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

Open access
Date
2020Type
- Journal Article
Citations
Cited 33 times in
Web of Science
Cited 30 times in
Scopus
ETH Bibliography
yes
Altmetrics
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 < 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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000405058Publication status
publishedExternal links
Journal / series
Nature CommunicationsVolume
Pages / Article No.
Publisher
Nature Publishing GroupMore
Show all metadata
Citations
Cited 33 times in
Web of Science
Cited 30 times in
Scopus
ETH Bibliography
yes
Altmetrics