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 Wilson, Simon P. Travis, Dan Turner, Christoph Klein, Scott B. Snapper, Aleixo M. Muise, COLORS IBD Study Grp NEOPICS

Research output: Contribution to journalArticlepeer-review

Abstract

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 languageEnglish
Pages (from-to)990-+
Number of pages21
JournalGastroenterology
Volume147
Issue number5
DOIs
Publication statusPublished - Nov 2014

Keywords

  • Inflammatory Bowel Disease
  • Crohn's Disease
  • Ulcerative Colitis
  • Unclassified Colitis
  • Indeterminate Colitis
  • Immunodeficiency
  • Pediatrics
  • IBD Unclassified
  • Genetics
  • Next-Generation Sequencing
  • Whole Exome Sequencing
  • CHRONIC GRANULOMATOUS-DISEASE
  • HERMANSKY-PUDLAK-SYNDROME
  • X-LINKED SYNDROME
  • MEVALONATE KINASE-DEFICIENCY
  • HOYERAAL-HREIDARSSON-SYNDROME
  • BONE-MARROW-TRANSPLANTATION
  • STEM-CELL TRANSPLANTATION
  • WISKOTT-ALDRICH-SYNDROME
  • HYPER-IGM SYNDROME
  • INTRACTABLE ULCERATING ENTEROCOLITIS

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