PROJECT SUMMARY This is a continuation application for the Baylor College of Medicine (BCM) Diagnostic Center of Excellence (DCoE) of the Undiagnosed Diseases Network (UDN). In phase I and II of the UDN, we provided patients with undiagnosed diseases (UDD) access to state-of-the-art diagnostic methods, accelerated discovery of new biological mechanisms linking genetic variants with disease causation, identified potential treatment approaches, and engaged with the UDN and broader community to share best practices and innovations. We have implemented innovative technologies like RNA sequencing- “first” directed genomic analysis on both whole blood and fibroblasts to complement exome and genome sequencing. This RNAseq- first analytical approach is now widely used in the broader community. In the current bridge phase III year, we have established collaboration with other NIH (NCATS Project GIVE, NHGRI Texome, and All of Us Evenings with Genetics Scholars) and community health programs (Texas Association of Community Health Clinics) to increase referral of under-represented and underserved communities to our site. We achieved this by leveraging an integrated genetics program housed within the Department of Molecular and Human Genetics (DMHG). This includes a full spectrum of service, teaching, and research activities spanning from adult, pediatric, and prenatal care, to gene discovery and study of disease mechanisms to clinical trials, to a leading medical genetics diagnostic laboratory joint venture (Baylor Genetics), to community engagement via the DMHG Office of Community Engagement and Equity. We propose to continue this remarkably integrated approach to discovery and care to achieve the objectives of the phase III UDN with 1) expansion of our hybrid- 3rd party payor/research supported, tiered evaluations, 2) focus on under-represented and under-served populations referred by our NIH program/community partners, 3) efficiencies afforded by our virtual Consult a gene platform, 4) application of ultra-low cost sequencing in partnership with Ultima Genomics to empower newer multi-omic analyses, and 4) data and resource sharing widely via the UDN DMCC. The Specific Aims of this BCM UDN DCoE are to: 1) Expand and scale our current model of integrated, tiered clinical and research assessments that leverages institutional infrastructure, resources, and previous programmatic successes; 2) Expand UDN access to underserved and under-represented communities by expanding pilot activities established during the current phase III bridge year; 3) Extend on our innovative multi-omic approaches from phase I and II; 4) Implement initiatives and contribute to DMCC and network wide protocols and governance as we have successfully done in our phase I and II activities.