholas
Subjects: Potassium Channels, 10039 Institute of Medical Genetics, BBS7, Ciliopathies, Transcriptome, Mice, 0302 clinical medicine, Gene duplication, Genetics(clinical), Non-U.S. Gov't, Child, Zebrafish, Genetics (clinical), Genetics, 0303 health sciences, Research Support, Non-U.S. Gov't, Brain, Voltage-Gated, Phenotype, medicine.anatomical_structure, Potassium Channels, Voltage-Gated, Chromosome Deletion, Human, 2716 Genetics (clinical), Child Development Disorders, DNA Copy Number Variations, 610 Medicine & health, Biology, Research Support, Article, Chromosomes, N.I.H, 03 medical and health sciences, Ciliary body, 1311 Genetics, Research Support, N.I.H., Extramural, mental disorders, medicine, Journal Article, Animals, Humans, 030304 developmental biology, Pervasive, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Pair 16, Ciliary Body, Extramural, Zebrafish Proteins, medicine.disease, biology.organism_classification, Ciliopathy, Gene Expression Regulation, Child Development Disorders, Pervasive, Chromosomes, Human, Pair 16, Schizophrenia, 570 Life sciences, biology, 030217 neurology & neurosurgery
Abstract: Item does not contain fulltext The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.
Published: 2015
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16. Chromosomal microarray among children with intellectual disability: a useful diagnostic tool for the clinical geneticist

Author: Alessandra Ferrarini, Danielle Martinet, Gian Paolo Ramelli, Marco Belfiore, Mario G. Bianchetti, Sebastiano A. G. Lava, and Stephanie Capobianco
Subjects: Chromosome Aberrations, Male, medicine.medical_specialty, Microarray, Adolescent, business.industry, Developmental Disabilities, Geneticist, medicine.disease, Young Adult, Developmental Neuroscience, Pediatrics, Perinatology and Child Health, Intellectual disability, Medicine, Humans, Female, Neurology (clinical), 610 Medicine & health, business, Psychiatry, Child, Oligonucleotide Array Sequence Analysis
Published: 2013

17. Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity

Author: François Pattou, Robert Sladek, Flore Zufferey, Matthias Nauck, Kari Stefansson, Unnur Thorsteinsdottir, Robin G. Walters, Katrin Männik, Tõnu Esko, Sébastien Jacquemont, Peter Vollenweider, Jaana Laitinen, Adam J. de Smith, Claudia Schurmann, Danielle Martinet, Anna-Liisa Hartikainen, Gérard Waeber, David Meyre, Julia S. El-Sayed Moustafa, Armand Valsesia, Lachlan J. M. Coin, Philippe Froguel, Alexandra I. F. Blakemore, Henry Völzke, Marjo-Riitta Järvelin, Jacques S. Beckmann, Gudmar Thorleifsson, Aimo Ruokonen, Andres Metspalu, Paul Elliott, Beverley Balkau, and Medical Research Council (MRC)
Subjects: Male, False discovery rate, Heredity, Kinesins, lcsh:Medicine, Genome-wide association study, Adolescent Adult Aged Body Mass Index Child Child, Preschool *Chromosome Deletion Chromosomes, Human, Pair 16/*genetics Cohort Studies Female Forkhead Transcription Factors/genetics *Genetic Loci Genome-Wide Association Study Humans Kinesin/genetics Male Middle Aged Obesity/*genetics, Body Mass Index, Cohort Studies, HIDDEN-MARKOV MODEL, Missing heritability problem, WIDE ASSOCIATION, Copy-number variation, Child, lcsh:Science, Genetics, education.field_of_study, Multidisciplinary, Forkhead Transcription Factors, Kinesin, Genomics, Middle Aged, Child, Preschool, Cohort, Science & Technology - Other Topics, Medicine, Female, CHILDHOOD OBESITY, Chromosome Deletion, Research Article, Adult, CHROMOSOME 16P11.2, Adolescent, General Science & Technology, Clinical Research Design, Population, EARLY-ONSET, Biology, MD Multidisciplinary, Humans, COHORT, Obesity, education, SNP GENOTYPING DATA, Genetic Association Studies, COPY NUMBER VARIATION, Aged, Nutrition, Science & Technology, MULTIDISCIPLINARY SCIENCES, Complex Traits, lcsh:R, Computational Biology, Human Genetics, Odds ratio, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, Genetic Loci, Case-Control Studies, Genetics of Disease, Multiple comparisons problem, Structural Genomics, lcsh:Q, Chromosomes, Human, Pair 16, Genome-Wide Association Study
Abstract: The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.
Published: 2013

