Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
Serra EG., Schwerd T., Moutsianas L., Cavounidis A., Fachal L., Pandey S., Kammermeier J., Croft NM., Posovszky C., Rodrigues A., Russell RK., Barakat F., Auth MKH., Heuschkel R., Zilbauer M., Fyderek K., Braegger C., Travis SP., Satsangi J., Parkes M., Thapar N., Ferry H., Matte JC., Gilmour KC., Wedrychowicz A., Sullivan P., Moore C., Sambrook J., Ouwehand W., Roberts D., Danesh J., Baeumler TA., Fulga TA., Karaminejadranjbar M., Ahmed A., Wilson R., Barrett JC., Elkadri A., Griffiths AM., Zurek M., Strisciuglio C., Elawad M., Lo B., Arancibia-Carcamo C., Bailey A., Barnes E., Bird-Lieberman EL., Brain O., Braden B., Collier J., East J., Howarth L., Keshav S., Klenerman P., Leedham S., Palmer R., Powrie F., Simmons A., Walker M., Tolkien Z., Kaptoge S., Allen D., Mehenny S., Mant J., Di Angelantonio E., Thompson SG., Yilmaz B., Juillerat P., Geuking M., Wiest R., Macpherson AJ., Bravo FD., Brügger L., Carstens O., Bigler UG., Heimgartner B., Rusticeanu M., Schmid (-Uebelhart) S., Strebel B., Tatu A., Tutuian R., Øyås O., Ramon C., Stelling J., Franc Y., Fournier N., Pittet VEH., Burnand B., Egger M., Golay D., Marot A., Musso L., Rossel JB., Seematter V., Sommer J., Vulliamy R., Michetti P., Maillard MH.
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.