A13 WHOLE EXOME SEQUENCING OF OVER 1000 PEDIATRIC IBD PATIENTS FROM A SINGLE CENTRE IDENTIFIES MONOGENIC FORMS OF IBD.

Abstract

Background: Inflammatory bowel disease (IBD) has a multifactorial aetiology, with complex interactions between genetic and environmental factors. Recent studies suggest an increasing spectrum of monogenic disease in the very young. The prevalence of these mutations in older children is unknown. Objectives: To determine the prevalence of monogenic forms of IBD in pediatric patients and identify any phenotypic characteristics allowing for accurate diagnosis. Methods: 2705 unique participants underwent whole exome sequencing (WES). This data was interrogated for a panel of 51 genes known to be associated with monogenic IBD. The Genome Analysis Toolkit was used to identify highly penetrant rare variants of interest. Sanger sequencing verified variant genotypes. A clinical database was reviewed to ascertain phenotypic characteristics. Results: A single centre retrospective study identified 1180 index cases, diagnosed over a 13 year period (2003-2015) who underwent WES. 2705 unique participants (556 trios, 31 quads, 34 affected siblings). Of sequenced affected cases, 56% CD, 26% UC, 11% IBD-U, 8% non-IBD. 21% < 6 years, 22% 7-10 years, 57% > 11 years. Across 51 genes, 82 protein coding variants predicted to be deleterious were identified, which were high quality and rare (maf <0.01). Disease causing mutations in XIAP, IL10R, SAP, TTC7A, LRBA, FOXP3, with rare damaging variants in NOX1, XIAP, DKC1 and FOXP3 over-represented in this cohort. Overall, approximately 1% of patients in a typical cohort of Pediatric IBD patients were found to have monogenic disease. Conclusion: WES of this largest pediatric cohort to date confirms the highly varied phenotypic spectrum of IBD associated with monogenic disease. Most children with causal VEOIBD mutations were diagnosed < 1 year of age, yet a significant number of older children were identified. Characterising genotypic-phenotypic features may provoke earlier recognition which will allow novel therapeutic approaches in this paediatric IBD population.