18. Molecular characterization of 39 de novo sSMC: contribution to prognosis and genetic counselling, a prospective study

Author: N. Lemeur, G. Bourrouillou, Véronique Satre, Muriel Payet, Anouck Schneider, B. Quilichini, Thierry Rousseau, A. Liquier, Jacques Puechberty, François Vialard, S. Fert Ferrer, D. Molina Gomes, S. Amblard, Patrick Callier, Martine Doco-Fenzy, H. Stora, Marie-Pierre Cordier, Nathalie Marle, Brigitte Simon-Bouy, Joris Andrieux, Laurence Faivre, A. L. Mosca, Azzedine Aboura, Florence Fellmann, F. Girard-Lemaire, Danielle Martinet, Pascal Chambon, A. Delaye, Damien Sanlaville, M. Becker, Elisabeth Flori, C. Rangon, Sébastien Jacquemont, Anne Bazin, V. Kremer, Eva Pipiras, R. Molignier, F. Mugneret, Géraldine Joly-Helas, Serge Aho, A. Vigouroux-Castera, and Anne-Claude Tabet
Subjects: Adult, Genetic Markers, Risk, Euchromatin, Karyotype, Context (language use), Prenatal diagnosis, Single-nucleotide polymorphism, Genetic Counseling, Biology, Polymorphism, Single Nucleotide, Young Adult, Pregnancy, Prenatal Diagnosis, Genetics, medicine, SNP, Humans, Genetic Predisposition to Disease, Prospective Studies, Genetics (clinical), Genetic Association Studies, In Situ Hybridization, Fluorescence, Chromosome Aberrations, Comparative Genomic Hybridization, medicine.diagnostic_test, Middle Aged, Prognosis, Molecular biology, Female, France, Switzerland, SNP array, Fluorescence in situ hybridization, Genome-Wide Association Study
Abstract: Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval (CI), 0.042-0.082]. Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array-CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context.
Published: 2012

19. Subtelomeric Deletion of Chromosome 10p15.3: Clinical Findings and Molecular Cytogenetic Characterization

Author: Surabhi Mulchandani, Anne C.H. Tsai, James Tepperberg, Ian D. Krantz, Danielle Martinet, Laura K. Conlin, Marie-Claude Addor, Cheryl DeScipio, Hilde Van Esch, Erik C. Thorland, Marie T. McDonald, Yvonne Hilhorst-Hofstee, Dinah Clark, Nancy B. Spinner, Romela Pasion, Thornton B.A. Mason, Alvaro H. Serrano, Marianne McGuire, Jennifer L. Goldstein, Jill A. Rosenfeld, Darlene Ho, Claudia A. L. Ruivenkamp, Livija Medne, Ankita Patel, Rosemarie Rupps, and Swaroop Aradhya
Subjects: Male, Proband, ZMYND11, Biology, Article, Genotype, Genetics, medicine, Humans, deletion, Child, DIP2C, Genetics (clinical), chromosomal microarray (CMA), Chromosomes, Human, Pair 10, Chromosome Deletion, Female, Infant, Infant, Newborn, Telomere, Chromosome, Subtelomere, Phenotype, Hypotonia, Speech delay, medicine.symptom, Haploinsufficiency, 10p15.3
Abstract: We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11,), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM# 608668) and DIP2C (OMIM# 611380) (UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.
Published: 2012
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20. Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats

