Monogenic IBD

Determining a definitive diagnosis

Monogenic inflammatory bowel disease (IBD) refers to a diverse spectrum of rare genetic disorders that present with intestinal inflammation.1 Unlike patients with polygenic IBD, most patients with monogenic IBD show symptoms before age 6. Because monogenic and polygenic IBD can have indistinguishable endoscopic or histologic features, establishing accurate diagnosis via traditional methods remains a challenge.2

Comprehensive genetic testing to confirm diagnosis and optimize treatment

Genetic testing can identify patients with monogenic IBD and primary immunodeficiencies that present with IBD-like features. Isolating the genetic cause of the illness enables clinicians to choose treatment options that enhance outcomes. Mayo Clinic Laboratories offers a genetic panel that detects variants in 51 genes with established genetic associations to monogenic IBD and primary immunodeficiencies that present with IBD-like features.

When to consider testing

Signs that should raise suspicion of monogenic IBD and prompt testing:

  • Onset at age 6 or younger
  • The younger the patient, the higher the suspicion of a monogenic disorder
  • Up to 15% of patients with IBD presenting before age 6 may have a monogenic disorder2
  • Frequent infections

  • Overt skin manifestations (e.g., eczema, granulomas, cutaneous vasculitis)
  • Dysmorphism
  • Hair abnormalities
  • Refractory disease, or does not respond to conventional IBD treatment

Which test should I order?

IBD-associated monogenic disorders and their linked genes

Epithelial Barrier

  • X-linked ectodermal immunodeficiency
    (IKBKG)
  • TTC7A deficiency
    (TTC7A)
  • ADAM17 deficiency
    (ADAM17)

Immune Dysregulation

  • IPEX/IPEX-like
    (FOXP3, IL2RA, STAT1)
  • IL10-signaling defects
    (IL10RA, IL10RB, IL10)
  • CTLA4 haploinsufficiency with autoimmune infiltration
    (CTLA4)

Phagocyte Defects

  • Chronic granulomatous disease
    (CYBB, CYBA, NCF2, NCF4)
  • Glycogen storage disease
    (SLC37A4)
  • Congenital neutropenia
    (G6PC3)
  • Leukocyte adhesion deficiency
    (ITGB2)

T- and B-Cell Defects

  • Common variable immunodeficiency
    (LRBA, ICOS)
  • IL-21 deficiency
    (IL21)
  • Agammaglobulinemia
    (BTK, PIK3R1)
  • Hyper IgM syndrome
    (CD40LG, AICDA)
  • Hyper IgE syndrome
    (DOCK8)
  • Wiskott-Aldrich syndrome
    (WAS, WIPF1)
  • Omenn syndrome/SCID
    (DCLRE1C, ZAP70, RAG2, IL2RG, LIG4, ADA, CD3γ)
  • Hoyeraal-Hreidarsson syndrome
    (DKC1, RTEL1)

Hyperinflammatory and Autoinflammatory Disorders

  • Mevalonate kinase deficiency
    (MVK)
  • Phospholipase C-γ2 defects
    (PLCG2)
  • Familial Mediterranean fever
    (MEFV)
  • Familial hemophagocytic lymphohistiocytosis
    (STXBP2)
  • X-linked lymphoproliferative syndrome
    (XIAP, SH2D1A)

Additional Genes Associated with IBD-Like Monogenic Diseases

  • MASP deficiency
    (MASP2)
  • Trichohepatoenteric syndrome
    (SKIV2L, TTC37)

Early-onset IBD: Genetic testing and clinical applications

Identification of early-onset IBD may enable tailored treatment and surveillance plans. With more than 50 genes implicated in early-onset IBD, genetic testing should be included in the workup of children with IBD under the age of 6. Join Mayo Clinic for a discussion of this testing and its clinical application.

Contextualizing patient phenotype

Because genetic testing is probabilistic in nature, variant classification and interpretation can be challenging. Guidelines with specific criteria are used to decipher results; however, professional judgement is required to determine whether a detected variant is the cause of a patient’s phenotype.

MCL test results are interpreted by a team of experienced laboratory directors and genetic counselors familiar with the latest literature who will classify variants detected using American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.

Learn more about how to order this evaluation at your institution.

References

  1. Shim, Jung. Recent advances in very early onset inflammatory bowel disease. Pediatr Gastroenterol Hepatol Nutr. 2019;21(1):41–49.
  2. Lega S, Pin A, Arrigo S, Cifaldi C, Girardelli M, et al. Diagnostic approach to monogenic inflammatory bowel disease in clinical practice: a ten-year multicentric experience. Inflamm Bowel Dis. 2019;20(20):1-8.