An international team of researchers has identified a previously unknown genetic cause of severe Crohn's disease in children, a breakthrough that could improve diagnosis and pave the way for more targeted treatments for inflammatory bowel disease (IBD). The findings were published in the journal Gastroenterology.
The study was led by researchers from Ludwig-Maximilians-Universität (LMU) Munich and The Hospital for Sick Children (SickKids), Toronto, as part of the global VEO-IBD Consortium. Scientists from Germany, Canada, the United States, China, Japan, France, Spain, and Saudi Arabia collaborated on the research.
Researchers discovered that harmful mutations in the BIRC3 gene can cause a rare but severe monogenic form of Crohn's disease. The team identified 14 patients from 10 unrelated families carrying disease-causing variants of this gene. Using advanced genetic, transcriptomic, proteomic, and laboratory model analyses, they uncovered how these mutations trigger intestinal inflammation.
The investigation revealed that loss of BIRC3 function disrupts the RIPK1 signaling pathway, leading to excessive death of intestinal epithelial cells. Since these cells form the protective lining of the gut, their damage weakens the intestinal barrier and promotes persistent inflammation, providing a biological explanation for disease development in affected patients.
Importantly, researchers believe the discovery has implications beyond this rare inherited condition. Early evidence suggests that the same cellular pathway may also contribute to more common forms of Crohn's disease, raising the possibility that therapies targeting the RIPK1 pathway could benefit a broader group of patients.
According to the investigators, the study demonstrates how international collaboration is essential for uncovering rare disease mechanisms. Because patients with this specific genetic defect are extremely uncommon, researchers from multiple countries combined their expertise and patient data to identify the underlying cause and potential therapeutic target.
The researchers say the discovery represents an important advance toward precision medicine for inflammatory bowel disease. Identifying BIRC3 deficiency not only offers affected families a definitive genetic diagnosis but also provides a promising direction for developing personalized treatments that may eventually benefit patients with both rare and more common forms of Crohn's disease.
Reference : Qi Li et al. BIRC3 (Encoding Cellular Inhibitor of Apoptosis Protein 2) Variants Result in Dysregulated Receptor-Interacting Protein Kinase 1 Signaling Leading to Increased Epithelial Cell Death and Are Associated With Monogenic Crohn's Disease. Gastroenterology. DOI: 10.1053/j.gastro.2026.05.022.
