The Department of Molecular and Human Genetics (DMHG) at Baylor College of Medicine (BCM) is an integrated Department housing the full spectrum of service, teaching, and research activities spanning from adult and pediatric genetics clinical care, to gene discovery and the study of disease mechanisms, to medical genetics diagnostic laboratory and clinical training, and to clinical treatment and trials. Because these activities are consumed under one organizational unit, we have been able to rapidly move discovery to practice, and to serve as a nexus for the research community at BCM, the Texas Medical Center, and nationally. An outgrowth of these activities is centers of excellence best exemplified by the Human Genome Sequencing Center (HGSC) that has driven clinical discoveries in undiagnosed disease. The leadership of the DMHG in the comprehensive practice of genetic medicine at BCM will help to ensure the integration of the partnering Departments of Pediatrics, Internal Medicine, and Neurology into the BCM Undiagnosed Disease Network (UDN) Clinical Site (CS). We propose to apply this integrated approach to achieve the objectives of the Undiagnosed Disease Network. The medical and research activities of the DMHG and its partner Departments are situated within the Texas Medical Center (TMC) and serve a regional, national, and international referral base including the Gulf Coast, the Southwest US, and Central and South America. As such, we are well positioned within a national recruitment and referral strategy. From the perspective of retention, Houston is a central hub of transportation facilitating travel to the clinical site. The BCM UDN CS will use the Institute for Clinical and Translational Research (ICTR) which coordinates the collaborative clinical translational research efforts among Baylor College of Medicine (BCM), Rice University, Texas Children's Hospital (TCH), the Michael E. Debakey Veterans Affairs Medical Center (MEDVAMC), Harris Health Systems (HS) for underinsured care, and St. Luke's Hospital (SLH). The BCM UDN CS leadership includes established clinical investigators in Genetics, Pediatrics, Medicine, and Neurology. They will lead a primary team of investigators housed in Medical Genetics with emphasis on areas of excellence and then draw upon consultants in partner Departments and institution-wide. Clinical delineation and subsequent DNA molecular diagnosis will leverage both an established Medical Genetics Laboratory bioinformatics pipeline as well as a research pipeline based in the Center for Mendelian Genomics. The interpretation and ultimate functional study of genomic data will flow to specialized organ-based research centers including the Center for Skeletal Medicine and Biology/Bone Disease Program of Texas (led by Dr. Brendan Lee), the Duncan Neurological Research Institute (led by Dr. Huda Zoghbi), and the Cardiovascular Research Institute (co-directed by Dr. John Belmont). The BCM UDN CS builds upon a strong established foundation of rare disease delineation, gene discovery, mechanistic study, and their clinical translation to therapy.