Author: Jill A. Rosenfeld, Marwan Shinawi, Scott Saunders, Livija Medne, Shashikant Kulkarni, Avinash V. Dharmadhikari, Carsten G. Bönnemann, Suneeta Madan-Khetarpal, Pawel Stankiewicz, Samarth Bhatt, Stephanie E. Vallee, Fernando Scaglia, Marshall L. Summar, Zhilian Xia, Carlos A. Bacino, Ann Martin, Brendan Lee, Alexander Asamoah, Jacques S. Beckmann, Wendy E. Smith, Sau Wai Cheung, Sumit Parikh, Rizwan Hamid, Tracy L. McGregor, Amber N. Pursley, Jean P. Pfotenhauer, Kathryn Platky, Lisa G. Shaffer, Chad A. Shaw, Ankita Patel, Polly Irwin, Paul S. Simons, Dorothy K. Grange, Sung-Hae L. Kang, Gary Bellus, Victoria P. Dalzell, John B. Moeschler, Jennifer Kussmann, Srirangan Sampath, Danielle Martinet, Alex R. Paciorkowski, Michael J. Noetzel, Carolyn Lovell, Susan Sparks, Blake C. Ballif, Kathryn Golden-Grant, Florence Fellmann, David B. Flannery, Jacqueline M. Hoover, Tamim H. Shaikh, M. Lance Cooper, Valerie Banks, and Jerome L. Gorski
Subjects: Male, Ataxia, DNA Copy Number Variations, Developmental Disabilities, Vesicular Acetylcholine Transport Proteins, Non-allelic homologous recombination, Penetrance, Biology, Article, Abnormalities, Multiple/genetics, Child, Child, Preschool, Chromosome Aberrations, Chromosome Mapping, Chromosomes, Human, Pair 10, Developmental Disabilities/complications, Developmental Disabilities/genetics, Female, Genetic Variation, Homologous Recombination, Humans, In Situ Hybridization, Fluorescence, Infant, Intellectual Disability/complications, Intellectual Disability/genetics, Nerve Growth Factors/genetics, Oligonucleotide Array Sequence Analysis, Segmental Duplications, Genomic/genetics, Sequence Deletion, Vesicular Acetylcholine Transport Proteins/genetics, Segmental Duplications, Genomic, Intellectual Disability, Genetics, medicine, Abnormalities, Multiple, Nerve Growth Factors, Expressivity (genetics), Gene, Genetics (clinical), Segmental duplication, Low copy repeats, Hypotonia, medicine.symptom
Abstract: We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.
Published: 2012

21. 16q24.1 microdeletion in a premature newborn: usefulness of array-based comparative genomic hybridation (array CGH) in persistent pulmonary hypertension of the newborn

Author: Danielle Martinet, Maria-Chiara Osterheld, Nathalie Besuchet Schmutz, Zhilian Xia, Eric Giannoni, Charles Shaw-Smith, Jacques S. Beckmann, Flore Zufferey, Claire Langston, Pawel Stankiewicz, Florence Fellmann, and Florence Niel-Bütschi
Subjects: Male, Pathology, medicine.medical_specialty, Hypertension, Pulmonary, Karyotype, Critical Care and Intensive Care Medicine, Persistent Fetal Circulation Syndrome, Article, medicine, Humans, Abnormalities, Multiple, Comparative Genomic Hybridization, business.industry, Persistent pulmonary hypertension, Infant, Newborn, medicine.disease, Infant newborn, Pulmonary hypertension, Pulmonary Alveoli, Array-Based Comparative Genomic Hybridization, Premature newborn, Pulmonary Veins, Pediatrics, Perinatology and Child Health, Chromosome Deletion, business, Multiple congenital malformations, Chromosomes, Human, Pair 16, Comparative genomic hybridization
Abstract: OBJECTIVE:: Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn and multiple congenital malformations. DESIGN:: Descriptive case report. SETTING:: Genetic department and neonatal intensive care unit of a tertiary care children's hospital. INTERVENTIONS:: None. PATIENT:: We report the case of a preterm male infant, born at 26 wks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 wks of gestation. Karyotype analysis was normal, and a 22q11.2 microdeletion was excluded by fluorescence in situ hybridization analysis. A cesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hrs of life. MEASUREMENTS AND MAIN RESULTS:: An autopsy revealed partial atrioventricular canal malformation and showed bilateral dilation of the renal pelvocaliceal system with bilateral ureteral stenosis and annular pancreas. Array-based comparative genomic hybridization analysis (Agilent oligoNT 44K, Agilent Technologies, Santa Clara, CA) showed an interstitial microdeletion encompassing the forkhead box gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins. Some features were less prominent due to the gestational age. CONCLUSIONS:: Our review of the literature shows that alveolar capillary dysplasia with misalignment of pulmonary veins is rare but probably underreported. Prematurity is not a usual presentation, and histologic features are difficult to interpret. In our case, array-based comparative genomic hybridization revealed a 16q24.1 deletion, leading to the final diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins. It emphasizes the usefulness of array-based comparative genomic hybridization analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory persistent pulmonary hypertension and multiple congenital malformations.
Published: 2011

