Project Summary / Abstract Undiagnosed diseases take a disproportionate toll on the health care system and on affected patients and families. The UCLA Clinical Site of the UDN has successfully participated in the formation and management of the UDN through UDN Steering Committee, Working Groups, UDN meetings, and innovation in genomic analysis. We propose here to recruit, select, evaluate, and follow at least 15 participants in the project period, and abide by all UDN guidelines. We will specifically recruit individuals from health disparity populations. We will work with the UDN Coordinating Center to review and accept cases for evaluation at UCLA with a special emphasis on disorders related to: neurology, neurodevelopment, hemihypertrophy, cancer predisposition, neuromuscular, cardiomyopathy, immunology, gastroenterology, or genetic diseases. We will maximize the use of telemedicine, remote assessments, and performance of directed clinical tests within medical systems available to participants (i.e., in network care providers). The UCLA Clinical site will coordinate activities to obtain comprehensive and integrated phenotypic information and augment this with research testing, genomic analysis not covered by insurance, and advanced genomic interpretation of non-coding DNA through transcriptomic assessments within the UCLA UDN Clinic in a sustainable manner. Our proposal addresses the overarching goals of the UDN as an integrated research enterprise within clinical practice to identify the causes of undiagnosed diseases by 1) collecting standardized, high-quality phenotypic data on rare disease patients 2) improving the efficiency of diagnosis through relevant medical records review/team discussion, and integration with transcriptomics to improve interpretation of genomic sequencing, and 3) working within the overall UDN to promote integration of data across its network to enhance understanding of rare diseases and mechanisms. 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 and refine a network-wide sustainable infrastructure for translational research on new and rare disorders.

Project Narrative Patients with undiagnosed diseases, that is, with longstanding symptoms that have not been diagnosed despite extensive clinical investigation, suffer from a costly, time-consuming, and psychologically taxing approach to their diagnosis, with uncertain outcomes and a high financial burden on the health care system. The sequencing of many human genomes, both with and without rare genetic disease has revolutionized the practice of genetic medicine, as large amounts of genomic information can be integrated together and resolve if and what genetic variants contribute to rare and undiagnosed diseases. Our UDN Clinical Site integrates state-of-the-art clinical and laboratory investigations with improvements in genomic analysis across the UDN to improve diagnosis and management of disease.