Novel pathogenic

Background: Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) haploinsufficiency is a rare monogenic immunodysregulatory disorder that can affect multiple organ systems, leading to a combination of autoimmunity, immunodeficiency, and lymphoproliferation. It is caused by heterozygous germline mutations of Methods: We performed whole-exome sequencing on a patient with adolescent-onset autoimmune enteropathy, early-onset gastric malignancy and multisystem comorbidities, who was initially misdiagnosed with Crohn's disease and refractory to multiple biologics. Functional assays assessed CTLA4 dimerization and CD80/CD86 binding capacity. Peripheral blood immunophenotyping was conducted using CyTOF and flow cytometry. Intestinal histopathology was evaluated by immunohistochemistry. The patient subsequently received targeted therapy with abatacept. Results: A novel heterozygous missense variant in Conclusion: These findings identify p.Phe56Cys as a novel loss-of-function CTLA4 variant that disrupts protein dimerization and ligand binding, expanding the mechanistic understanding of CTLA4 haploinsufficiency and supporting genetic screening in patients with refractory autoimmune enteropathy and early-onset gastric malignancy.