22. The phenotype of recurrent 10q22q23 deletions and duplications

Author: Pawel Stankiewicz, Swaroop Aradhya, Elizabeth Cameron, Danielle Martinet, Rolph Pfundt, Eliane Roulet, Angelo Selicorni, Jacques S. Beckmann, Bregje W.M. van Bon, Mira Irons, Sébastien Jacquemont, Lorraine Potocki, Barry Wolf, Melissa Bellini, Ankita Patel, Nine V A M Knoers, Annalisa Vetro, Scott B. Selleck, Han G. Brunner, James R. Lupski, Jorune Balciuniene, Sau Wai Cheung, Orsetta Zuffardi, Margherita Silengo, Sandesh C.S. Nagamani, Roberto Ciccone, Petr E. Jira, Gary Fruhman, Bert B.A. de Vries, Diane L Broome, Nicole de Leeuw, and Brendan Lee
Subjects: Proband, Male, Candidate gene, PTEN, DNA Copy Number Variations, Developmental Disabilities, 10q22.3q23.2, Breast aplasia, breast development, Genomic disorders and inherited multi-system disorders Functional Neurogenomics [IGMD 3], Biology, Article, Mice, Segmental Duplications, Genomic, Gene duplication, Genetics, medicine, Animals, Humans, Abnormalities, Multiple, Language Development Disorders, NRG3, BMPR1A, GRID1, Child, Genetics (clinical), Bone Morphogenetic Protein Receptors, Type I, Adaptor Proteins, Signal Transducing, Natural Cytotoxicity Triggering Receptor 3, Chromosomes, Human, Pair 10, Breakpoint, Macrocephaly, Body Dysmorphic Disorders, Phenotype, Penetrance, Megalencephaly, Genetics and epigenetic pathways of disease Renal disorder [NCMLS 6], Female, medicine.symptom, Chromosome Deletion, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6]
Abstract: Item does not contain fulltext The genomic architecture of the 10q22q23 region is characterised by two low-copy repeats (LCRs3 and 4), and deletions in this region appear to be rare. We report the clinical and molecular characterisation of eight novel deletions and six duplications within the 10q22.3q23.3 region. Five deletions and three duplications occur between LCRs3 and 4, whereas three deletions and three duplications have unique breakpoints. Most of the individuals with the LCR3-4 deletion had developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed. For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene. For cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function. Duplications between LCRs3 and 4 are associated with variable phenotypic penetrance. Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip. In conclusion, duplications between LCRs3 and 4 on 10q22.3q23.2 may lead to a distinct facial appearance and delays in speech and motor development. However, the phenotypic spectrum is broad, and duplications have also been found in healthy family members of a proband. Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects.
Published: 2011

23. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author: Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), 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), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], 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), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), 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), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), 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), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413
Published: 2011
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24. Corrigendum to 'Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5' [Eur J Med Genet 56 (8) (2013) 452–457]

Author: Danielle Martinet, Diana Ballhausen, Luisa Bonafé, D. Hull, Ana Belinda Campos-Xavier, and Peter Kannu
Subjects: Genetics, Autistic traits, Polydactyly, medicine, Chromosome, General Medicine, Biology, medicine.disease, Genetics (clinical)
Abstract: journal homepage: http: / /www.elsevier .com/locate/ejmg 56 57 58 59 60 61 62 63 64 Corrigendum 65 66 67 68 69 70 71 72 73 74 75 76 77 Corrigendum to “Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5” [Eur J Med Genet 56 (8) (2013) 452e457] P. Kannu *, A.B. Campos-Xavier , D. Hull , D. Martinet , D. Ballhausen , L. Bonafe b
Published: 2014
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25. Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres

Author: Claudio Pollo, Kristof van Dommelen, Marc Levivier, Robert-Charles Janzer, Roger Stupp, Annie-Claire Diserens, Danielle Martinet, Davide Sciuscio, Marie-France Hamou, Monika E. Hegi, Greg Jones, and Bernd Kaina
Subjects: Adult, Male, Cancer Research, Methyltransferase, DNA repair, Biology, DNA methyltransferase, Gene dosage, O(6)-Methylguanine-DNA Methyltransferase, Gene Frequency, Tumor Cells, Cultured, Humans, Promoter Regions, Genetic, neoplasms, Aged, Aged, 80 and over, Brain Neoplasms, O-6-methylguanine-DNA methyltransferase, Methylation, DNA Methylation, Middle Aged, Molecular biology, digestive system diseases, Chromatin, Oncology, CpG site, DNA methylation, Female, Glioblastoma
Abstract: Purpose: Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Experimental Design: Ten paired samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity. Results: In glioblastoma, MGMT-methylated alleles ranged from 10% to 90%. In contrast, methylated alleles were highly enriched (100% of clones) in respective GS, even when 2 MGMT alleles were present, with 1 exception ( Conclusions: In MGMT-methylated glioblastoma, MGMT promoter methylation is highly enriched in GS that supposedly comprise glioma-initiating cells. Thus, even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy. Clin Cancer Res; 17(2); 255–66. ©2010 AACR.
Published: 2010

26. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author: Peter Vollenweider, Leena Peltonen, Audrey Labalme, Jessica L. Buxton, Alessandra Ferrarini, Dawn M. Waterworth, Sven Bergmann, Gérard Waeber, Marie Pigeyre, Sébastien Jacquemont, Vincent Mooser, Audrey Guilmatre, C. Lecoeur, Muriel Holder-Espinasse, Bettina Blaumeiser, Elena G. Bochukova, Ni Huang, Andrew Walley, Danielle Martinet, Peter Jacobson, B. Leheup, Marie-Pierre Lemaitre, A. Brioschi, Julia M. Keogh, Damien Sanlaville, Stephen O'Rahilly, Robert Sladek, Bruno Delobel, Fanny Stutzmann, Sophie Dupuis-Girod, Philippe Froguel, Muriel Gaillard, Anne Philippe, Katrin Männik, Jean-Marie Cuisset, M. Béri-Dexheimer, Lachlan J. M. Coin, Fei Chen, François Pattou, Katrin Õunap, Mari Nelis, A.-L. Hartikainen, Jean-Claude Chèvre, Philippe Jonveaux, Alice Goldenberg, Kay D. MacDermot, Elana Henning, Odile Boute, Sonia Bouquillon, Armand Valsesia, Valérie Malan, Stéphane Lobbens, R. F. Kooy, Alexandra I. F. Blakemore, Marie-Pierre Cordier, Lena M. S. Carlsson, Marjo-Riitta Järvelin, Lars Sjöström, Paul Elliott, C Le Caignec, Florence Fellmann, Nadège Calmels, Dominique Campion, M. M. van Haelst, Vincent Vatin, B. Balkau, Jacques S. Beckmann, Mark I. McCarthy, Robert Caiazzo, Jean-Louis Mandel, Joris Andrieux, Nouchine Hadjikhani, Catherine Vincent-Delorme, David Meyre, Ants Kurg, J. S. El-Sayed Moustafa, Johanna C. Andersson, Jean Chiesa, Michèle Mathieu-Dramard, R. Touraine, Tõnu Esko, Albert David, Alexandre Reymond, Priit Palta, Ghislaine Plessis, Andres Metspalu, Robin G. Walters, Vittorio Giusti, Richard J. Ellis, Bertrand Isidor, Anne-Emmanuelle Ambresin, A J de Smith, I. S. Farooqi, Matthew E. Hurles, Mario Falchi, Medical Research Council (MRC), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), and Other departments
Subjects: Male, Aging, SAMPLE, Inheritance Patterns, Genome-wide association study, Penetrance, MC4R, Body Mass Index, Cohort Studies, 0302 clinical medicine, SH2B1, Missing heritability problem, Age of Onset, Child, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, Sex Characteristics, Multidisciplinary, Mental-Retardation, Adolescent Adult Age of Onset Aging Body Mass Index Case-Control Studies Child *Chromosome Deletion Chromosomes, Human, Pair 16/*genetics Cognition Disorders/complications/genetics Cohort Studies Europe Female Genome-Wide Association Study Heterozygote Humans Inheritance Patterns/genetics Male Mutation/genetics Obesity/complications/*genetics/*physiopathology *Penetrance Reproducibility of Results Sex Characteristics Young Adult, 3. Good health, Multidisciplinary Sciences, Europe, Adolescent, Adult, Case-Control Studies, Chromosome Deletion, Chromosomes, Human, Pair 16/genetics, Cognition Disorders/complications, Cognition Disorders/genetics, Female, Genome-Wide Association Study, Heterozygote, Humans, Inheritance Patterns/genetics, Mutation/genetics, Obesity/complications, Obesity/genetics, Obesity/physiopathology, Reproducibility of Results, Young Adult, Medical genetics, Science & Technology - Other Topics, CHILDHOOD OBESITY, medicine.medical_specialty, Childhood Obesity, BIRTH, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, Article, Childhood obesity, 03 medical and health sciences, medicine, MICRODELETION, Obesity, GENOME-WIDE ASSOCIATION, AUTISM, education, 030304 developmental biology, COPY NUMBER VARIATION, Science & Technology, MULTIDISCIPLINARY SCIENCES, FRAMESHIFT MUTATION, Individuals, medicine.disease, RISK LOCI, INDIVIDUALS, CIRCULAR BINARY SEGMENTATION, Mutation, Human medicine, Cognition Disorders, MENTAL-RETARDATION, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 16
Abstract: Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
Published: 2010
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27. Transcription Factor CTF1 Acts as a Chromatin Domain Boundary That Shields Human Telomeric Genes from Silencing▿ †

