DOCSLIB.ORG

Identification Des Bases Moléculaires Et Physiopathologiques Des Syndromes Oro-Facio-Digitaux Ange-Line Bruel

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification Des Bases Moléculaires Et Physiopathologiques Des Syndromes Oro-Facio-Digitaux Ange-Line Bruel Identification des bases moléculaires et physiopathologiques des syndromes oro-facio-digitaux Ange-Line Bruel To cite this version: Ange-Line Bruel. Identification des bases moléculaires et physiopathologiques des syndromes oro-facio- digitaux. Génétique. Université de Bourgogne, 2016. Français. NNT : 2016DIJOS043. tel-01635713 HAL Id: tel-01635713 https://tel.archives-ouvertes.fr/tel-01635713 Submitted on 15 Nov 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE DE BOURGOGNE UFR des Sciences de Santé THÈSE Pour obtenir le grade de Docteur de l’Université de Bourgogne Discipline : Sciences de la vie par Ange-Line Bruel 21 Septembre 2016 Identification des bases moléculaires et physiopathologiques des syndromes oro-facio-digitaux Directeur de thèse Pr Christel Thauvin-Robinet Co-directeur de thèse Dr Laurence Jego Dr Jean-Baptiste Rivière Jury Pr Faivre Laurence, Président Pr Thauvin-Robinet Christel, Directeur de thèse Dr Saunier Sophie, Rapporteur Pr Geneviève David, Rapporteur Pr Attié-Bittach Tania, Examinateur 1 A ma famille 2 Remerciements Je voudrais remercier en premier lieu Laurence Faivre, de m’avoir accueillie au sein du laboratoire Génétique des Anomalies du Développement, pour l’intérêt porté à mes travaux et pour son soutien. Toute ma reconnaissance va naturellement à Christel Thauvin-Robinet qui a encadrée cette thèse. Merci de m’avoir donnée cette chance de participer à ce beau projet, d’apprendre et d’évoluer au cours de ces trois dernières années. Merci pour ta confiance, ta disponibilité et tes encouragements. Je remercie également mes deux co-directeurs de thèse : Laurence Jego pour avoir veillée au bon déroulement de ces trois années, et Jean-Baptiste Rivière pour m’avoir fait découvrir le monde du SHD. Je souhaite remercier les rapporteurs de cette thèse, David Geneviève, Tania Attié-Bitach et Sophie Saunier pour avoir accepté de lire ce manuscrit durant l’été. Cette thèse est aussi le fruit de nombreuses collaborations nationales et internationales, je tiens donc à remercier tous les collaborateurs qui ont participé à ce travail, ainsi que les patients et leurs familles. Rien n’aurait été pareil sans la bonne entente qui règne dans l’équipe, je tiens donc à remercier toutes les personnes qui m’ont côtoyée quotidiennement: Julien Thevenon, pour m’avoir entrainée dans tous ces projets « hors thèse » et toute l’aide qui tu as pu m’apporter, Yannis Duffourd et Emilie Tisserant, pour votre indispensable savoir en bio-informatique, L’équipe des techniciens, Charlotte Poë, Judith St-Onge, Thibaut Jouan, Martin Chevarin et Nadège Gigot, pour tous les précieux coups de main dans les manips, Les post-docs, thésards, étudiants et voisins de bureau, Virginie Carmignac, Mirna Assoum, Romain Da Costa, Arthur Sorlin, Alexia Cossard, Aurélie Boucharny, Mathilde Lefebvre, Paul Kuentz, Sophie Nambot, Antonio Vitobello, pour votre bonne humeur communicative, ainsi que tous les stagiaires qui sont venus gonfler les rangs, le temps de quelques mois. 3 L’ensemble des cliniciens, internes et personnels administratifs pour leur travail, Je remercie également Patrick Callier et l’ensemble de l’équipe de biologie moléculaire et cytogénétique du PTB pour leur aide et leur sympathie. J’adresse aussi une pensée à mes anciens directeurs de stage, Sylvie Mazoyer et Khaled Bouhouch, qui m’ont fait découvrir le monde de la recherche et poussé à poursuivre dans cette voie. Ces trois