Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
Creators: name: Serra, Eva Gonçalves
name: Schwerd, Tobias
name: Moutsianas, Loukas
name: Cavounidis, Athena
name: Fachal, Laura
name: Pandey, Sumeet
name: Kammermeier, Jochen
name: Croft, Nicholas M.
name: Posovszky, Carsten
name: Rodrigues, Astor
name: Russell, Richard K.
name: Barakat, Farah
name: Auth, Marcus K. H.
name: Heuschkel, Robert
name: Zilbauer, Matthias
name: Fyderek, Krzysztof
name: Braegger, Christian
name: Travis, Simon P.
name: Satsangi, Jack
name: Parkes, Miles
name: Thapar, Nikhil
name: Ferry, Helen
name: Matte, Julie C.
name: Gilmour, Kimberly C.
name: Wedrychowicz, Andrzej
name: Sullivan, Peter
name: Moore, Carmel
name: Sambrook, Jennifer
name: Ouwehand, Willem
name: Roberts, David
name: Danesh, John
name: Baeumler, Toni A.
name: Fulga, Tudor A.
name: Karaminejadranjbar, Mohammad
name: Ahmed, Ahmed
name: Wilson, Rachel
name: Barrett, Jeffrey C.
name: Elkadri, Abdul
name: Griffiths, Anne M.
name: Snapper, Scott B.
name: Shah, Neil
name: Muise, Aleixo M.
name: Wilson, David C.
name: Uhlig, Holm H.
name: Anderson, Carl A.
name: Zurek, Marlen
name: Strisciuglio, Caterina
name: Elawad, Mamoun
name: Lo, Bernice
name: Arancibia-Carcamo, Carolina
name: Bailey, Adam
name: Barnes, Ellie
name: Bird-Lieberman, Elizabeth Louise
name: Brain, Oliver
name: Braden, Barbara
name: Collier, Jane
name: East, James
name: Howarth, Lucy
name: Keshav, Satish
name: Klenerman, Paul
name: Leedham, Simon
name: Palmer, Rebecca
name: Powrie, Fiona
name: Simmons, Alison
name: Walker, Matthew
name: Tolkien, Zoe
name: Kaptoge, Stephen
name: Allen, David
name: Mehenny, Susan
name: Mant, Jonathan
name: Di Angelantonio, Emanuele
name: Thompson, Simon G.
name: Yilmaz, Bahtiyar
name: Juillerat, Pascal
name: Geuking, Markus
name: Wiest, Reiner
name: Macpherson, Andrew J.
name: Bravo, Francisco Damian
name: Brügger, Lukas
name: Carstens, Ove
name: Bigler, Ulrike Graf
name: Heimgartner, Benjamin
name: Rusticeanu, Monica
name: Schmid (-Uebelhart), Sybille
name: Strebel, Bruno
name: Tatu, Aurora
name: Tutuian, Radu
name: Øyås, Ove
name: Ramon, Charlotte
name: Stelling, Jörg
name: Franc, Yannick
name: Fournier, Nicolas
name: Pittet, Valerie E. H.
name: Burnand, Bernard
name: Egger, Mara
name: Golay, Delphine
name: Marot, Astrid
name: Musso, Leilla
name: Pittet, Valérie
name: Rossel, Jean-Benoît
name: Seematter, Vivianne
name: Sommer, Joachim
name: Vulliamy, Rachel
name: Michetti, Pierre
name: Maillard, Michel H.
name: Keller, Céline
name: Nydegger, Andreas
name: Schoepfe, Alain
name: Archanioti, Eva
name: Ezri, Jessica
name: Fraga, Montserrat
name: Schoepfer, Alain
name: Müller, Christoph
name: Rogler, Gerhard
name: Biedermann, Luc
name: Blattmann, Mirjam
name: Burk, Sabine
name: Dora, Barbara
name: Fried, Michael
name: Misselwitz, Benjamin
name: Müllhaupt, Beat
name: Obialo, Nicole
name: Pohl, Daniel
name: Raschle, Nadia
name: Scharl, Michael
name: Vavricka, Stephan
name: Von Känel, Roland
name: Zeitz, Jonas
name: Abdelrahman, Karim
name: Ademi, Gentiana
name: Borovicka, Jan
name: Brand, Stephan
name: Frei, Remus
name: Haarer, Johannes
name: Knellwolf (-Grieger), Christina
name: Krieger(-Grübel), Claudia
name: Künzler, Patrizia
name: Meyenberger, Christa
name: Meyer, Pamela
name: Röhrich, Nina
name: Sawatzki, Mikael
name: Schelling, Martin
name: Semadeni, Gian-Marco
name: Sulz, Michael
name: Zimmermann, Dorothee
name: Aepli, Patrick
name: Criblez, Dominique H.