Author: Nathalie Besuchet-Schmutz, Danielle Martinet, Nicolas Mermod, Stefano Majocchi, Jacques S. Beckmann, and Germain Esnault
Subjects: Genetics, Recombinant Fusion Proteins, Cell Biology, Articles, Biology, DNA Methylation, Telomere, Chromatin remodeling, Chromatin, Histones, NFI Transcription Factors, Epigenetics of physical exercise, Histone H1, Genes, Reporter, Histone methyltransferase, Histone H2A, Histone methylation, Histone code, Humans, Gene Silencing, Transgenes, Molecular Biology, Chromatin immunoprecipitation, In Situ Hybridization, Fluorescence, HeLa Cells
Abstract: Telomeres are associated with chromatin-mediated silencing of genes in their vicinity. However, how epigenetic markers mediate mammalian telomeric silencing and whether specific proteins may counteract this effect are not known. We evaluated the ability of CTF1, a DNA- and histone-binding transcription factor, to prevent transgene silencing at human telomeres. CTF1 was found to protect a gene from silencing when its DNA-binding sites were interposed between the gene and the telomeric extremity, while it did not affect a gene adjacent to the telomere. Protein fusions containing the CTF1 histone-binding domain displayed similar activities, while mutants impaired in their ability to interact with the histone did not. Chromatin immunoprecipitation indicated the propagation of a hypoacetylated histone structure to various extents depending on the telomere. The CTF1 fusion protein was found to recruit the H2A.Z histone variant at the telomeric locus and to restore high histone acetylation levels to the insulated telomeric transgene. Histone lysine trimethylations were also increased on the insulated transgene, indicating that these modifications may mediate expression rather than silencing at human telomeres. Overall, these results indicate that transcription factors can act to delimit chromatin domain boundaries at mammalian telomeres, thereby blocking the propagation of a silent chromatin structure.
Published: 2009

28. IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation

Author: Michel Gilliet, Pierre-Yves Bochud, Jacques S. Beckmann, Natalia Ramirez, Federica Angelini, Marco Belfiore, Daniel Hohl, Onur Boyman, Annette von Scheven-Gete, Yannick Perrin, Matthieu Perreau, Danielle Martinet, Gregoire Simon, Jacqueline Wassenberg, Florence Fellmann, Stéphanie Christen-Zaech, Olivier Demaria, Michael Hofer, Pierre-Alexandre Bart, and Maya Beck Popovic
Subjects: Vasculitis, 0301 basic medicine, Adenosine Deaminase 2 Deficiency, Adolescent, Adenosine Deaminase, Immunology, Mucocutaneous zone, Biology, Systemic inflammation, Proinflammatory cytokine, 03 medical and health sciences, Fatal Outcome, 0302 clinical medicine, medicine, Humans, Immunology and Allergy, Chronic mucocutaneous candidiasis, Child, Immunodeficiency, Sequence Deletion, Inflammation, 030203 arthritis & rheumatology, Comparative Genomic Hybridization, Receptors, Interleukin-17, Siblings, Candidiasis, Chronic Mucocutaneous, medicine.disease, 3. Good health, Adenosine deaminase deficiency, 030104 developmental biology, Child, Preschool, Chronic Disease, Intercellular Signaling Peptides and Proteins, Female, medicine.symptom
Abstract: Background Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. Objective We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. Methods We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 ( CECR1 ). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. Results As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1β and TNF-α, which is consistent with the persistent systemic inflammation. Conclusions This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation.
Published: 2016

29. Fast generation of high producer cho cell lines by an iterative transfection process

Author: Danielle Martinet, Pierre-Alain Girod, Mélanie Grandjean, Jacques S. Beckmann, David Calabrese, and Nicolas Mermod
Subjects: business.industry, Scientific method, Chinese hamster ovary cell, lcsh:QR1-502, Bioengineering, Transfection, Biology, business, Applied Microbiology and Biotechnology, lcsh:Microbiology, Biotechnology, Cell biology
Published: 2006

