Abstract The last decade of clinical progress in intellectual and developmental disabilities (IDD)—which affect one in six individuals in the U.S.—has been characterized by unprecedented advances in understanding the nature and complexity of genetic susceptibility to IDD. Rare copy number and sequence variants are now known to account for a major share of population-attributable risk for IDD, and are being identified in over 30% of individuals who undergo clinical genomic sequencing. Clinical identification of pathogenic variants has generated major translational opportunities to accelerate discovery and improve clinical treatment, but these opportunities are constrained by serious gaps in our understanding of how to estimate the pathogenicity of a given genetic abnormality in an individual patient. This U01 Collaborative Innovation Award of the Clinical and Translational Science Award (CTSA) Program addresses this major roadblock, capitalizing upon the fact that genomic information is now commonly acquired in clinical settings and substantially subsidized by U.S. health insurers. Ensuring that clinically-acquired sequencing data of IDD patients is systematically integrated with standardized information on neurobehavioral variation and clinical course (this is currently uncommon) stands to accelerate understanding of the relationship between genetic variation and disease. The aims of this program are to establish standards for feasible neurobehavioral characterization of IDD patients in clinical health systems across the CTSA Network, to integrate phenotypic and clinical genomic characterization of patients to directly promote progress in the national agenda for IDD gene and variant curation, and to establish a dynamic, state-of-the-art IDD patient registry, as an extension of NCAT’s Center for Data To Health (CD2H) Initiative. This registry will be designed to co-register phenotypic, genotypic, and electronic health record data on brain imaging, EEG, laboratory biomarkers, and clinical course, for the purpose of specifying nuanced profiles of risk, resilience, and intervention response, and to elucidate both common and rare pathogenic mechanisms in IDD. Once established, the CTSA-IDD Registry will constitute a self-perpetuating open science platform for translational advances in IDD, by providing major new opportunity for patients affected by individually-rare IDD conditions to be identified by qualified scientists and clinicians, to be sub grouped according to genetic or phenotypic profile, and to participate in focused discovery efforts, clinical trials, and/or innovations in personalized intervention specific to their conditions.