ABSTRACT/SUMMARY Down syndrome (DS) is one of the most common genetic syndromes, with a birth prevalence of 1 in 700 that has been increasing in recent years. Children with DS encounter many adverse health outcomes including 1) structural birth defects – which are associated with significant morbidity and mortality; 2) abnormal hematopoiesis – which infers a 20-fold increased risk of acute leukemia; and 3) neurodevelopmental disorders – which significantly impact functional independence and quality of life. However, there are important gaps in our understanding: 1) inter-individual variability exists among children with DS in relation to these phenotypes that cannot be fully explained; 2) the natural history of these phenotypes among children with DS has not been comprehensively evaluated, limiting health supervision guidelines and targets for intervention; and 3) children with DS, particularly those from underrepresented minorities, have often been excluded from participation in research that could improve their outcomes. In this application, we seek to address these gaps in knowledge. Specifically, in response to RFA-OD-24-003 (Down Syndrome Cohort Research Sites for the INCLUDE Project), we propose to leverage the Texas Birth Defects Registry (TBDR) – one of the world’s largest and most diverse population-based active birth defects surveillance systems – to develop the Down syndrome Early Childhood Omics, Deep phenotyping, and Epidemiology In Texas: DECODE IT Cohort. As part of DECODE IT, we will recruit an ethnically and geographically diverse birth cohort of children with DS with the objectives of 1) conducting deep phenotyping and 2) collecting biospecimens for omics assessments. Our research team is uniquely poised to develop this population-based cohort of children with DS. We bring expertise in DS research and recruitment (Lupo and Rasmussen), DS-related birth defects (Agopian), DS-associated hematopoiesis (Rabin), and neurodevelopment in children with DS (Jacola). Furthermore, we have an extensive record of collaborations. Therefore, we propose the following aims: 1) recruit children with DS to the DECODE IT Cohort; 2) Conduct deep phenotyping on children with DS enrolled in DECODE IT – with a particular emphasis on structural birth defects, hematopoietic development, and neurodevelopment; 3) Prospectively collect biospecimens on children with DS enrolled in DECODE IT for biomarker and omics studies. IMPACT: Through DECODE IT we will establish a large population-based cohort (N=1,000 children with DS) that will provide the necessary foundation for propelling our understanding, prediction, and prevention of associated adverse health outcomes in children with DS.