PROJECT SUMMARY The proposed Baylor College of Medicine Mendelian Genomics Research Center (BCM-MGRC) builds on the extensive discoveries and infrastructure established in the Baylor Hopkins Center for Mendelian Genomics. This research program is nested within the Department of Molecular and Human Genetics at BCM and will benefit from an extensive collaborative research infrastructure which includes, the Human Genome Sequencing Center, the Undiagnosed Diseases Network Clinical Site, the Undiagnosed Diseases Network Model Organism Screening Center, Baylor Genetics diagnostic laboratory, and the Baylor Knockout Mouse Program. Notably, each of these programs has established their own national and international collaborations. A phenotypically and ethnically diverse, international cohort of ~15,000 individuals and families with challenging-to-diagnose rare disease conditions (those unsolved by routine clinical studies such as exome sequencing) and who are re-contactable and consented for broad data-sharing will form the basis of the BCM- MGRC research program. The Center will integrate novel methods of genomic data analysis, data sharing across networks, implementation of newer genomic sequencing technologies, and methods for molecular and organismal phenotypic interrogation of prioritized candidate disease genes and variants. The existing Data Lake infrastructure will integrate with the Mendelian Genomics Data Coordinating Center (MGDCC) and AnVIL to share key deliverables including genomic and phenotypic data, case metadata, and a BCM-MGRC- developed Genomic Medicine Toolbox. As a fully integrated Mendelian Genomics Research Center, the BCM- MGRC will inform development and delivery of an algorithm for solving the unsolved that will tackle complex molecular mechanisms in the rare and common disease research space, with seamless integration of anticipated discoveries to support clinical diagnostics and the generation of molecular floorplans from which to develop precision therapeutics.