30. High-level transgene expression by homologous recombination-mediated gene transfer

Author: Pierre-Alain Girod, David Calabrese, Danielle Martinet, Jacques S. Beckmann, Kaja Kostyrko, M. Wicht, Mélanie Grandjean, Nicolas Mermod, Christian Mazza, and Florence Yerly
Subjects: Transgene, Genetic Vectors, Active Transport, Cell Nucleus, Gene Dosage, Gene Expression, Biology, Transfection, Gene dosage, Cell Line, Sequence Homology, Nucleic Acid, Gene expression, Genetics, Animals, Gene silencing, Transgenes, Scaffold/matrix attachment region, Gene, Cell Nucleus, Recombination, Genetic, Cell Cycle, DNA, Matrix Attachment Regions, Regulatory sequence, Methods Online, Homologous recombination, Plasmids
Abstract: Gene transfer and expression in eukaryotes is often limited by a number of stably maintained gene copies and by epigenetic silencing effects. Silencing may be limited by the use of epigenetic regulatory sequences such as matrix attachment regions (MAR). Here, we show that successive transfections of MAR-containing vectors allow a synergistic increase of transgene expression. This finding is partly explained by an increased entry into the cell nuclei and genomic integration of the DNA, an effect that requires both the MAR element and iterative transfections. Fluorescence in situ hybridization analysis often showed single integration events, indicating that DNAs introduced in successive transfections could recombine. High expression was also linked to the cell division cycle, so that nuclear transport of the DNA occurs when homologous recombination is most active. Use of cells deficient in either non-homologous end-joining or homologous recombination suggested that efficient integration and expression may require homologous recombination-based genomic integration of MAR-containing plasmids and the lack of epigenetic silencing events associated with tandem gene copies. We conclude that MAR elements may promote homologous recombination, and that cells and vectors can be engineered to take advantage of this property to mediate highly efficient gene transfer and expression.
Published: 2011
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31. Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma

Author: Paola Benaglio, Mark Ibberson, Manfredo Quadroni, Armand Valsesia, Danielle Martinet, Jacques S. Beckmann, Carlo Rivolta, Donata Rimoldi, Brian Stevenson, Andrew J. G. Simpson, Christian Iseli, Muriel Gaillard, Ioannis Xenarios, Mireille Pidoux, C. Victor Jongeneel, Patrice Waridel, Blandine Rapin, and Stylianos E. Antonarakis
Subjects: Candidate gene, Gene regulatory network, lcsh:Medicine, Genetic Networks, SCNA, medicine.disease_cause, Metastasis, 0302 clinical medicine, Gene duplication, Basic Cancer Research, Databases, Genetic, ddc:576.5, Gene Regulatory Networks, Neoplasm Metastasis, lcsh:Science, Melanoma, In Situ Hybridization, Fluorescence, Genetics, 0303 health sciences, Comparative Genomic Hybridization, Multidisciplinary, Wnt signaling pathway, Proto-Oncogene Proteins c-mdm2, Genomics, Polymorphism, Single Nucleotide/genetics, Genes, Neoplasm/genetics, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Medicine, Research Article, Signal Transduction, DNA Copy Number Variations, RNA, Messenger/genetics/metabolism, Computational biology, DNA Copy Number Variations/genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genome Analysis Tools, Cell Line, Tumor, medicine, Cancer Genetics, Humans, Proto-Oncogene Proteins c-mdm2/genetics, RNA, Messenger, Gene Networks, Gene, 030304 developmental biology, lcsh:R, Computational Biology, Karyotyping, Signal Transduction/genetics, Melanoma/genetics/pathology, lcsh:Q, Carcinogenesis, Genome Expression Analysis, Gene Regulatory Networks/genetics, Comparative genomic hybridization, Genes, Neoplasm
Abstract: Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression ('SCNA-genes') in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two large, independent melanoma SCNA datasets showed less than 10% overlap at the individual gene level, but network-guided analysis revealed 66% shared pathways, including all but three of the pathways identified in our data. Frequently altered pathways included WNT, cadherin signalling, angiogenesis and melanogenesis. Additionally, our results emphasize the potential of the EPHA3 and FRS2 gene products, involved in angiogenesis and migration, as possible therapeutic targets in melanoma. Our study demonstrates the utility of network-guided approaches, for both large and small datasets, to identify pathways recurrently perturbed in cancer.
Published: 2011
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32. Abstract 4927: MGMT promoter methylation is enriched in glioblastoma derived spheres as compared to respective original tumor tissue and is associated with loss of expression

