TY - JOUR
T1 - Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
AU - COLORS in IBD group investigators
AU - Oxford IBD cohort study investigators
AU - INTERVAL Study
AU - Swiss IBD Cohort Investigators
AU - UK IBD Genetics Consortium
AU - NIDDK IBD Genetics Consortium
AU - Serra, Eva Gonçalves
AU - Schwerd, Tobias
AU - Moutsianas, Loukas
AU - Cavounidis, Athena
AU - Fachal, Laura
AU - Pandey, Sumeet
AU - Kammermeier, Jochen
AU - Croft, Nicholas M.
AU - Posovszky, Carsten
AU - Rodrigues, Astor
AU - Russell, Richard K.
AU - Barakat, Farah
AU - Auth, Marcus K.H.
AU - Heuschkel, Robert
AU - Zilbauer, Matthias
AU - Fyderek, Krzysztof
AU - Braegger, Christian
AU - Travis, Simon P.
AU - Satsangi, Jack
AU - Parkes, Miles
AU - Thapar, Nikhil
AU - Ferry, Helen
AU - Matte, Julie C.
AU - Gilmour, Kimberly C.
AU - Wedrychowicz, Andrzej
AU - Sullivan, Peter
AU - Moore, Carmel
AU - Sambrook, Jennifer
AU - Ouwehand, Willem
AU - Roberts, David
AU - Danesh, John
AU - Baeumler, Toni A.
AU - Fulga, Tudor A.
AU - Karaminejadranjbar, Mohammad
AU - Ahmed, Ahmed
AU - Wilson, Rachel
AU - Barrett, Jeffrey C.
AU - Elkadri, Abdul
AU - Griffiths, Anne M.
AU - Zurek, Marlen
AU - Strisciuglio, Caterina
AU - Elawad, Mamoun
AU - Lo, Bernice
AU - Arancibia-Carcamo, Carolina
AU - Sauter, Bernhard
AU - Merad, M.
AU - Sands, B.
AU - Peter, I.
AU - Itan, Y.
AU - Gettler, K.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85079788431&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-14275-y
DO - 10.1038/s41467-019-14275-y
M3 - Article
C2 - 32081864
AN - SCOPUS:85079788431
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 995
ER -