220.5: Diagnosis and management of congenital enteropathies: analysis of a large multi-center cohort and the role of Next Generation Sequencing.

Abstract

Introduction: A small percentage of children with intestinal failure suffer from congenital enteropathies responsible for chronic diarrhea associated with severe growth failure and dehydration. These disorders usually present early in infancy and result from monogenic mutations in genes affecting intestinal epithelial function. Recently, next-generation sequencing (NGS) technology has revolutionized the approach to molecular diagnosis, although there still remains little information about the associated natural history, and complete clinical phenotype. To better understand the natural history and the impact of NGS, we studied a historical cohort of children with congenital enteropathies. Methods: A retrospective analysis of children followed in the intestinal failure / congenital enteropathy programs at Necker-Enfants Malades and Boston Children’s Hospitals was done. Diagnosis was obtained either from pathology, targeted sequencing, and from 2012 (Boston)/ 2014 (Paris) by NGS (whole exome, or targeted gene panels). Genetic findings were validated clinically and/or functionally. Results: 85 patients were included (53% female, age 2 months to 25 years). Three out 85 patients died. In 82% (70/85) of cases, a diagnosis could be established. 25 (29%) patients were diagnosed with microvillus inclusion disease (MYO5B mutation), 19 (22%) patients were diagnosed with tufting enteropathy (EPCAM mutations). Other diagnoses included DGAT1 mutations (8,5%), TTC37/SKIV2L, and SLC26A3 [UMO1] mutations. Since 2012, 37 out of 46 patients (80%) obtained a molecular diagnosis, including the discovery of novel genes (DGAT1, UNC45A, WNT2B). 9 out of 42 patients at Necker-Enfants Malades underwent intestinal transplantation. In a number of patients, diagnosis facilitated by NGS led to significant changes in clinical management such as removal of high-risk immunosuppressive medications. Conclusion: We carried out an analysis of a large cohort of children with congenital enteropathy, across two major pediatric centers. Mutations in MYO5B and EPCAM were responsible for 51% of our cohort, with considerable genetic heterogeneity in the rest of the cohort. Since 2012, most patients underwent NGS, with a molecular diagnosis achieved in 80% of cases[UMO2]. NGS was critical in achieving a diagnosis particularly in atypical or hypomorphic presentations and enabled clinically significant changes in management as well as the discovery of novel disease-causing genes.