années n’auraient pas eu la même saveur sans l’aventure Expérimentarium. Merci à Lionel Maillot, Coralie Biguzzi ainsi que les doctorants dijonnais pour les ateliers Expé, les apéros et les soirées restos que l’on a passé ensemble. Un grand merci également à ma famille : A mon petit frère, Benjamin, pour tous nos moments de complicité et de chamaillerie qui, je crois, ne cesseront jamais ! A mes parents, Marie-Claire et Patrick, pour avoir cru en moi, pour votre soutien indéfectible et votre disponibilité au cours de toutes ces années. C’est grâce à vous si j’ai pu en arriver là aujourd’hui, merci infiniment. A mes grands-parents, Aline et Christian, Annie et René, et mon arrière-grand-mère, Gisèle. A mes cousins, Renaud, Guillaume, Marline, Anna, Bérengère, Sylvain, Lucie, Elinah, Ayden, Raphael et Louane, pour tous les jeux, rires, … et chutes que l’on a partagé et qui ont marqués les annales familiales à jamais ; sans oublier les nouveaux membres Lucile et Virginie et la nouvelle génération Enoha et Gabriel qui font la joie de tous! A Chantal, Jean-Marc, Joël, Valérie, Jacques, Philippe, Dominique et Marie-Nöelle, ainsi qu'à toute la famille pour tous ces bons moments partagés. Mention spéciale à Chantal et Jean- Marc pour avoir suivi de très très près mon parcours. Je souhaite remercier tous mes amis d’Auvergne ou d’ailleurs, la promo M2GP 2013 et les thésards clermontois pour tous les weekends retrouvailles ainsi que les amis globe-trotteurs pour tous les séjours à l’autre bout du monde passés et à venir. Enfin je remercie tous ceux qui ont suivi de près ou de loin cette thèse. 4 Résumé Les syndromes oro-facio-digitaux (OFD) sont caractérisés par la présence d'une atteinte orale, faciale et digitale. Leur classification initiale en 13 sous-types, est basée principalement sur leur mode de transmission et leurs signes cliniques associés (malformations cérébrales, rénales, dysplasie osseuse, atteinte rétinienne). Pendant longtemps seul le gène OFD1, responsable du type I et codant pour une protéine centrosomale et du corps basal, était principalement connu, faisant suspecter l’implication du cil primaire dans les syndromes OFD. Des mutations ont été rapportées plus récemment dans les gènes TMEM216, DDX59, SCLT1, TBC1D32 et TCTN3 chez un ou deux patients. Dans le but d’identifier de nouveaux gènes impliqués dans ces syndromes, nous avons réalisé une stratégie de séquençage haut débit d’exome chez 24 patients. Cette stratégie a permis d’identifier 5 nouveaux gènes (C2CD3, TMEM107, INTU, KIAA0753, IFT57), d'étendre aux syndromes OFD le spectre clinique de 3 gènes déjà connus dans d'autres ciliopathies (C5orf42, TMEM138, TMEM231) et de confirmer l'implication de 3 gènes déjà connus comme responsable de syndrome OFD (OFD1, DDX59, WDPCP). Les analyses fonctionnelles ont montré l’implication de la croissance centriolaire, de la zone de transition et du transport intraflagellaire, avec notamment la caractérisation de 3 complexes protéiques principaux : le complexe ternaire KIAA0753/OFD1/FOPNL, régulant la croissance centriolaire, le complexe MKS (TMEM107, TMEM231, TMEM216) constituant majeur de la zone de transition et le complexe CPLANE (INTU/FUZ/WDPCP), favorisant l’assemblage des protéines périphériques du complexe de transport intraflagellaire IFT-A. En conclusion, cette étude, la plus importante consacrée aux syndromes OFD, démontre la très grande hétérogénéité clinique et génétique de ces syndromes, de même que de nombreux allélismes avec d’autres ciliopathies. Elle étend à 15 le nombre de gènes causaux, rendant la classification clinique initiale de 13 sous-types totalement obsolète et permettant de considérer les syndromes OFD comme un nouveau