Project Summary This is an administrative supplement 2 for the Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) Clinical Site (CS). In years 1-8 of the UDN CS, we provided patients with undiagnosed diseases (UDD) access to state of the art diagnostic methods, accelerated discovery in diagnosing and managing UDD, elucidated biological mechanisms of identified genetic variants in disease causation, leading to potential pathways for improved treatments, and actively engaged the UDN and broader community to share best practices and technology innovations. We have been among the leading extramural (non NIH UDP) sites in patient acceptances and completion of in person evaluations, achieving 100% target for these two key milestones of the program. Of the cases with in-person evaluations completed to date, we have achieved a 36% solve rate with an additional 12% with strong candidates. We have implemented systematic RNA sequencing on fibroblasts to complement exome and genome sequencing. We have achieved this by leveraging an integrated genetics program housed within the Department of Molecular and Human Genetics (DMHG). We propose to complete years' 1-8 work in year 9 of this second “with cost extension” to be supported by this proposed administrative supplement. This includes completion of clinical evaluation of subjects accrued prior to July 1, 2022. We project that we will accept an additional 10 subjects and have completed evaluation of 10 additional by end of year 9 (June 30, 2022). The Specific Aims are to: 1) Review, recruit, and evaluate 10 new subjects referred by the UDN coordination center as part of the ongoing NIH UDN protocol. 2) Integrate this UDN workflow into the broader BCM-specific UDN sustainability plan which is to establish a streamlined standard operating procedure for the Undiagnosed Diseases Center (UDC) at BCM. 3) Prioritize under/uninsured and under-represented populations for UDN evaluation by leveraging existing programs with the same focus for referral and recruitment.