BCM CENTER FOR PRECISION MEDICINE MODELS

1. ABSTRACT - Overall 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 30% of patients with a suspected genetic diagnosis. These technologies have led to the discovery of thousands of new disease genes and to phenotypic expansion within known genetic diagnoses. This continued discovery of new disease genes leads to mechanistic studies 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) have yet to be discovered or the clinical significance of identified variants is unclear. Critically, even when genetic testing is diagnostic, 90-95% of rare genetic disorders have no therapy. 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. The Center for Precision Medicine Models (CPMM) was established to aid researchers, clinicians, genetic counselors, patients, and family organizations in the study of precision animal models of undiagnosed, rare, and Mendelian diseases. Our goal has been to use our models to end the diagnostic odyssey and advance personalized medicine approaches for the millions of people around the world affected by rare genetic diseases. To achieve this goal, CPMM has generated and phenotyped precision fly and mouse models of human disease- associated genetic variants submitted by the rare disease community. CPMM has received 124 submissions for modeling, encompassing 175 unique variants in 120 different genes, and accepted 52 nominations involving 68 variants in 51 genes. Our modeling has contributed to the discovery of new disease genes and phenotypic expansion and is testing new treatment strategies. We propose to continue and expand our efforts by pursing the following aims: (1) Leverage existing multidisciplinary expertise harnessed by the CPMM and use cutting- edge genome modification and phenotyping approaches to generate and characterize precision animal models that answer clinical questions with impact on patient care; (2) Engage human genome discovery programs, including those that focus on populations underrepresented in research, as well as clinicians, researchers, families, and patient organizations to recruit disease-associated variant nominations for precision model studies within the Center; (3) Perform bidirectional translation of findings from precision animal models and patient clinical studies for integration into clinical diagnostics, clinical care, or clinical trials; (4) Enhance and develop new bioinformatics platforms that optimize Center disease modeling and organizational activities. Although the focus of CPMM builds on our expertise in undiagnosed, and rare Mendelian diseases, our long-term goal is to broaden our scope by modeling multigenic and common diseases.