sous- groupe de ciliopathies à part entière. Mots-clés : Syndromes oro-facio-digitaux, séquençage haut-débit 5 Abstract Oral-facial-digital syndromes (OFDS) are characterized by the association of oral, facial and digital anomalies. The different modes of inheritance and additional features lead to clinically delineate 13 subtypes. For a long time, only the OFD1 gene, responsible for OFDI subtype and coding for a centrosomal protein, has been known, suggesting the involvement of the primary cilium in OFDS. Mutations have recently been reported in the TMEM216, DDX59, SCLT1, TBC1D32 and TCTN3 genes in anecdotic cases. To identify new genes involved in OFDS, we performed whole-exome sequencing in 24 patients. In 14/24 cases, we identified 5 novel genes (C2CD3, TMEM107, INTU, KIAA0753, IFT57), enlarged the clinical spectrum of OFDS of 3 known genes responsible for other ciliopathies (C5orf42, TMEM138, TMEM231) and confirmed the involvement of 3 known genes in OFDS (OFD1, DDX59, WDPCP). Functional studies demonstrated the involvement of the centriolar growth, the transition zone and the intraflagellar transport, through the characterization of 3 major protein complexes: the KIAA0753/OFD1/FOPNL complex controlling the centriole elongation, the MKS module (TMEM107/TMEM231/TMEM216), an essential component of the transition zone, and the CPLANE complex (INTU/FUZ/WDPCP) enabling in the IFT-A assembly. We demonstrated the large clinical and genetic heterogeneity of OFDS, yielding the initial classification in 13 subtypes obsolete, extending the number of 15 causal genes, and confirming OFDS as a new full subgroup of ciliopathies. Keywords: Oral-facial-digital syndromes, whole-exome sequencing 6 Table des matières INTRODUCTION .................................................................................................................... 16 1- Généralités ......................................................................................................................
Load more

Recommended publications
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • Supplemental Information
    Supplemental information Dissection of the genomic structure of the miR-183/96/182 gene. Previously, we showed that the miR-183/96/182 cluster is an intergenic miRNA cluster, located in a ~60-kb interval between the genes encoding nuclear respiratory factor-1 (Nrf1) and ubiquitin-conjugating enzyme E2H (Ube2h) on mouse chr6qA3.3 (1). To start to uncover the genomic structure of the miR- 183/96/182 gene, we first studied genomic features around miR-183/96/182 in the UCSC genome browser (http://genome.UCSC.edu/), and identified two CpG islands 3.4-6.5 kb 5’ of pre-miR-183, the most 5’ miRNA of the cluster (Fig. 1A; Fig. S1 and Seq. S1). A cDNA clone, AK044220, located at 3.2-4.6 kb 5’ to pre-miR-183, encompasses the second CpG island (Fig. 1A; Fig. S1). We hypothesized that this cDNA clone was derived from 5’ exon(s) of the primary transcript of the miR-183/96/182 gene, as CpG islands are often associated with promoters (2). Supporting this hypothesis, multiple expressed sequences detected by gene-trap clones, including clone D016D06 (3, 4), were co-localized with the cDNA clone AK044220 (Fig. 1A; Fig. S1). Clone D016D06, deposited by the German GeneTrap Consortium (GGTC) (http://tikus.gsf.de) (3, 4), was derived from insertion of a retroviral construct, rFlpROSAβgeo in 129S2 ES cells (Fig. 1A and C). The rFlpROSAβgeo construct carries a promoterless reporter gene, the β−geo cassette - an in-frame fusion of the β-galactosidase and neomycin resistance (Neor) gene (5), with a splicing acceptor (SA) immediately upstream, and a polyA signal downstream of the β−geo cassette (Fig.
