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

Nat Commun. 2020 Feb 21;11(1):995. doi: 10.1038/s41467-019-14275-y.

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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Genes, Recessive
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Infant
  • Infant, Newborn
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / genetics*
  • Loss of Function Mutation
  • Male
  • Mosaicism*
  • Multifactorial Inheritance
  • Mutation
  • NADPH Oxidase 2 / genetics
  • Pedigree
  • Primary Immunodeficiency Diseases / complications
  • Primary Immunodeficiency Diseases / genetics
  • Risk Factors
  • Whole Exome Sequencing

Substances

  • CYBB protein, human
  • NADPH Oxidase 2