Undiagnosed diseases and rare diseases occur without respect to age, geography, socioeconomic status or level of education. They are frustratingly hard to define scientifically and to classify, yet rare diseases affect 30 million people in the USA and the undiagnosed are as yet uncounted. Referrals to the CHOP/UPENN UDN reflect a larger catchment area than just the four-state geographical region and reflect the inherent dichotomy of the undiagnosed and rare disease patient populations. Our UDN program has a mature collaborative approach to address the needs of the undiagnosed patient population and we are poised to grow through improved workflows and computational approaches. This application proposes three Aims to serve additional patients beyond the expectation of our original allocation. Aim 1 describes our overall diagnostic approach and changes we will implement in enrollment and evaluation workflows. In Aim 2, we describe new diagnostic strategies, focusing on improved bioinformatics. In Aim 3, we describe our long term sustainability plans and transition to this new model. We have been seeing patients in the Clinical and Translational Research Center, named Center for Human Phenomic Science (CHPS), which facilitates a standardized approach and we have developed a template for a narrow data capture to more easily define the key phenotypes. The newly envisioned workflow incorporates a tiered approach to diagnostics. Patients will have next generation sequencing, metabolomics, and/or immunology testing prior to being seen, reasoning that some diagnoses can be easily made in this way and thus streamlining the patient experience. Those that remain unsolved will have deep phenotyping and a multi-omics approach to diagnosis. Our Clinical Site has valuable expertise and has been successful in achieving diagnosis for nearly a quarter of the patients. Our future model is informed heavily by our current UDN practices and will additionally incorporate opportunities to streamline genomic analytic methods, interfacing with ongoing efforts at our institutions to incorporate the “omics” mindset more fully into the diagnostic journey. Our sustainability model will also improve diversity, sharing technology infrastructure and computational methods, accelerating outreach and dissemination approaches, and interfacing more widely with the research community for variant and gene validation. We have the promise of institutional funds and are poised to grow our program to accommodate more patients, improve the demographic diversity, improve the patient diagnostic diversity, and use the UDN model to improve clinician proficiancy with technologic approaches to diagnosis.

PROJECT NARRATIVE Undiagnosed Diseases Network Clinical Site will focus on the diagnosis of patients using innovative approaches to facilitate data capture, data analysis, and to improve training in the field of rare diseases. With two new patient outreach efforts, we will improve diversity. During the year of funding, we will transition to a self-sustaining model, ultimately using institutional funding.