Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

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)

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:

28 Nov 2020 02:30

Publisher DOI:

10.1038/s41467-019-14275-y

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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