DIAGNOSTIC APPROACH TO MONOGENIC INFLAMMATORY BOWEL DISEASE WITH NEXT-GENERATION SEQUENCING TECHNOLOGIES.

Abstract

Background & aims: 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, suggest a diagnostic approach to monogenic IBD. Methods: Clinical information of patients with VEO-IBD and EO-IBD s/a referred to 3 Italian Centers 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: 93 patients were collected and 14 (15%) reached a genetic diagnosis. Selective sequencing was performed in 47 patients (50%), NGS in 84 patients (90%). Causative defects were revealed by NGS in 5 patients (NOD2, TTC37, DKC1, XIAP, FERMT3) and candidate sequencing in 8 patients (2WAS, 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. One patient with WAS, in whom Sanger sequencing had not revealed mutations, was diagnosed externally through WGS which revealed a large genomic inversion. Genetic diagnosis impacted patient management in 10 patients (71%): 6 underwent bone marrow transplant (2XIAP, 2WAS, 2CD40L, FOXP3), 1 gene therapy, 2 anti-infective prophylaxis and 1 introduced danazole (DKC1). Patients with monogenic IBD more frequently had a history of infections (71%vs30%; p<.001), thrombocytopenia (21% vs 3%; p.003), hemophagocytosis (21% vs 3%; p.02), and disease onset 64 1 month of life (36% vs 1%; p<.001) when compared to 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

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