PROJECT SUMMARY/ABSTRACT The scientific premise of this application is that the individualized translational research process of the Undiagnosed Diseases Network (UDN) is sustainable and that its impact on patients, families, and disease discovery can be further extended by increasing its accessibility to a broader participant population. This application would support the Washington University in St. Louis (WashU) UDN Diagnostic Center of Excellence (DCoE). WashU and BJC Healthcare together represent a large academic medical center, hospital, and outpatient clinical system that is fully integrated with world-renowned basic science capabilities and demonstrated expertise in finding diagnoses for patients with undiagnosed diseases. The highly collaborative clinical and biomedical research culture at WashU promotes interactions within and across Departments, with institutional genomic, clinical, computational, and model system experts, and with colleagues regionally, nationally, and internationally. These interactions support recruitment, selection, evaluation, diagnosis discovery, and follow up of pediatric and adult patients with undiagnosed diseases through both established networks and individual referrals. Building on this infrastructure, we propose to continue to advance the success of the UDN in diagnosing and managing disease in undiagnosed patients by utilizing a system for clinical and genomic review of applications and participant cases, with expanded, expert clinical, laboratory, and informatics expertise to solve cases that are and are not suspected to have genetic underpinnings. Specific strengths of our DCoE include neurological disorders (neurodevelopmental, neuromuscular), inborn errors of immunity, inherited pulmonary disorders, and disorders caused by somatic mosaicism. Second, we aim to improve equity and access to the UDN for participants from underserved populations. In particular, we will focus our outreach program for underrepresented minority populations and populations with lower socioeconomic status through a Community Engagement Strategy that includes establishment of a collaboration with healthcare organization supporting federally-qualified health centers and the Saint Louis County Health Department, with appointment of a new Equity Officer. Third, we will implement a Sustainability Strategy including research support, insurance billing, charitable funds, and departmental cost-sharing. We will work closely with the UDN Network and the Data Management and Coordinating Center to implement collaborative, highly effective, equitable, and sustainable methods for undiagnosed patients.