{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T06:56:31Z","timestamp":1758351391238,"version":"3.44.0"},"reference-count":42,"publisher":"Wiley","issue":"5-6","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":92,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82201891","82270544","82470546","82400599"],"award-info":[{"award-number":["82201891","82270544","82470546","82400599"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Digest Diseases"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Difficult\u2010to\u2010treat Crohn's disease (DTT\u2010CD) 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\u2010CD cases through integrated trio\u2010based whole exome sequencing (WES) and longitudinal phenotyping.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this cross\u2010sectional cohort study, DTT\u2010CD patients who met the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) criteria and their first\u2010degree relatives underwent trio\u2010WES 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among the 24 patients with DTT\u2010CD, 87.5% failed at least two biologics, 33.3% required dual targeted therapy, and drug persistence declined across treatment lines (<jats:italic>p<\/jats:italic>\u2009=\u20090.0193). Remission rates were suboptimal (clinical: 41.7%; endoscopic: 50.0%). Trio\u2010WES analysis identified 15 likely pathogenic candidate variants across 12 genes, including the established monogenic IBD gene <jats:italic>XIAP<\/jats:italic> (two novel variants: p.Asp247Glufs*19, p.Ser43X; two known variants: p.Arg381X, p.Arg238X), genome\u2010wide association studies\u2010implicated IBD risk genes (<jats:italic>MAML2<\/jats:italic> and <jats:italic>PLA2R1<\/jats:italic>), and novel candidate variants (<jats:italic>KIZ<\/jats:italic>, <jats:italic>LAMA5<\/jats:italic>, <jats:italic>SAMD9<\/jats:italic>, etc.) that were potentially linked to epithelial\u2010immune dysregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This is the first trio\u2010WES study of DTT\u2010CD that reveals a high prevalence of monogenic <jats:italic>XIAP<\/jats:italic> deficiency (16.7%), advocating for genetic screening in refractory cases. Novel candidate genes implicate polygenic mechanisms of therapeutic resistance. Family\u2010based sequencing may be used to elucidate the genetic background of DTT\u2010CD cases to guide molecular diagnosis and personalized therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1751-2980.13358","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T14:52:03Z","timestamp":1754059923000},"page":"230-240","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic and Clinical Characteristics of Difficult\u2010To\u2010Treat Crohn's Disease: Trio\u2010Based Exome Sequencing in 24 Families"],"prefix":"10.1111","volume":"26","author":[{"given":"Hui Bo","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"},{"name":"Guangdong Institute of Gastroenterology  Guangzhou Guangdong Province China"},{"name":"Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhao Yuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"},{"name":"Guangdong Institute of Gastroenterology  Guangzhou Guangdong Province China"},{"name":"Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"},{"name":"Guangdong Institute of Gastroenterology  Guangzhou Guangdong Province China"},{"name":"Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1979-5891","authenticated-orcid":false,"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong 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