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-center cohort of patients with VEOIBD and universal access to whole exome sequencing (WES).
Patients receiving IBD care at a single center 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 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.
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 ICU hospitalization, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, hematopoietic stem cell transplant, and death. Forty-one 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.
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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