Project Summary The Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) Clinical Site (CS) has successfully advanced the objectives of phase I and II UDN. We established a high throughput integrated pipeline for patients with undiagnosed diseases (UDD) to access a state-of-the-art diagnostic, clinical, and molecular evaluation. We led extramural UDN clinical sites in number of patient acceptances and in person evaluations, while being one of four sites to achieve 100% for completed phase II evaluations. We developed innovative approaches including RNA sequencing-directed analyses that led us to achieve a diagnostic rate for solved and strong candidate genes in 51% of cases completed to date. Finally, we engaged the UDN and the broader scientific/lay community in sharing best practices, collaborative discovery, and education. This was achieved by leveraging the integrated genetic and genomic program that is the Department of Molecular and Human Genetics (DMHG) at BCM. The Department is a combination of basic science, clinical, and molecular pathology departments. Because these are consumed under one organizational unit, we have rapidly translated discovery to practice and served as a nexus for the research community at BCM, the Texas Medical Center, and nationally. The leadership of the DMHG in genetic and genomic medicine at BCM has ensured the integration of the partnering Departments of Pediatrics, Internal Medicine, and Neurology into phase I and II of the BCM UDN CS. In phase III we propose to apply this integrated approach to achieve the new and ongoing objectives of the UDN. The BCM UDN CS leadership includes established clinical investigators in Genetics, Pediatrics, Medicine, and Neurology who will lead a primary team while drawing from consultants in partner Departments institution-wide. Clinical delineation and subsequent DNA molecular diagnosis will leverage both established (Human Genome Sequencing Center and Baylor Genetics laboratory) and BCM UDN CS-specific bioinformatics pipelines. The interpretation and ultimate functional study of genomic data will flow to specialized organ-based research centers of excellence including NIH programs including KOMP and CPMM. For sustainability, BCM has 1) established and financially support a Center for Undiagnosed Diseases that leverage 3rd party payor support for standard of care, philanthropy for research studies, and institutional support, 2) leveraged a DMHG-developed virtual platform for medical genetics care delivery platform (Consultagene.org) to increase efficiency, decrease cost, and expand access for patient and provider engagement, 3) translate research tools to the clinical diagnostic arena, i.e., Baylor Genetics laboratory and low cost WGS and deep RNAseq with Ultima Genomics, 4) focus on engagement and recruitment of underserved and underinsured populations leveraging existing NIH funded projects within the DMHG (NHGRI Texome and NCATS Project GIVE), and 5) widely disseminate patient variants to stimulate collaboration with basic scientists for functional studies.

Project Narrative This proposal describes the continuation of an Undiagnosed Diseases Network (UDN) Clinical Site at Baylor College of Medicine as a regional and national referral site for clinical evaluation of undiagnosed disease with focus on virtual engagement and under-served and under-insured populations.