ABSTRACT Although gene panels and exome and genome sequencing (GS) have enabled molecular diagnosis for many rare disease patients, a significantly large proportion of these patients remain undiagnosed. A combination of clinical expertise, advanced genomic and multi-omic technologies and efficient computational tools is needed for higher diagnostic yield. Lack of insurance or denial of test reimbursement by insurance further negatively impacts rare disease patients from underprivileged and economically weak backgrounds, making it critical to improve the outreach and diversity in rare disease study cohorts. The Center for Undiagnosed Diseases (CUD) at Stanford will continue our efforts toward sustainability, refinement of methods, and integration with regular clinical practice. Here, we propose a program of study that will (1) facilitate accurate diagnosis of patients with undiagnosed diseases, with emphasis on those without or with limited insurance or economical or language barriers; (2) use novel approaches in data analysis and integration of different ‘omes to improve diagnostic rates; and (3) enhance our understanding of the impact of diversity on the diagnostic process. In Aim 1, we propose to triage and enroll patients, complete clinical evaluations and associated work. This will include pre- visit chart review and genetic counseling followed by an individualized visit during which standardized phenotypic and environmental data are collected. Biosamples facilitate genomic, multi-omic, and cellular evaluation of disease. We will apply novel computational approaches for systematic integration of genomic, transcriptomic, metabolomic, and phenotypic data with the entire medical literature to improve diagnostic yield. We will continue our efforts to seek diagnosis using available resources for all participants. In Aim 2, we will focus on increasing participant diversity, engagement, and advocacy. This will be accomplished by expanding our local patient advocacy partnerships, including a local UDN PEER group. We aim to increase applications from underrepresented and underinsured patients through regional outreach to safety net hospital systems and providers. Further, our streamlined evaluations will increase access to underserved participants. Finally, we will prioritize onboarding multilingual staff to enhance participant experience.