Project Summary Genomic research presents a unique opportunity for molecular diagnosis of individuals with rare disease, which may empower precision therapies to alleviate the individual and public health burden of these conditions. However, minoritized populations remain underrepresented in rare disease genomic research, and optimal strategies to address this lack of representation remain poorly understood. The consequences of these knowledge gaps extend beyond the research realm and threaten the equitable provision of genomic medicine services in clinical practice. This project takes the critical next step towards further understanding, and ultimately breaking down, barriers to rare disease genomic research participation for historically underrepresented populations, in a hybrid type 3 effectiveness-implementation study design informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. A diversity, equity, and inclusion toolkit for genomic researchers will be developed and implemented within the Broad Institute’s Rare Genomes Project (Aim 1), with concurrent evaluation of multiple dimensions of effectiveness employing a mixed-methods approach (Aims 2 and 3). In Aim 1, stakeholder interviews will be conducted with both rare disease genomic research participants as well as providers who refer these participants to further explore barriers and facilitators of research engagement, with specific attention to study logistics and inclusive practices. This qualitative analysis will inform development and refinement of a toolkit comprising specific strategies portable to other environments to improve diversity, equity, and inclusion. This toolkit will then be implemented within the Rare Genomes Project in order to enroll a cohort of 200 participants who are historically underrepresented in rare disease genomic research, with concurrent evaluation of the following implementation outcomes: Reach, as reflected in the demographics of study participants; Adoption, as reflected in the characteristics of referring providers; and Implementation fidelity, as reflected in the proportion of participants who complete the study process from enrollment to sequencing. In Aim 2, Effectiveness of genome sequencing (GS) for this cohort of 200 participants will be evaluated, reflected in diagnostic and clinical utility, with analysis taking into account the impact of social and structural informants of health on these outcomes. In Aim 3, patient-centered utility of GS will be assessed both in this cohort as well as a larger, diverse cohort of rare disease genomic research participants to better assess longitudinal, multidimensional impact (Maintenance). This study will therefore generate utility data from a diverse population that provides real-world guidance regarding equitable applications of GS for rare disease diagnosis. Study results will inform strategies to improve access to GS and will identify key areas of clinical impact in or...