Project Summary / Abstract Undiagnosed diseases take a disproportionate toll on the health care system and on affected patients and families. This second Administrative Supplement for 08/05/22-06/30/23 for the UCLA Clinical Site of the UDN is specifically to support re-initiation of ongoing recruitment, case evaluations pre-acceptance, determination of acceptance, and enrollment/consenting of the affected individual and relevant family members as well as clinical evaluation using the sustainable clinic approach with data return and wrap-up for 15 new UDN participants. This proposal is organized relative to a concurrent administrative supplement without budgetary overlap. We are poised to restart enrollment by 09/01/22, and complete evaluations by 6/30/22. This funding will allow the UCLA clinical site to cover research related costs for new enrollees. Our sustainable clinic model at UCLA will use the administrative supplement to provide for some of the costs associated with basic and clinical data collection related to the new enrollments, and clinical evaluations will be billed to patient insurance. This results in an improved diagnostic process for undiagnosed diseases. Investigating rare diseases involving multiple systems and incorporating comprehensive genomic data into clinical care creates considerable challenges, from the interpretation of vast amounts of genetic variants to their relevance to the symptoms, to the communication issues linked to their disclosure, and to their impact on clinical management. The Second Administrative Supplement of the UCLA Clinical Site of the UDN will support the ongoing communications with applicants, review of medical records, case discussion, acceptance decisions and communications, case evaluation at UCLA by telemedicine or in person within UCLA Health clinics and with insurance billing and patient co-pay, with coverage of research structure and research testing from NIH funds including a combination of a previously approved Administrative Supplement, this second supplement request, and a carryforward request from prior year unobligated balance. We continue to reach these overarching goals by implementing the following specific aims: Aim 1: Implement a UDN clinic model that functions locally and network-wide; Aim 2: Investigate the clinical phenotypes of new and rare disorders; Aim 3: Investigate the underlying mechanisms of new and rare disorders; Aim 4: Build a network-wide sustainable infrastructure for translational research on new and rare disorders