The funding will assist HMS in its efforts to build upon the foundation provided by the Undiagnosed Diseases Network. The UDN is committed to maintaining and expanding the network after the legislative mandated expiration of NIH Common Fund support on June 30, 2022. There are important questions of great scientific and societal interest that the UDN provides a good platform to explore but does not itself answer. HMS will seek to address questions insufficiently addressed by current UDN efforts. This project will focus on three areas: (1) increasing representation of patients from underserved communities and rapidly growing immigrant populations, (2) bridging the divide between diagnosis of rare or novel disease-causing mutations in individuals and find effective therapies, and (3) creating an ”orphan diseases molecular machines” initiative, which will pipeline a gene-to-structure effort to uncover molecular functions for the genes mutated in monogenic diseases identified by the UDN.