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

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

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

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

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

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

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

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

Abstract

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.