The North Carolina Clinical Genomic Evaluation by Next-generation Exome Sequencing 2 (NCGENES 2) study will generate evidence regarding the clinical utility of genomic sequencing as a first-line diagnostic test using a prospective randomized controlled trial that compares usual care plus exome sequencing to usual care. Patient-reported data, electronic health records data, and administrative claims data will be used to evaluate defined health outcomes, to address pressing questions about the utility of exome sequencing. Furthermore, we will examine communication between patients and physicians, and between physicians and laboratories, and how these critical interactions affect the utility of genomic sequencing. We will incorporate a second, nested randomized trial (crossed with exome sequencing in a full-factorial design) to test the hypothesis that a theory-based, multi-component pre-clinic preparation intervention for patients will improve patient-centered outcomes. An “embedded ELSI” component will provide feedback to providers regarding communication discrepancies to iteratively improve care. Finally, we will address the challenges of integrating clinical data and genomic information across a state-wide network of sites and examine different models of interaction between genomic clinicians and molecular diagnostic laboratorians.