Genetic and Clinical Characteristics of Difficult‐To‐Treat Crohn's Disease: Trio‐Based Exome Sequencing in 24 Families

ABSTRACT Objectives Difficult‐to‐treat Crohn's disease (DTT‐CD) represents a critical unmet need in inflammatory bowel disease (IBD) management. However, its genetic architectures remain poorly understood. We aimed to evaluate the genetic characteristics and clinical manifestations of DTT‐CD cases through integrated trio‐based whole exome sequencing (WES) and longitudinal phenotyping. Methods In this cross‐sectional cohort study, DTT‐CD patients who met the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) criteria and their first‐degree relatives underwent trio‐WES analysis. Treatment persistence and remission rates were analyzed. Genetic variants were prioritized via cosegregation analysis, the American College of Medical Genetics and Genomics (ACMG) guidelines, and functional prediction algorithms. Results Among the 24 patients with DTT‐CD, 87.5% failed at least two biologics, 33.3% required dual targeted therapy, and drug persistence declined across treatment lines ( p = 0.0193). Remission rates were suboptimal (clinical: 41.7%; endoscopic: 50.0%). Trio‐WES analysis identified 15 likely pathogenic candidate variants across 12 genes, including the established monogenic IBD gene XIAP (two novel variants: p.Asp247Glufs*19, p.Ser43X; two known variants: p.Arg381X, p.Arg238X), genome‐wide association studies‐implicated IBD risk genes ( MAML2 and PLA2R1 ), and novel candidate variants ( KIZ , LAMA5 , SAMD9 , etc.) that were potentially linked to epithelial‐immune dysregulation. Conclusions This is the first trio‐WES study of DTT‐CD that reveals a high prevalence of monogenic XIAP deficiency (16.7%), advocating for genetic screening in refractory cases. Novel candidate genes implicate polygenic mechanisms of therapeutic resistance. Family‐based sequencing may be used to elucidate the genetic background of DTT‐CD cases to guide molecular diagnosis and personalized therapy.