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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; Thapar, Nikhil; Ferry, Helen; Matte, Julie C.; Gilmour, Kimberly C.; [...]

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

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  • Media type: E-Article
  • Title: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
  • Contributor: 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; Thapar, Nikhil; Ferry, Helen; Matte, Julie C.; Gilmour, Kimberly C.; [...]
  • imprint: Springer Science and Business Media LLC, 2020
  • Published in: Nature Communications
  • Language: English
  • DOI: 10.1038/s41467-019-14275-y
  • ISSN: 2041-1723
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>XIAP, CYBA, SH2D1A, PCSK1</jats:italic>). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in <jats:italic>CYBB</jats:italic>. 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; <jats:italic>P</jats:italic> &lt; 4 × 10<jats:sup>−10</jats:sup>), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; <jats:italic>P</jats:italic> &lt; 5 × 10<jats:sup>−10</jats:sup>). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.</jats:p>
  • Access State: Open Access