Lauren V Collen1, David Y Kim1, Michael Field1, Ibeawuchi Okoroafor1, Gwen Saccocia1, Sydney Driscoll Whitcomb1, Julia Green1, Michelle Dao Dong1, Jared Barends1, Bridget Carey1, Madison E Weatherly1, Shira Rockowitz2, Piotr Sliz2,3, Enju Liu1,4, Alal Eran5,6,7, Leslie Grushkin-Lerner1, Athos Bousvaros1, Aleixo M Muise8,9,10, Christoph Klein11, Vanessa Mitsialis1,12, Jodie Ouahed1, Scott B Snapper1,12. 1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. 2. Manton centre for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. 3. Division of Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. 4. Institutional centres for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA. 5. Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. 6. Harvard Medical School, Department of Biomedical Informatics, Boston, MA, USA. 7. Department of Life Sciences and Zlotowski centre for Neuroscience, Ben Gurion University of the Negev, Beer-Sheva, Israel. 8. SickKids Inflammatory Bowel Disease centre, Research Institute, Hospital for Sick Children, Toronto, ON, Canada. 9. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Toronto, Toronto, ON, Canada. 10. Institute of Medical Science, University of Toronto, Toronto, ON, Canada. 11. Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU Klinikum, and Gene centre, Ludwig Maximilians Universität München, München,Germany. 12. Division of Gastroenterology, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
Abstract
BACKGROUND AND AIMS: Over 80 monogenic causes of very early onset inflammatory bowel disease [VEOIBD] have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES]. METHODS: Patients receiving IBD care at a single centre were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise a VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function, or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. RESULTS: This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients [7.9%] had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 patients [19.0%] had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. CONCLUSIONS: Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.
BACKGROUND AND AIMS: Over 80 monogenic causes of very early onset inflammatory bowel disease [VEOIBD] have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES]. METHODS: Patients receiving IBD care at a single centre were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise a VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function, or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. RESULTS: This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients [7.9%] had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 patients [19.0%] had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. CONCLUSIONS: Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.
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