title: The diagnostic approach to monogenic very early onset inflammatory bowel disease.
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.
authors: Translational Gastroenterology Unit, University of Oxford, Oxford, England; Department of Pediatrics, University of Oxford, Oxford, England. Electronic address: holm.uhlig@ndm.ox.ac.uk.
authors: Holm H
authors: HH
authors: Uhlig
authors: Translational Gastroenterology Unit, University of Oxford, Oxford, England.
authors: Tobias
authors: T
authors: Schwerd
authors: Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors: Sibylle
authors: S
authors: Koletzko
authors: Great Ormond Street Hospital London, London, England; Catholic University, Leuven, Belgium.
authors: Neil
authors: N
authors: Shah
authors: Great Ormond Street Hospital London, London, England.
authors: Jochen
authors: J
authors: Kammermeier
authors: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Abdul
authors: A
authors: Elkadri
authors: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Jodie
authors: J
authors: Ouahed
authors: Child Life and Health, University of Edinburgh, Edinburgh, Scotland; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Royal Hospital for Sick Children, Edinburgh, Scotland.
authors: David C
authors: DC
authors: Wilson
authors: Translational Gastroenterology Unit, University of Oxford, Oxford, England.
authors: Simon P
authors: SP
authors: Travis
authors: Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Dan
authors: D
authors: Turner
authors: Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors: Christoph
authors: C
authors: Klein
authors: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Scott B
authors: SB
authors: Snapper
authors: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Aleixo M
authors: AM
authors: Muise
mesh_terms: D017668:Age of Onset; D003093:Colitis, Ulcerative / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D003424:Crohn Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D012307:Risk Factors
keywords: Crohn’s Disease; Genetics; IBD Unclassified; Immunodeficiency; Indeterminate Colitis; Inflammatory Bowel Disease; Next-Generation Sequencing; Pediatrics; Ulcerative Colitis; Unclassified Colitis; Whole Exome Sequencing