Yale Diagnostic Center of Excellence for Undiagnosed Diseases

SUMMARY Undiagnosed disease remains a major burden for millions of Americans and their families. Here, we propose the Yale Diagnostic Center of Excellence (YDCoE) as a new site for the Undiagnosed Diseases Network (UDN). The YDCoE builds on the outstanding track record of human genetics, next generation sequencing (NGS) and rare disease discovery at Yale over many decades. To expand access to the UDN, we will partner with multiple community healthcare organizations that provide services for poor individuals who are under/uninsured, all of whom see >90% patients belonging to racial and ethnic minority groups. These partnerships are mutually beneficial, as the YDCoE will provide training and education opportunities in undiagnosed and rare diseases for these organizations. We will work with the DMCC to develop an enrollment plan that utilizes a tiered evaluation strategy. Our highly efficient clinical evaluation approaches and infrastructure will allow us scale clinical capacity to engage more participants over time, a significant portion of which will be covered by community and third-party payer support. For patients who remain without a diagnosis, we will leverage our extensive expertise in NGS approaches, cutting-edge bioinformatics and functional genomics – including in vivo and MPRA approaches - to increase diagnostic yield. Finally, we will conduct additional site-specific studies to enhance clinical evaluation efficiency, enrollment and patient experience. These include novel machine learning approaches to extract clinical information from EHR for more efficient evaluation and diagnoses, an augmented enrollment approach for uniquely vulnerable individuals, and a novel tool to measure patient-reported measures of discrimination in care. We have further secured additional institutional and industry support, which will allow us to prioritize NIH funds for under/uninsured patients. Altogether, our in-house clinical genetics operations together with our extensive network of community and industry partnerships, our expertise in NGS and bioinformatics innovation, our innovative track record in rare disease discovery and the vast clinical knowledge base across multiple specialties at YSM to form a DCoE that is fully equipped to engage a diverse cohort of underserved patients at an unprecedented clinical scale.