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; ... (2020). Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. Nature communications, 11(1), p. 995. 10.1038/s41467-019-14275-y
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine |
ISSN: |
2041-1723 |
Language: |
English |
Submitter: |
Professor Andrew Macpherson |
Date Deposited: |
24 Jun 2020 11:56 |
Last Modified: |
01 Feb 2023 10:39 |
Publisher DOI: |
10.1038/s41467-019-14275-y |
Related URLs: |
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PubMed ID: |
32081864 |
Additional Information: |
Collaborators: Andrew J. Macpherson |
BORIS DOI: |
10.7892/boris.144824 |
URI: |
https://boris.unibe.ch/id/eprint/144824 |
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