ABSTRACT The introduction of clinical exome sequencing, whole genome sequencing, RNA sequencing, and metabolomics has transformed our ability to diagnose patients with suspected genetic disease. With the introduction of these technologies, a potential molecular DNA lesion can be identified in at least 25-30% of patients with a suspected genetic diagnosis. These technologies have also led to the discovery of hundreds of new disease genes and to phenotypic expansion within known genetic diagnoses. This continued discovery of new disease genes leads to structure, function and mechanistic discoveries that assist personalized approaches for management and therapy. However, up to 70% of patients with suspected genetic disease remain undiagnosed likely because their disease-causing variant(s) has yet to be discovered or the clinical significance of identified variants remains unclear. Precision models produced using various genome modification techniques in Drosophila melanogaster (fly) and Mus musculus (mouse) are important tools aiding in the interpretation of these variants of uncertain clinical significance and are critical for testing therapeutic paradigms. We will leverage the expertise, infrastructures, and established collaborations between the rare, Mendelian disease clinical and gene discovery programs; fly, mouse, and nonhuman primate animal modeling programs; and database infrastructure programs within the Department of Molecular and Human Genetics (DMHG) at the Baylor College of Medicine (BCM) to establish the BCM Center for Precision Medicine Modeling (BCPMM). The vision of our Center is to support local, national, and international programs and individual researchers in the development of precision models that will end the diagnostic odyssey of patients with undiagnosed, rare, and Mendelian diseases and serve as resources for pre-clinical studies investigating personalized medicine approaches to their care. We will achieve these goals by pursuing the following aims: (1) leverage existing multidisciplinary expertise within BCM to design, generate, and identify precision animal models for studies that answer clinical questions with impact on patient care; (2) conduct demonstration projects that showcase the Center’s capacity to model undiagnosed and rare diseases and to translate model organism findings back to patient care; (3) Engage human genome discovery programs, clinicians, and researchers to recruit disease-associated variant nominations for precision model studies within the Center; (4) Perform bidirectional translation of findings from precision animal models and from patient clinical studies for integration into clinical diagnostics, clinical care, or clinical trials; (5) Implement bioinformatics platforms that optimize Center disease modeling and organizational activities. Although our initial focus will build on our expertise in undiagnosed, rare, and Mendelian diseases, our long-term goal is to broaden our scope by establishing...