SUMMARY A rare disease is a condition that affects fewer than 200,000 people in the United States or 1 in 2,000 individuals in the general population. There are approximately 7000 distinct rare diseases, creating a substantial collective public health burden. Approximately 80% of rare diseases are genetic, and molecular diagnosis is essential for the management, treatment, and development of therapy. In Indiana there are several barriers to identification of rare disease and access to care: Indiana is a state that has a longstanding history of being underserved for genetics services; there is a large rural population; the education level is in the bottom quartile among states and the median income level is also in the bottom echelon. We have outstanding expertise in rare disease within the state, but it is geographically concentrated. For all these reasons, we recognize that while genetics holds the promise of improving health outcomes, it also may serve to widen health inequity. Our development of the Indiana Collaborative for Undiagnosed Rare Disease is based on the concept that we must be inclusive in our approach to rare disease to implement access to care and diagnostics that will significantly impact statewide health. Our collaborative team also includes experts in urban medicine, community-based participation in research, and health inequity. Our central goal is to improve the health of Indiana by improving recognition, access, and diagnostic evaluation for patients at risk for rare diseases. Using a multi-omics approach that combines genome sequencing (GS), transcriptomics, metabolic testing, and proteomics with deep phenotyping, we will leverage the resources and expertise of our collaborative network. We propose to overcome the barriers/challenges to improving undiagnosed rare disease by 1) consolidating statewide rare disease expertise, leveraging our UDN Diagnostic center of excellence; 2) partnering with communities and experts in health care disparity to develop a novel toolkit to screen patients at risk for rare disease and to implement telehealth NICU genomics screening using a toolkit already piloted at IU and found to have high sensitivity and specificity for the detection of genetic disease; and 3) developing innovative approaches to rare disease discovery and training including technologies aimed at improving the post-exome/genome diagnosis rate. We will use Long-Read Sequencing, proteomics, Massively Parallel Reporter Assays, and collaborations with internal and external resources to accomplish this.