Gastroenterology

Gastroenterology

Volume 147, Issue 5, November 2014, Pages 990-1007.e3
Gastroenterology

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

https://doi.org/10.1053/j.gastro.2014.07.023Get rights and content
Under a Creative Commons license
open access

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.

Keywords

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

Abbreviations used in this paper

CD
Crohn’s disease
CGD
chronic granulomatous disease
CVID
combined variable immunodeficiency
EOIBD
early-onset inflammatory bowel disease
HSCT
hematopoietic stem cell transplantation
IBD
inflammatory bowel disease
Ig
immunoglobulin
IL
interleukin
IPEX
immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
NADPH
reduced nicotinamide adenine dinucleotide phosphate
NEMO
nuclear factor κB essential modulator protein
NK
natural killer
PID
primary immunodeficiency
SCID
severe combined immunodeficiency
UC
ulcerative colitis
VEOIBD
very early onset inflammatory bowel disease
WAS
Wiskott–Aldrich syndrome
WES
whole-exome sequencing

Cited by (0)

Author names in bold designate shared co-first authorship.

Conflicts of interest The authors disclose the following: H.H.U. has participated in industrial project collaboration with Eli Lilly, UCB Pharma, and Vertex Pharmaceuticals and received travel support from GlaxoSmithKline Foundation, Essex Pharma, Actelion, and MSD. T.S. has received speaker’s fees from MSD and travel support from Nestlé Nutrition. S.K. has received consulting or speaker’s fees from AbbVie, Danone, Janssen Pharmaceutical Research & Development, Merck, MSD, Nestlé Nutrition, Vifor, and Wyeth and has participated in industrial project collaboration with Euroimmun, Eurospital, Inova, Mead Johnson, Phadia/Thermo Fisher Scientific, and Nestlé Nutrition. N.S. has served as an advisory board member for Mead Johnson and received a unrestricted educational grant from MSD. D.C.W. has received consulting fees, speaker’s fees, meeting attendance support, or research support from MSD, Ferring Pharmaceuticals, Falk, Pfizer, and Nestlé. S.P.T. has received consulting fees from AbbVie, Cosmo Technologies, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutical Research & Development, Merck, Novartis, Novo Nordisk, Pfizer, Santarus, Schering-Plough, Shire Pharmaceuticals, Sigmoid Pharma, Tillotts Pharma AG, UCB Pharma, Vifor, and Warner Chilcott UK; research grants from AbbVie, Janssen Pharmaceutical Research & Development, Novartis, Pfizer, and UCB Pharma; and payments for lectures from AbbVie, Ferring Pharmaceuticals, Merck, Sanofi, and Tillotts Pharma AG. D.T. has received consulting fees, research grants, royalties, or honorarium from MSD, Janssen, Shire, Bristol-Myers Squibb, Hospital for Sick Children, and Abbott. S.B.S. has received consulting fees from AbbVie, Janssen Pharmaceutical Research & Development, Talecris, Cubist, Ironwoods, and Pfizer; speaking fees from UCB; and research grants from Pfizer. The remaining authors disclose no conflicts.

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.