Program Director/Principal Investigator (Last, First, Middle): ABSTRACT Undiagnosed diseases are collectively common, affecting ~30 million Americans. With the vast majority (85%) of undiagnosed diseases believed to have underlying genetic causes, the utilization of exome sequencing (ES) and to a lesser extent, whole genome sequencing (GS) has resulted in diagnosis rates of 25-40%. In Phases I and II of the undiagnosed diseases network (UDN), the Duke/Columbia clinical site has been able to capitalize upon both of these technologies as well as deep phenotyping and innovative bioinformatics, with an overall diagnosis rate of ~41%, and a ~28% diagnostic rate in patients with prior ES that had been non-diagnostic. We have also demonstrated that parents of children with undiagnosed diseases have high rates of anxiety and depression and have developed a survey to measure patients' and parents expectations and utilization of genome sequencing results. Beyond work at our site, the team has contributed to UDN policies, has established successful collaborations, and has been active in key network leadership positions. With an already established infrastructure and successful outcomes, we are well positioned to continue this work for the next year and to sustain it beyond. Our aims are: (1) Comprehensively evaluate 15 patients annually with undiagnosed diseases. We will capitalize on our site's experience to streamline medical record review without compromising the application review process, offer telehealth as a way to mitigate the need to travel to the UDN. We will evaluate patients in any specialty, use phenotypic data to aid genome interpretations, and effectively communicate results to patients and their families with genetic counseling. We will also explore factors underlying low participation in the UDN by patients from rural and medically underserved areas. (2) Analyze the ES and GS of patients to provide diagnoses and use RNA Sequencing as an adjunct when ES/GS does not provide a diagnosis. We will adopt optical genome mapping in selected GS negative patients. (3) Prospectively examine genomic healthcare empowerment due to genomic sequencing. This will be the first study to provide data on the change in genomic healthcare empowerment with sequencing results. (4) Participate in network activities, including utilizing common protocols, share data, continue collaborative activities, provide leadership and implement our plan for long-term sustainability of the UDN. We have all the capabilities required to be a successful clinical site for Phase III of the UDN, to achieve the goal of evaluating patients with undiagnosed diseases and improve the health and well-being of the patients and their families. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

Project Narrative Undiagnosed diseases are a public health problem that cause patients and families medical, psychological and financial distress. In Phase I and 2, we made diagnoses in ~41% of patients at our clinical site. In Phase III, we plan to increase the number of diagnoses for new and existing UDN patients to improve the well-being of the patients and their families and to work towards continuing the UDN beyond 2024.