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Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.
Serra, Eva Gonçalves; Schwerd, Tobias; Moutsianas, Loukas; Cavounidis, Athena; Fachal, Laura; Pandey, Sumeet; Kammermeier, Jochen; Croft, Nicholas M; Posovszky, Carsten; Rodrigues, Astor; Russell, Richard K; Barakat, Farah; Auth, Marcus K H; Heuschkel, Robert; Zilbauer, Matthias; Fyderek, Krzysztof; Braegger, Christian; Travis, Simon P; Satsangi, Jack; Parkes, Miles; Thapar, Nikhil; Ferry, Helen; Matte, Julie C; Gilmour, Kimberly C; Wedrychowicz, Andrzej; Sullivan, Peter; Moore, Carmel; Sambrook, Jennifer; Ouwehand, Willem; Roberts, David; Danesh, John; Baeumler, Toni A; Fulga, Tudor A; Carrami, Eli M; Ahmed, Ahmed; Wilson, Rachel; Barrett, Jeffrey C; Elkadri, Abdul; Griffiths, Anne M; Snapper, Scott B; Shah, Neil; Muise, Aleixo M; Wilson, David C; Uhlig, Holm H; Anderson, Carl A.
Afiliação
  • Serra EG; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Schwerd T; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Moutsianas L; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilians University, Munich, Germany.
  • Cavounidis A; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Fachal L; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Pandey S; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Kammermeier J; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Croft NM; Great Ormond Street Hospital, London, UK.
  • Posovszky C; Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
  • Rodrigues A; The Royal London Children's Hospital, Barts Health NHS Trust, London, UK.
  • Russell RK; Universitätsklinikum, Ulm, Germany.
  • Barakat F; Department of Paediatrics, University of Oxford, Oxford, UK.
  • Auth MKH; Royal Hospital for Children, Glasgow, UK.
  • Heuschkel R; Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
  • Zilbauer M; The Royal London Children's Hospital, Barts Health NHS Trust, London, UK.
  • Fyderek K; Alder Hey Children's Hospital, Liverpool, UK.
  • Braegger C; Addenbrooke's Hospital, Cambridge, UK.
  • Travis SP; Addenbrooke's Hospital, Cambridge, UK.
  • Satsangi J; Department of Paediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Krakow, Poland.
  • Parkes M; Division of Gastroenterology and Nutrition and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
  • Thapar N; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Ferry H; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Matte JC; Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland, UK.
  • Gilmour KC; IBD Research Unit, Department of Gastroenterology, Addenbrooke's Hospital, Cambridge, UK.
  • Wedrychowicz A; Great Ormond Street Hospital, London, UK.
  • Sullivan P; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Moore C; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Sambrook J; Great Ormond Street Hospital, London, UK.
  • Ouwehand W; Department of Paediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Krakow, Poland.
  • Roberts D; Department of Paediatrics, University of Oxford, Oxford, UK.
  • Danesh J; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Baeumler TA; INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Fulga TA; INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Carrami EM; Department of Haematology, University of Cambridge, Cambridge, UK.
  • Ahmed A; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Wilson R; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Barrett JC; INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Elkadri A; Department of Haematology, University of Cambridge, Cambridge, UK.
  • Griffiths AM; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Snapper SB; Weatherall Institute of Molecular Medicine and the Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • Shah N; Weatherall Institute of Molecular Medicine and the Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • Muise AM; National Institute of Health Research Oxford Biomedical Research Centre, Surgical Innovation and Evaluation and Molecular Diagnostics Themes, University of Oxford, Oxford, UK.
  • Wilson DC; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Uhlig HH; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Anderson CA; Department of Biochemistry and Pediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Nat Commun ; 11(1): 995, 2020 02 21.
Article em En | MEDLINE | ID: mdl-32081864
ABSTRACT
Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10-10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10-10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Inflamatórias Intestinais / Mosaicismo Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Adult / Child / Child, preschool / Female / Humans / Infant / Male / Newborn Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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XML
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Inflamatórias Intestinais / Mosaicismo Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Adult / Child / Child, preschool / Female / Humans / Infant / Male / Newborn Idioma: En Ano de publicação: 2020 Tipo de documento: Article