This paper presents a case of twin brothers afflicted with Crohn’s Disease (CD), characterized by a rare missense mutation c.-12+198G>T in the interferon regulatory factor 5 (IRF5) gene, which is extremely uncommon in the Chinese population and reportedly identified for the first time internationally. The clinical features of the patients are described in detail, and potential pathogenic mechanisms are discussed. In terms of treatment, both twins experienced significant improvement in clinical symptoms and endoscopic findings after treatment with Ustekinumab. Furthermore, through a literature review, this paper anticipates the role of IRF5 in Inflammatory Bowel Disease (IBD) and summarizes its mechanisms, aiming to provide a theoretical basis for future research into personalized treatment of CD.