Author: Marc Levivier, Monika E. Hegi, Annie-Claire Diserens, Danielle Martinet, Robert-Charles Janzer, Roger Stupp, Claudio Pollo, Marie-France Hamou, Ilse Vlassenbroeck, and Davide Sciuscio
Subjects: Cancer Research, Predictive marker, Bisulfite sequencing, Clone (cell biology), Cancer, Methylation, Biology, medicine.disease, Molecular biology, digestive system diseases, Oncology, DNA methylation, medicine, Stem cell, Allele, neoplasms
Abstract: Epigenetic silencing of the O6-methylaguanine DNA methyl transferase (MGMT) gene by promoter hypermethylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Quantitative methylation specific PCR (Q-MSP) suggests that not all cells in a glioblastoma exhibiting MGMT methylation carry a methylated MGMT allele, even after adjustment for tumor cell content. This raises the question of the clinically relevant methylation threshold for predicting response to therapy for treatment stratification. There are several potential reasons: heterogeneity of glioblastoma; contaminating normal tissue; a heterogenous methylation pattern not correctly detectable by the assay, or presence of MGMT methylation in distinct subpopulations of cells, namely tumor initiating cells. In order to address the question we investigated the degree and pattern of MGMT promoter methylation in 10 paired samples of glioblastoma and spheres derived thereof using Q-MSP and methylation specific clone sequencing. We observed that in MGMT methylated glioblastoma, the percentage of methylated alleles ranged from 10 to 90%. In contrast, in most of the respective glioblastoma derived spheres, cultured under stem cell conditions, methylated alleles were highly enriched (10/10 clones), even if both MGMT-alleles were retained. The methylation pattern was conserved in the spheres, even when passing them in nude mice. Most importantly, this hypermethylation was associated with complete loss of MGMT expression. For one case we observed only 50% methylated clones in the sphere fraction, associated with low expression of MGMT. Taken together, our data suggest that in MGMT methylated glioblastoma, cells with MGMT promoter hypermethylation are enriched in the sphere fraction which supposedly comprises cancer initiating cells. Thus, even a low percentage of MGMT methylation in a glioblastoma could be predictive marker for a benefit from alkylating agent therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4927.
Published: 2010
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32 results on '"Danielle Martinet"'

1. A single epidermal stem cell strategy for safe ex vivo gene therapy

2. Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

3. Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma.

4. Data from Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres

5. Supplementary Data from Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres

6. Xq28 duplication includingMECP2in six unreported affected females: what can we learn for diagnosis and genetic counselling?

7. SCRIB and PUF60 Are Primary Drivers of the Multisystemic Phenotypes of the 8q24.3 Copy-Number Variant

8. Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5

9. Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial

10. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

11. The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

12. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome

13. A new CRB1 rat mutation links Müller glial cells to retinal telangiectasia

14. A single epidermal stem cell strategy for safe ex vivo gene therapy

15. A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology

16. Chromosomal microarray among children with intellectual disability: a useful diagnostic tool for the clinical geneticist

17. Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity

18. Molecular characterization of 39 de novo sSMC: contribution to prognosis and genetic counselling, a prospective study

19. Subtelomeric Deletion of Chromosome 10p15.3: Clinical Findings and Molecular Cytogenetic Characterization

20. Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats

21. 16q24.1 microdeletion in a premature newborn: usefulness of array-based comparative genomic hybridation (array CGH) in persistent pulmonary hypertension of the newborn

22. The phenotype of recurrent 10q22q23 deletions and duplications

23. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

24. Corrigendum to 'Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5' [Eur J Med Genet 56 (8) (2013) 452–457]

25. Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres

26. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

27. Transcription Factor CTF1 Acts as a Chromatin Domain Boundary That Shields Human Telomeric Genes from Silencing▿ †

28. IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation

29. Fast generation of high producer cho cell lines by an iterative transfection process

30. High-level transgene expression by homologous recombination-mediated gene transfer

31. Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma

32. Abstract 4927: MGMT promoter methylation is enriched in glioblastoma derived spheres as compared to respective original tumor tissue and is associated with loss of expression

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32 results on '"Danielle Martinet"'

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