P1311 Genetic and Clinical Characteristic of Difficult-to-treat Crohn’s Disease: Trio-Based Exome Sequencing in 24 Families
Abstract
Abstract Background Difficult-to-treat Crohn’s disease (DTT-CD) poses a substantial therapeutic challenge, yet the genetic determinants underlying its aggressive phenotype remain poorly defined. Methods We retrospectively analyzed DTT-CD patients (n = 24 families) from the Inflammatory Bowel Disease Center at the Sixth Affiliated Hospital of Sun Yat-sen University. Patients met the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) criteria for DTT-CD and underwent trio-based whole-exome sequencing (WES). Clinical trajectories, therapeutic responses, and genetic variants were systematically evaluated. Putative pathogenic mutations were functionally validated using luciferase reporter assays in HEK293T cells transfected with wild-type or mutant overexpression plasmids. Results Our cohort exhibited aggressive disease progression. Longitudinal treatment in dot plot showed declining therapeutic durability across therapeutic lines (p = 0.0139). Venn diagram and Sankey diagram presented the reasons for refractoriness and the continuous switching of treatment regimens in DTT-CD patients. Through segregation analysis of WES results within families and ACMG evaluation, we identified 15 potentially damaging variants in 12 genes. Specifically, there were 4 pathogenic variants in XIAP, meeting the monogenic diagnostic criteria with a diagnosis rate of 16.6%. We also found 2 mutations in IBD - susceptibility genes and 9 novel potentially pathogenic mutations. Of these 9 candidate variants, in-vitro experiments showed that the KIZ-I142V reduced its inhibitory effect on the NF-κB pathway compared to the wild-type. Conclusion Trio-WES may serve as a useful tool for molecular diagnosis in DTT-CD, highlighting potential genetic contributors to therapeutic resistance and disease pathogenesis that have not been previously recognized. KIZ-I142V may be implicated in the pathogenesis of DTT-CD. Conflict of interest: Dr. Xu, Zhaoyuan: No conflict of interest Wu, Huibo: No conflict of interest Peng, Xiang: No conflict of interest Zhang, Min: No conflict of interest Zhi, Min: No conflict of interest