Journal Article

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

Zilbauer, Matthias, Wedrychowicz, Andrzej, Serra, Eva Gonçalves, Sullivan, Peter, Muise, Aleixo M., Pandey, Sumeet, Ouwehand, Willem, Fulga, Tudor A., Fachal, Laura, Croft, Nicholas M., Cavounidis, Athena, Auth, Marcus K. H., Carrami, Eli M., Moutsianas, Loukas, Ferry, Helen, Fyderek, Krzysztof, Braegger, Christian, Danesh, John, Anderson, Carl A., Travis, Simon P., Ahmed, Ahmed, Moore, Carmel, Griffiths, Anne M., Wilson, Rachel, Roberts, David, Barrett, Jeffrey C., Elkadri, Abdul, Kammermeier, Jochen, Gilmour, Kimberly C., Satsangi, Jack, Russell, Richard K., Matte, Julie C., Baeumler, Toni A., Barakat, Farah, Rodrigues, Astor, Snapper, Scott B., Uhlig, Holm H., Sambrook, Jennifer, Wilson, David C., Thapar, Nikhil, Posovszky, Carsten, Heuschkel, Robert, Parkes, Miles, Schwerd, Tobias, Shah, Neil

2020

Overview

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. Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 45 / 45/22 / 45/23 / 49 / 49/31 / 631/208/1516 / 631/208/248 / 631/250/249/2510/257 / 692/699/249/1570 / Adult / Age / Age of Onset / Case studies / Case-Control Studies / Child / Child, Preschool / Cohort Studies / Disorders / Exome Sequencing / Female / Gene sequencing / Genes, Recessive / Genetic diversity / Genetic Predisposition to Disease / Genetic Variation / Genomes / Genotyping / Humanities and Social Sciences / Humans / Immunodeficiency / Infant / Infant, Newborn / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - etiology / Inflammatory Bowel Diseases - genetics / Intestine / Loss of Function Mutation / Male / Mosaicism / Mosaics / multidisciplinary / Multifactorial Inheritance / Mutation / NADPH Oxidase 2 - genetics / Pathogenesis / Patients / Pedigree / Phagocytes / Phenotypes / Polygenic inheritance / Population control / Primary immunodeficiencies / Primary Immunodeficiency Diseases - complications / Primary Immunodeficiency Diseases - genetics / Risk Factors / Risk management / Science / Science (multidisciplinary) / SH2D1A protein / XIAP protein