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

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 <sup>-10</sup> ), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10 <sup>-10</sup> ). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

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

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 <sup>-10</sup> ), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10 <sup>-10</sup> ). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

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

Correction to: Nature Communications https://doi.org/10.1038/s41467-019-14275-y, published online 21 February 2020.Since the publication of this work, Eli M Carrami has changed their name from Mohammad Karaminejadranjbar. This has now been amended in the HTML and PDF versions of the article.</div