    [Show full text]
  • Isolation and Characterization of a Novel Gene CLUAP1 Whose Expression Is Frequently Upregulated in Colon Cancer
    Oncogene (2004) 23, 9289–9294 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc SHORT REPORT Isolation and characterization of a novel gene CLUAP1 whose expression is frequently upregulated in colon cancer Meiko Takahashi1, Yu-Min Lin2, Yusuke Nakamura1 and Yoichi Furukawa*,1 1Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai Minato-ku, Tokyo 108-8639, Japan; 2Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Taipei 11160, Taiwan To disclose mechanisms of colorectal carcinogenesis and appear to be upregulated frequently in the cancer tissues identify novel diagnostic markers and drug targets for compared with the corresponding noncancerous cells. treatment of these tumors, we previously analysed the Since carcinogenesis involves activation of oncogenes expression profiles of 11 colorectal cancers using a and/or inactivation of tumor suppressor genes, en- genome-wide cDNA microarray containing 23 040 genes. hanced expression of at least some of these upregulated Among the genes commonly transactivated in the cancers, genes may reflect oncogenic properties. we identified a novel human gene, which we termed Among the genes with frequently elevated expression CLUAP1 (clusterin-associated protein 1). It encodes a in cancer tissues in our microarray data, an EST with an nuclear protein of 413 amino acids containing a coiled-coil in-house accession number of B9223 corresponding to domain. To investigate its function, we searched for KIAA0643, Hs. 155995 in UniGene cluster (http:// CLUAP1-interacting proteins using yeast two-hybrid www.ncbi.nlm.nih.gov/UniGene/), was upregulated in system and identified nuclear Clusterin.
    [Show full text]
  • The Ciliopathy-Associated CPLANE Proteins Direct Basal Body Recruitment of Intraflagellar Transport Machinery
    The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Toriyama, M., C. Lee, S. P. Taylor, I. Duran, D. H. Cohn, A. Bruel, J. M. Tabler, et al. 2016. “The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.” Nature genetics 48 (6): 648-656. doi:10.1038/ng.3558. http:// dx.doi.org/10.1038/ng.3558. Published Version doi:10.1038/ng.3558 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626113 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Genet Manuscript Author . Author manuscript; Manuscript Author available in PMC 2016 November 09. Published in final edited form as: Nat Genet. 2016 June ; 48(6): 648–656. doi:10.1038/ng.3558. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery Michinori Toriyama1, Chanjae Lee1, S. Paige Taylor2, Ivan Duran2, Daniel H. Cohn3, Ange- Line Bruel4, Jacqueline M. Tabler1, Kevin Drew1, Marcus R. Kelley5, Sukyoung Kim1, Tae Joo Park1,**, Daniella Braun6, Ghislaine Pierquin7, Armand Biver8, Kerstin Wagner9, Anne Malfroot10, Inusha Panigrahi11, Brunella Franco12,13, Hadeel Adel Al-lami14, Yvonne Yeung14, Yeon Ja Choi15, University of Washington Center for Mendelian Genomics16, Yannis Duffourd4, Laurence Faivre4,17, Jean-Baptiste Rivière4,18, Jiang Chen15, Karen J.
