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P212 Diagnostic approach to monogenic inflammatory bowel disease in clinical practice: a 10-year multi-centric experience

S. Lega*1, A. Pin1, S. Arrigo2, C. Cifaldi3, M. Girardelli1, A. Bianco1, M. Malamisura4, G. Angelino4, S. Faraci4, E. F. Romeo4, B. Papadatou4, M. Miano5, M. Aloi6, G. Magazzù7, C. Romano7, P. Calvo8, A. Barabino2, S. Martelossi1, A. Tommasini1, G. Di Matteo3, C. Cancrini3, P. De Angelis4, A. Finocchi3, M. Bramuzzo1

1Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy, 2Institute Giannina Gaslini, Pediatric Gastroenterology and Endoscopy Unit,, Genoa, Italy, 3Children’s Hospital Bambino Gesù, Department of Pediatrics, Rome, Italy, 4Children’s Hospital Bambino Gesù, Digestive diseases Unit, Rome, Italy, 5Institute Giannina Gaslini, Pediatric Hematology-Oncology Unit, Genoa, Italy, 6Sapienza University of Rome, Pediatric Gastroenterology And Liver Unit, Rome, Italy, 7University of Messina, Pediatric Gastroenterology and Cystic Fibrosis Unit, Messina, Italy, 8Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino, Pediatric Gastroenterology Unit, Turin, Italy

Background

Up to 15% inflammatory bowel diseases (IBD) rising before the age of 6 years, defined as very-early-onset IBD (VEO-IBD), may have a monogenic disease. More rarely monogenic defects are found in later onset IBD. Monogenic IBD are associated with high morbidity and mortality and timely genetic diagnosis is essential for adequate treatment. Due to the wide phenotypic and genetic heterogeneity of these conditions, it is often difficult to reach a genetic diagnosis and the best diagnostic approach is still debated. Next-generation sequencing (NGS) techniques have been proposed as a screening tool especially in patients with poorly defined phenotypes. In a cohort study that included patients with VEO-IBD and early-onset IBD with severe/atypical phenotypes (EO-IBD s/a) we aimed to describe the genetic diagnoses and their therapeutic implications, define the clinical characteristics associated with monogenicity, and suggest a diagnostic approach to monogenic IBD.

Methods

Clinical information of patients with VEO-IBD and EO-IBD s/a referred to 2 Italian Centers (IRCCS Burlo Garofolo and Ospedale Bambino Gesù) for a genetic work-up over 10 years (2008–2017) were collected. From 2015 newly diagnosed patients and patients without a previous genetic diagnosis were screened using NGS, except patients with disease-specific features in whom candidate gene analysis was chosen.

Results

In total, 93 patients were collected and 14 (15%) reached a genetic diagnosis. Selective sequencing was performed in 46 patients (49%), NGS in 84 patients (90%). Causative defects were revealed by NGS in 5 patients (NOD2, TTC37, DKC1, XIAP, FERMT3) and candidate sequencing in 9 patients (3WAS, CYBA, CYBB, FOXP3, 2CD40L, XIAP). In 8 of 9 patients diagnosed with candidate sequencing, the analysis was guided by the presence of disease-specific features. One patient, with unspecific presentation, underwent sequential sequencing of multiple genes over 15 months before reaching the diagnosis (XIAP). NGS identified a new NOD2 mutation previously missed with single-gene approach. Genetic diagnosis impacted patient management in 9 patients (64%): 8 underwent bone marrow transplant (2XIAP, 3WAS, 2CD40L, FOXP3) and 1 patient introduced danazole (DKC1). Patients with monogenic IBD more frequently had thrombocytopenia (21% vs. 3%; p = 0.003), hemophagocytosis (21% vs. 3%; p = 0.02), extraintestinal symptoms (100% vs. 32%; p < 0.001) and disease onset ≤ 1 month of life (36% vs. 1%; p < 0.001) when compared with the non-monogenic group.

Conclusion

We suggest using NGS in all patients presenting with non-specific clinical profiles and selective gene sequencing when clinical characteristics suggestive of specific monogenic conditions are present.