In:
Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-02-21)
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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-019-14275-y
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
2553671-0
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