    [Show full text]
  • Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies Timothy M
    Published OnlineFirst May 26, 2016; DOI: 10.1158/0008-5472.CAN-16-0058 Cancer Therapeutics, Targets, and Chemical Biology Research Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies Timothy M. Shaver1,2, Brian D. Lehmann1,2, J. Scott Beeler1,2, Chung-I Li3, Zhu Li1,2, Hailing Jin1,2, Thomas P. Stricker4, Yu Shyr5,6, and Jennifer A. Pietenpol1,2 Abstract Triple-negative breast cancer (TNBC) and other molecularly discovered a clinical occurrence and cell line model of the target- heterogeneous malignancies present a significant clinical chal- able FGFR3–TACC3 fusion in TNBC. Expanding our analysis to lenge due to a lack of high-frequency "driver" alterations amena- other malignancies, we identified a diverse array of novel and ble to therapeutic intervention. These cancers often exhibit geno- known hybrid transcripts, including rearrangements between mic instability, resulting in chromosomal rearrangements that noncoding regions and clinically relevant genes such as ALK, affect the structure and expression of protein-coding genes. How- CSF1R, and CD274/PD-L1. The over 1,000 genetic alterations ever, identification of these rearrangements remains technically we identified highlight the importance of considering noncod- challenging. Using a newly developed approach that quantita- ing gene rearrangement partners, and the targetable gene tively predicts gene rearrangements in tumor-derived genetic fusions identified in TNBC demonstrate the need to advance material, we identified
    [Show full text]
  • Rabbit Anti-CLUAP1/FITC Conjugated Antibody-SL6805R-FITC
    SunLong Biotech Co.,LTD Tel: 0086-571- 56623320 Fax:0086-571- 56623318 E-mail:[email protected] www.sunlongbiotech.com Rabbit Anti-CLUAP1/FITC Conjugated antibody SL6805R-FITC Product Name: Anti-CLUAP1/FITC Chinese Name: FITC标记的成簇相关蛋白1抗体 Alias: Clusterin associated protein 1; FLJ13297; KIAA0643; CLUA1_HUMAN. Organism Species: Rabbit Clonality: Polyclonal React Species: Human,Mouse,Rat,Chicken,Dog,Pig,Horse,Rabbit,Sheep, IF=1:50-200 Applications: not yet tested in other applications. optimal dilutions/concentrations should be determined by the end user. Molecular weight: 48kDa Form: Lyophilized or Liquid Concentration: 1mg/ml immunogen: KLH conjugated synthetic peptide derived from human CLUAP1 Lsotype: IgG Purification: affinity purified by Protein A Storage Buffer: 0.01M TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Store at -20 °C for one year. Avoid repeated freeze/thaw cycles. The lyophilized antibodywww.sunlongbiotech.com is stable at room temperature for at least one month and for greater than a year Storage: when kept at -20°C. When reconstituted in sterile pH 7.4 0.01M PBS or diluent of antibody the antibody is stable for at least two weeks at 2-4 °C. background: CLUAP1 (Clusterin associated protein 1) is a 413 amino acid nuclear protein that exists as two alternatively spliced isoforms that interact with Clusterin. CLUAP1 is suggested to play a role in apoptosis and cell proliferation, and is expressed in testis, thrachea and thyroid, with low levels found in adrenal gland and spinal cord. The gene encoding Product Detail: CLUAP1 maps to human chromosome 16, which encodes over 900 genes and comprises nearly 3% of the human genome.
    [Show full text]
  • A High Throughput, Functional Screen of Human Body Mass Index GWAS Loci Using Tissue-Specific Rnai Drosophila Melanogaster Crosses Thomas J
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2018 A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J. Baranski Washington University School of Medicine in St. Louis Aldi T. Kraja Washington University School of Medicine in St. Louis Jill L. Fink Washington University School of Medicine in St. Louis Mary Feitosa Washington University School of Medicine in St. Louis Petra A. Lenzini Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Baranski, Thomas J.; Kraja, Aldi T.; Fink, Jill L.; Feitosa, Mary; Lenzini, Petra A.; Borecki, Ingrid B.; Liu, Ching-Ti; Cupples, L. Adrienne; North, Kari E.; and Province, Michael A., ,"A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses." PLoS Genetics.14,4. e1007222. (2018). https://digitalcommons.wustl.edu/open_access_pubs/6820 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Thomas J. Baranski, Aldi T. Kraja, Jill L. Fink, Mary Feitosa, Petra A. Lenzini, Ingrid B. Borecki, Ching-Ti Liu, L. Adrienne Cupples, Kari E. North, and Michael A. Province This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/6820 RESEARCH ARTICLE A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J.
