Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Eva Gonçalves Serra, Tobias Schwerd, Loukas Moutsianas, Athena Cavounidis, Laura Fachal, Sumeet Pandey, Jochen Kammermeier, Nicholas M. Croft, Carsten Posovszky, Astor Rodrigues, Richard K. Russell, Farah Barakat, Marcus K. H. Auth, Robert Heuschkel, Matthias Zilbauer, Krzysztof Fyderek, Christian Braegger, Simon P. Travis, Jack Satsangi, Miles Parkes, Nikhil Thapar, Helen Ferry, Julie C. Matte, Kimberly C. Gilmour, Andrzej Wedrychowicz, Peter Sullivan, Carmel Moore, Jennifer Sambrook, Willem Ouwehand, David Roberts, John Danesh, Toni A. Baeumler, Tudor A. Fulga, Eli M. Carrami, Ahmed Ahmed, Rachel Wilson, Jeffrey C. Barrett, Abdul Elkadri, Anne M. Griffiths, Scott B. Snapper, Neil Shah, Aleixo M. Muise, David C. Wilson, Holm H. Uhlig () and Carl A. Anderson ()
Additional contact information
Eva Gonçalves Serra: Wellcome Genome Campus
Tobias Schwerd: University of Oxford
Loukas Moutsianas: Wellcome Genome Campus
Athena Cavounidis: University of Oxford
Laura Fachal: Wellcome Genome Campus
Sumeet Pandey: University of Oxford
Jochen Kammermeier: Great Ormond Street Hospital
Nicholas M. Croft: Queen Mary University of London
Carsten Posovszky: Universitätsklinikum
Astor Rodrigues: University of Oxford
Richard K. Russell: Royal Hospital for Children
Farah Barakat: Queen Mary University of London
Marcus K. H. Auth: Alder Hey Children’s Hospital
Robert Heuschkel: Addenbrooke’s Hospital
Matthias Zilbauer: Addenbrooke’s Hospital
Krzysztof Fyderek: Jagiellonian University Medical College
Christian Braegger: University Children’s Hospital Zurich
Simon P. Travis: University of Oxford
Jack Satsangi: University of Oxford
Miles Parkes: Addenbrooke’s Hospital
Nikhil Thapar: Great Ormond Street Hospital
Helen Ferry: University of Oxford
Julie C. Matte: Wellcome Genome Campus
Kimberly C. Gilmour: Great Ormond Street Hospital
Andrzej Wedrychowicz: Jagiellonian University Medical College
Peter Sullivan: University of Oxford
Carmel Moore: University of Cambridge
Jennifer Sambrook: University of Cambridge
Willem Ouwehand: Wellcome Genome Campus
David Roberts: University of Cambridge
John Danesh: Wellcome Genome Campus
Toni A. Baeumler: University of Oxford, John Radcliffe Hospital
Tudor A. Fulga: University of Oxford, John Radcliffe Hospital
Eli M. Carrami: University of Oxford, John Radcliffe Hospital
Ahmed Ahmed: University of Oxford, John Radcliffe Hospital
Rachel Wilson: University of Oxford
Jeffrey C. Barrett: Wellcome Genome Campus
Abdul Elkadri: University of Toronto
Anne M. Griffiths: University of Toronto
Scott B. Snapper: Boston Children’s Hospital
Neil Shah: Great Ormond Street Hospital
Aleixo M. Muise: University of Toronto
David C. Wilson: University of Edinburgh
Holm H. Uhlig: University of Oxford
Carl A. Anderson: Wellcome Genome Campus

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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

Date: 2020
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DOI: 10.1038/s41467-019-14275-y

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