PROJECT SUMMARY/ABSTRACT We propose to establish an Intermountain West Clinical Site at the University of Utah for the Undiagnosed Disease Network. The proposed site will provide unprecedented access to a vast area across five states that encompasses ~10% of the Continental US. Its residents are among the most underserved in the United States; with rural, minority, and low-income groups historically `genetically underserved', including a large Native American population. To advance state-of-the-art diagnosis and management, we will leverage our successful pediatric Penelope program—our `innovation laboratory' and proof-of concept program for undiagnosed and rare diseases--to further develop and test processes, protocols, and tools for clinical assessment and care of people with undiagnosed diseases of all ages. Integrally connected to the clinical program, our bioinformatics team will bring to the UDN innovative bioinformatics tools to advance the power and the reach of genomic discovery. Our internationally recognized team has developed tools that integrate sequencing data with clinical and pedigree information (VAAST, GEMINI, RUFUS) to better find disease-causing variants. Importantly, some of these tools (IOBIO) are designed for clinicians without extensive bioinformatics background, to quicken the pace and expand the reach of state-of-the-art genetic testing beyond academic centers and into the community. To improve sustainability, we will refine and share our program's tools and care process models that integrate clinical and research workflows efficiently. In summary, the Intermountain West Clinical Site will bring the team, experience, resources, and institutional support to advance the shared goal of UDN – improve the diagnosis and management of difficult-to-diagnose and new diseases—efficiently, equitably, and sustainably.