The diagnostic approach to monogenic very early onset inflammatory bowel disease

Holm H. Uhlig*, Tobias Schwerd, Sibylle Koletzko, Neil Shah, Jochen Kammermeier, Abdul Elkadri, Jodie Ouahed, David C. Wilson, Simon P. Travis, Dan Turner, Christoph Klein, Scott B. Snapper, Aleixo M. Muise

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

496 Scopus citations


Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

Original languageAmerican English
Pages (from-to)990-1007.e3
Issue number5
StatePublished - 1 Nov 2014

Bibliographical note

Funding Information:
Funding H.H.U. is supported by the Crohn’s & Colitis Foundation of America . T.S. is supported by the Deutsche Forschungsgemeinschaft ( SCHW1730/1-1 ). C.K. is supported by DFG SFB1054, BaySysNet, and DZIF. S.B.S is supported by National Institutes of Health grants HL59561 , DK034854 , and AI50950 and the Wolpow Family Chair in IBD Treatment and Research. A.M.M. is supported by an Early Researcher Award from the Ontario Ministry of Research and Innovation and a Canadian Institute of Health Research operating grant (MOP119457). This work was supported in part by a grant from The Leona M. and Harry B. Helmsley Charitable Trust (to A.M.M., C.K., and S.B.S.). The COLORS in IBD Study Group is supported by a grant from Wellcome Trust Sanger Institute , a Crohn’s and Colitis UK grant to the UK and Irish Paediatric IBD Genetics Group, and in part by an Medical Research Council grant for the Paediatric-Onset Inflammatory Bowel Disease Cohort and Treatment Study (PICTS) study.


  • Crohn's Disease
  • Genetics Next-Generation Sequencing
  • Immunodeficiency Pediatrics IBD Unclassified
  • Indeterminate Colitis
  • Inflammatory Bowel Disease
  • Ulcerative Colitis
  • Unclassified Colitis
  • Whole Exome Sequencing


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