    [Show full text]
  • 2014-Platform-Abstracts.Pdf
    American Society of Human Genetics 64th Annual Meeting October 18–22, 2014 San Diego, CA PLATFORM ABSTRACTS Abstract Abstract Numbers Numbers Saturday 41 Statistical Methods for Population 5:30pm–6:50pm: Session 2: Plenary Abstracts Based Studies Room 20A #198–#205 Featured Presentation I (4 abstracts) Hall B1 #1–#4 42 Genome Variation and its Impact on Autism and Brain Development Room 20BC #206–#213 Sunday 43 ELSI Issues in Genetics Room 20D #214–#221 1:30pm–3:30pm: Concurrent Platform Session A (12–21): 44 Prenatal, Perinatal, and Reproductive 12 Patterns and Determinants of Genetic Genetics Room 28 #222–#229 Variation: Recombination, Mutation, 45 Advances in Defining the Molecular and Selection Hall B1 Mechanisms of Mendelian Disorders Room 29 #230–#237 #5-#12 13 Genomic Studies of Autism Room 6AB #13–#20 46 Epigenomics of Normal Populations 14 Statistical Methods for Pedigree- and Disease States Room 30 #238–#245 Based Studies Room 6CF #21–#28 15 Prostate Cancer: Expression Tuesday Informing Risk Room 6DE #29–#36 8:00pm–8:25am: 16 Variant Calling: What Makes the 47 Plenary Abstracts Featured Difference? Room 20A #37–#44 Presentation III Hall BI #246 17 New Genes, Incidental Findings and 10:30am–12:30pm:Concurrent Platform Session D (49 – 58): Unexpected Observations Revealed 49 Detailing the Parts List Using by Exome Sequencing Room 20BC #45–#52 Genomic Studies Hall B1 #247–#254 18 Type 2 Diabetes Genetics Room 20D #53–#60 50 Statistical Methods for Multigene, 19 Genomic Methods in Clinical Practice Room 28 #61–#68 Gene Interaction
    [Show full text]
  • Genomic Approach in Idiopathic Intellectual Disability Maria De Fátima E Costa Torres
    ESTUDOS DE 8 01 PDPGM 2 CICLO Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres D Autor. Maria de Fátima e Costa Torres D.ICBAS 2018 Genomic approach in idiopathic intellectual disability Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres SEDE ADMINISTRATIVA INSTITUTO DE CIÊNCIAS BIOMÉDICAS ABEL SALAZAR FACULDADE DE MEDICINA MARIA DE FÁTIMA E COSTA TORRES GENOMIC APPROACH IN IDIOPATHIC INTELLECTUAL DISABILITY Tese de Candidatura ao grau de Doutor em Patologia e Genética Molecular, submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Orientadora – Doutora Patrícia Espinheira de Sá Maciel Categoria – Professora Associada Afiliação – Escola de Medicina e Ciências da Saúde da Universidade do Minho Coorientadora – Doutora Maria da Purificação Valenzuela Sampaio Tavares Categoria – Professora Catedrática Afiliação – Faculdade de Medicina Dentária da Universidade do Porto Coorientadora – Doutora Filipa Abreu Gomes de Carvalho Categoria – Professora Auxiliar com Agregação Afiliação – Faculdade de Medicina da Universidade do Porto DECLARAÇÃO Dissertação/Tese Identificação do autor Nome completo _Maria de Fátima e Costa Torres_ N.º de identificação civil _07718822 N.º de estudante __ 198600524___ Email institucional [email protected] OU: [email protected] _ Email alternativo [email protected] _ Tlf/Tlm _918197020_ Ciclo de estudos (Mestrado/Doutoramento) _Patologia e Genética Molecular__ Faculdade/Instituto _Instituto de Ciências
    [Show full text]
  • Abstracts Selected for Platform Presentation
    Abstracts Selected for Platform Presentation Using semantic similarity analysis based on Human Phenotype Ontology terms to identify genetic etiologies for epilepsy and neurodevelopmental disorders Ingo Helbig1,2,3, Shiva Ganesan1,2, Peter Galer1,2, Colin A. Ellis3, Katherine L. Helbig1,2 1 Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USA 2 Department of Biomedical and Health Informatics (DBHi), Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USA 3 Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104 USA More than 25% of children with intractable epilepsies have an identifiable genetic cause, and the goal of epilepsy precision medicine is to stratify patients based on genetic findings to improve diagnosis and treatment. Large-scale genetic studies in > 15,000 epilepsy patients have provided deep insights into causative genetic changes. However, the understanding of how these changes link to specific clinical features is lagging behind. This deficit is largely due to the lack of frameworks to analyze large-scale phenotypic data, which dramatically impedes the ability to translate genetic findings into improved treatment. The Human Phenotype Ontology (HPO) has been developed as a curated terminology, with formal semantic relationships between more than 13,500 phenotypic terms, and has been adopted by many diagnostic laboratories, the UK’s 100,000 Genomes Project, the NIH Undiagnosed Diseases Network, the GA4GH, and hundreds of global initiatives. The HPO also contains a rich vocabulary for epilepsy-related phenotypes, which we have developed in prior large research networks and expanded in current projects. However, analytical approaches leveraging this rich data resource have not been implemented so far.
