Overall Project Abstract For the third cycle of the Intellectual and Developmental Disabilities Research Center at Washington University, we propose a next phase in a comprehensive approach to understanding, ameliorating, and/or preventing neurodevelopmental disability through translational scientific investigation at the respective levels of cell, synapse, circuit, and behavior, capitalizing upon major strengths of WUSTL in genomics, behavioral/cognitive neuroscience, and clinical-translational science. The overarching goals of our Center are as follows: (1) To sustain and evolve an integrated structure of core scientific facilities that occupy a critical niche in the scientific community, attract and support highly-qualified investigators, and facilitate high-caliber, translational research on the pathogenesis and treatment of IDDs. In this application we propose specific enhancements to each of our scientific core facilities: an expanded technical team for the Developmental Neuroimaging Core, a dedicated cellular models unit within the Model Systems Core (methods calibrated with a cross-IDDRC working group for cellular models of IDD co-led by the IDDRC@WUSTL), and a new clinical trials / natural history studies unit within the Clinical-Translational Core (CTC). The CTC will continue to facilitate the collection and interpretation of genomic, phenotypic, environmental and biomarker data across generations, and promote step-wise translation of new discoveries on risk and pathogenesis to higher-impact interventions for patients. The IDDRC@WUSTL will provide critical infrastructure for research efforts that have created synergies with other intramural and extramural Centers/Institutes, including a newly-funded in-depth longitudinal study of infants born to mothers enrolled in the March of Dimes Prematurity Research Center Cohort, the launch of a prospective replication cohort for the Infant Brain Imaging Study of Autism (IBIS), two multisite initiatives in Down Syndrome, and an NIH Autism Center of Excellence Network in gene discovery. (2) To cultivate nodes of new interdisciplinary scientific activity within the Center, in frontiers of IDD research which are critical for the derivation of higher-impact treatment and preventive intervention, along the Center’s four major themes: (i) the prevention of prematurity and its neurodevelopmental consequences; (ii) the identification of intermediate phenotypes in the development of IDD; (iii) structural and functional characterization of the developing human brain, and (iv) functional genomics relevant to IDD pathogenesis. In this cycle we will build on prior successes in cultivating a dynamic, interactive, and productive community of scientists engaged in IDD-science, challenging itself to generate and harness new knowledge toward translational advances in therapeutics and prevention. (3) To conduct a signature research project that represents a bold, critical step toward higher-impact intervention for IDD. In this project, a novel platform for standardizing multi-omic characterization of the consequences of variation in gene dosage will be implemented across dozens of isogenic cell lines, each representing haploinsufficiency in a different high-confidence IDD-related gene, to identify convergent mechanisms of IDD.

Overall Project Narrative Intellectual and Developmental Disabilities adversely affect 1 in 6 U.S. children and their families. The IDD Research Center at the Washington University School of Medicine (IDDRC@WUSTL) is a program that comprises three scientific core facilities, one dedicated to exploration of cellular and molecular mechanisms of causation in model systems of IDD, one dedicated to the identification of “signatures” of developmental disability through imaging of the developing brain, and one dedicated to specifying behavioral and genomic atypicalities in patients and translating new understanding of causal mechanisms into higher impact intervention.