name: Hess, Cyrill
name: Richterich, Jean-Pierre
name: Spalinger, Johannes
name: Staudenmann, Dominic
name: Stulz, Andreas
name: Wöhrle, Stefanie
name: Thomas, Amman
name: Anderegg, Claudia
name: Köhler, Henrik
name: Kusche, Rachel
name: Antonino, Anca-Teodora
name: Arrigoni, Eviano
name: Bengoa, José M.
name: Cunningham, Sophie
name: De Saussure, Philippe
name: Girard, Laurent
name: De Jong, Diana Bakker
name: Bastürk, Polat
name: Brunner, Simon
name: Degen, Lukas
name: Hruz, Petr
name: Bakker, Carolina Khalid-De
name: Niess, Jan
name: Balsiger, Bruno
name: Haldemann, Janine
name: Saner, Gaby
name: Seibold, Frank
name: Bauerfeind, Peter
name: Becocci, Andrea
name: Belli, Dominique
name: Binek, Janek
name: Hengstler, Peter
name: Boehm, Stephan
name: Boldanov, Tujana
name: Bühr, Patrick
name: Koller, Rebekka
name: Rueger, Vanessa
name: Senning, Arne
name: Burri, Emanuel
name: Buyse, Sophie
name: Cao, Dahlia-Thao
name: D’Angelo, Fabrizia
name: Delarive, Joakim
name: Doerig, Christopher
name: Hessler, Roxane
name: Preissler, Claudia
name: Rentsch, Ronald
name: Risti, Branislav
name: Ritz, Marc Alain
name: Steuerwald, Michael
name: Vögtlin, Jürg
name: Sagmeister, Markus
name: Sauter, Bernhard
name: Schibli, Susanne
name: Sokollik, Christiane
name: Schlauri, Hugo
name: Schnegg, Jean-François
name: Seirafi, Mariam
name: Spangenberger, Holger
name: Stadler, Philippe
name: Staub, Peter
name: Stenz, Volker
name: Tempia-Caliera, Michela
name: Thorens, Joël
name: Truninger, Kaspar
name: Urfer, Patrick
name: Viani, Francesco
name: Vouillamoz, Dominique
name: Zander, Silvan
name: Wyli, Tina
name: Jostins, L.
name: Kennedy, N. A.
name: Ahmad, T.
name: Lamb, C. A.
name: Edwards, C.
name: Hart, A.
name: Hawkey, C.
name: Mansfield, J. C.
name: Mowat, C.
name: Newman, W. G.
name: Simmons, A.
name: Tremelling, M.
name: Lee, J. C.
name: Prescott, N. J.
name: Mathew, C. G.
name: Lees, C. W.
name: McGovern, D. P. B.
name: Targan, S. R.
name: Botwin, G.
name: Mengesha, E.
name: Fleshner, P.
name: Landers, C.
name: Li, D.
name: Rioux, J. D.
name: Bitton, A.
name: Côté-Daigneault, J.
name: Daly, M. J.
name: Xavier, R.
name: Morris, K.
name: Boucher, G.
name: Cho, J. H.
name: Abraham, C.
name: Merad, M.
name: Sands, B.
name: Peter, I.
name: Hao, K.
name: Itan, Y.
name: Duerr, R. H.
name: Konnikova, L.
name: Schwartz, M. B.
name: Proksell, S.
name: Johnston, E.
name: Miladinova, V.
name: Chen, W.
name: Brant, S. R.
name: Datta, L.
name: Silverberg, M. S.
name: Schumm, L. P.
name: Birch, S.
name: Giri, M.
name: Gettler, K.
name: Sharma, Y.
name: Stevens, C.
name: Lazarev, M.
name: Haritunians, T.
Publisher: name: Apollo - University of Cambridge Repository
Year: 2020
Subjects: Article
/631/208/248
/631/208/1516
/631/250/249/2510/257
/692/699/249/1570
/45
/45/23
/49
/49/31
/45/22
/13
article

description: 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 &lt; 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P &lt; 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.