    [Show full text]
  • Genetic Variants Are Identified to Increase Risk of COVID-19 Related Mortality From
    medRxiv preprint doi: https://doi.org/10.1101/2020.11.05.20226761; this version posted November 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 Genetic variants are identified to increase risk of COVID-19 related mortality from 2 UK Biobank data 3 Jianchang Hu1, Cai Li1, Shiying Wang, Ting Li, Heping Zhang* 4 Department of Biostatistics, Yale University 5 1Co-first Author 6 *Correspondence Author 7 Email: [email protected] 8 300 George Street, Ste 523, New Haven, CT, 06511 9 10 11 12 13 14 15 16 17 18 19 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.11.05.20226761; this version posted November 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 20 Abstract 21 Background 22 The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute 23 respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogenous. Studies have 24 reported that males and some ethnic groups are at increased risk of death from COVID- 25 19, which implies that individual risk of death might be influenced by host genetic 26 factors.
    [Show full text]
  • Diagnóstico Molecular Do Transtorno Do Espectro Autista Através Do Sequenciamento Completo De Exoma Molecular Diagnosis Of
    Universidade de São Paulo Tatiana Ferreira de Almeida Diagnóstico molecular do transtorno do espectro autista através do sequenciamento completo de exoma Molecular diagnosis of autism spectrum disorder through whole exome sequencing São Paulo 2018 Universidade de São Paulo Tatiana Ferreira de Almeida Diagnóstico molecular do transtorno do espectro autista através do sequenciamento completo de exoma Molecular diagnosis of autism spectrum disorder through whole exome sequencing Tese apresentada ao Instituto de Biociências da Universidade de São Paulo, para a obtenção de Título de Doutor em Ciências, na Área de Biologia/Genética. Versão corrigida. Orientador(a): Maria Rita dos Santos Passos-Bueno São Paulo ii 2018 Dedico esta tese à ciência, e a todos os seus amantes. O, reason not the need! Our basest beggars Are in the poorest thing superfluous. Allow not nature more than nature needs, Man’s life is cheap as beast’s. Thou art a lady: If only to go warm were gorgeous, Why, nature needs not what thou gorgeous wear’st Which scarcely keeps thee warm. But, for true need- You heavens, give me that patience, patience I need! You see me here, you gods, a poor old man, As full of grief as age; wretched in both.” iii King Lear, William Shakespeare, 1608 Agradecimentos Agradeço em primeiro lugar ao meu grande amor Danilo, sem ele, há 11 anos, essa jornada não teria começado, a vida não teria me surpreendido e eu estaria de volta em casa, com todos os peixinhos do mar, e infeliz pelo resto da minha vida. Agradeço minha família, principalmente minha mãe Flávia e meu pai Airton por sacrificarem com mínimos protestos, as melhores horas que passaríamos juntos para que eu cumprisse meu trabalho.
    [Show full text]