Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
Authors: 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. ,   COLORS in IBD group investigators, Zurek Marlen , Strisciuglio Caterina , Elawad Mamoun , Lo Bernice ,   Oxford IBD cohort study investigators, Arancibia-Carcamo Carolina , Bailey Adam , Barnes Ellie , Bird-Lieberman Elizabeth Louise , Brain Oliver , Braden Barbara , Collier Jane , East James , Howarth Lucy , Keshav Satish , Klenerman Paul , Leedham Simon , Palmer Rebecca , Powrie Fiona , Simmons Alison ,   INTERVAL Study, Walker Matthew , Tolkien Zoe , Kaptoge Stephen , Allen David , Mehenny Susan , Mant Jonathan , Di Angelantonio Emanuele , Thompson Simon G. ,   Swiss IBD cohort investigators, Yilmaz Bahtiyar , Juillerat Pascal , Geuking Markus , Wiest Reiner , Macpherson Andrew J. , Bravo Francisco Damian , Brügger Lukas , Carstens Ove , Bigler Ulrike Graf , Heimgartner Benjamin , Rusticeanu Monica , Schmid Sybille , Strebel Bruno , Tatu Aurora , Tutuian Radu , Wiest Reiner , Øyås Ove , Ramon Charlotte , Stelling Jörg , Franc Yannick , Fournier Nicolas , Pittet Valerie E. H. , Burnand Bernard , Egger Mara , Franc Yannick , Golay Delphine , Marot Astrid , Musso Leilla , Pittet Valérie , Rossel Jean-Benoît , Seematter Vivianne , Sommer Joachim , Vulliamy Rachel , Michetti Pierre , Maillard Michel H. , Keller Céline , Maillard Michel H. , Nydegger Andreas , Schoepfe Alain , Archanioti Eva , Ezri Jessica , Fraga Montserrat , Schoepfer Alain , Müller Christoph , Rogler Gerhard , Biedermann Luc , Blattmann Mirjam , Burk Sabine , Dora Barbara , Fried Michael , Misselwitz Benjamin , Müllhaupt Beat , Obialo Nicole , Pohl Daniel , Raschle Nadia , Rogler Gerhard , Scharl Michael , Vavricka Stephan , Von Känel Roland , Zeitz Jonas , Abdelrahman Karim , Ademi Gentiana , Borovicka Jan , Brand Stephan , Frei Remus , Haarer Johannes , Knellwolf Christina , Krieger Claudia , Künzler Patrizia , Meyenberger Christa , Meyer Pamela , Röhrich Nina , Sawatzki Mikael , Schelling Martin , Semadeni Gian-Marco , Sulz Michael , Zimmermann Dorothee , Aepli Patrick , Criblez Dominique H. , Hess Cyrill , Richterich Jean-Pierre , Spalinger Johannes , Staudenmann Dominic , Stulz Andreas , Wöhrle Stefanie , Thomas Amman , Anderegg Claudia , Köhler Henrik , Kusche Rachel , Antonino Anca-Teodora , Arrigoni Eviano , Bengoa José M. , Cunningham Sophie , de Saussure Philippe , Girard Laurent , de Jong Diana Bakker , Bastürk Polat , Brunner Simon , Degen Lukas , Hruz Petr , Bakker Carolina Khalid-de , Niess Jan , Balsiger Bruno , Haldemann Janine , Saner Gaby , Seibold Frank , Bauerfeind Peter , Becocci Andrea , Belli Dominique , Binek Janek , Hengstler Peter , Boehm Stephan , Boldanov Tujana , Bühr Patrick , Koller Rebekka , Rueger Vanessa , Senning Arne , Burri Emanuel , Buyse Sophie , Cao Dahlia-Thao , D’Angelo Fabrizia , Delarive Joakim , Doerig Christopher , Hessler Roxane , Preissler Claudia , Rentsch Ronald , Risti Branislav , Ritz Marc Alain , Steuerwald Michael , Vögtlin Jürg , Sagmeister Markus , Sauter Bernhard , Schibli Susanne , Sokollik Christiane , Spalinger Johannes , Schlauri Hugo , Schnegg Jean-François , Seirafi Mariam , Spangenberger Holger , Stadler Philippe , Staub Peter , Stenz Volker , Tempia-Caliera Michela , Thorens Joël , Truninger Kaspar , Urfer Patrick , Viani Francesco , Vouillamoz Dominique , Zander Silvan , Wyli Tina ,   UK IBD Genetics Consortium, Jostins L. , Kennedy N. A. , Ahmad T. , Lamb C. A. , Edwards C. , Hart A. , Hawkey C. , Mansfield J. C. , Mowat C. , Newman W. G. , Simmons A. , Tremelling M. , Lee J. C. , Prescott N. J. , Mathew C. G. , Lees C. W. ,   NIDDK IBD Genetics Consortium, McGovern D. P. B. , Targan S. R. , Botwin G. , Mengesha E. , Fleshner P. , Landers C. , Li D. , Rioux J. D. , Bitton A. , Côté-Daigneault J. , Daly M. J. , Xavier R. , Morris K. , Boucher G. , Cho J. H. , Abraham C. , Merad M. , Sands B. , Peter I. , Hao K. , Itan Y. , Duerr R. H. , Konnikova L. , Schwartz M. B. , Proksell S. , Johnston E. , Miladinova V. , Chen W. , Brant S. R. , Datta L. , Silverberg M. S. , Schumm L. P. , Birch S. , Giri M. , Gettler K. , Sharma Y. , Stevens C. , Lazarev M. , Haritunians T. , Snapper Scott B. , Shah Neil , Muise Aleixo M. , Wilson David C. , Uhlig Holm H. , Anderson Carl A. 
Published: February 2020

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.