Diagnostic Approach to Monogenic Inflammatory Bowel Disease in Clinical Practice: A Ten-Year Multicentric Experience

Lega S1, Pin A1, Arrigo S2, Cifaldi C3, Girardelli M4, Bianco AM4, Malamisura M5, Angelino G5, Faraci S5, Rea F5, Romeo EF5, Aloi M6, Romano C7, Barabino A2, Martelossi S4, Tommasini A4, Di Matteo G3, Cancrini C3, De Angelis P5, Finocchi A3, Bramuzzo M4. Inflamm Bowel Dis. 2019 Aug 3. pii: izz178. doi: 10.1093/ibd/izz178. [Epub ahead of print]


Author information

University of Trieste, Department of Medicine, Surgery and Health Sciences, Trieste, Italy.

Pediatric Gastroenterology and Endoscopy Unit, Institute Giannina Gaslini, Genoa, Italy.

Department of Pediatrics, Children's Hospital Bambino Gesù, Rome, Italy.

Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.

Digestive Diseases Unit, Children's Hospital Bambino Gesù, Rome, Italy.

Pediatric Gastroenterology And Liver Unit, Sapienza University of Rome, Rome, Italy.

Pediatric Gastroenterology and Cystic Fibrosis Unit, University of Messina, Messina, Italy.


BACKGROUND AND AIMS: Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients' management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis.

METHODS: Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008-2017 who underwent a genetic workup were collected.

RESULTS: Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT.

CONCLUSION: A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients' management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.

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