Project Summary This is an administrative supplement 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). This includes a full spectrum of service, teaching, and research activities spanning from adult, pediatric, and prenatal genetic clinical care, to gene discovery and study of disease mechanisms, to a leading medical genetics diagnostic laboratory joint venture (Baylor Genetics), to clinical training, to clinical treatment and trials, to community engagement. We propose to complete years' 1-8 work in year 9 of this “with cost extension” to be supported by this proposed administrative supplement. This includes completion of clinical evaluation of subjects accrued prior to June 30, 2022. We project that we will have accepted 280 subjects by that time, 25 above the total NIH milestone of 255 for our site during years 1-8. We will also complete the multi-omic analyses of our cohort. The functional studies will be advanced and transitioned to completion by other sources including both NIH and non-NIH supported mechanisms. We expect this work will lead to an approximately 20 addition manuscripts reporting new genotype-phenotype associations, phenotypic expansions, and phenotypic delineation of existing syndromes. The Specific Aims are to: 1) Complete multi-omic analyses, and functional/modeling studies in subjects accepted into the CS as part of milestones in years 1-8. 2) Complete clinical site evaluation, multi-omic analysis, functional studies on subjects accepted in year 8 prior to July 1, 2022 and those that are in addition to the target NIH milestone of years 1-8. 3) Develop transition plan for functional and modeling studies that are ongoing in support of above subject evaluations to funding mechanisms and projects outside of the UDN including within BCM the Neurological Research Institute, the Center for Skeletal Medicine and Biology, and Center for Precision Medicine Modeling.