PROJECT SUMMARY. People with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display a unique clinical profile across the lifespan. Early on, children with DS present stunted growth and neurodevelopmental delays. Later in life, adults with DS experience an atypical form of accelerated ageing. Furthermore, they also experience a differential clinical risk profile, marked by high risk of congenital heart defects, leukemias, autism spectrum disorders, seizure disorders, autoimmune conditions, and Alzheimer’s disease, among others. Therefore, research efforts investigating the mechanisms by which T21 causes the hallmarks of DS, as well as the factors that modify these effects, will accelerate discoveries to improve health outcomes in this population. Within this context, in 2016 we launched the Human Trisome Project (HTP), a natural history of study of DS, including deep annotation of clinical metadata, cognitive phenotyping, a multidimensional biobank, and generation of -omics datasets. The HTP has enrolled >1150 participants, >750 with T21, from all around the USA. The HTP was one of the first studies that released data in INCLUDE Data Hub, including unpublished multi-omics datasets and its biospecimen catalog. Despite these important efforts, the potential of the HTP remains unfulfilled, as it does not capture the massive diversity of the global community with T21. Therefore, we propose to develop an international component for the INCLUDE Project through the following Specific Aims: 1. To develop a network of research sites across Latin America. Led by a polyglottal and multicultural team at the Linda Crnic Institute for Down Syndrome, we recently launched the HTP – Latin America Network to support research activities in México, Colombia, Brazil, Argentina, and Chile. Each Latin America site provides massive expertise through decades of managing the largest DS clinics in their respective countries, while also contributing populations of unparalleled racial, ethnic, and cultural diversity. 2. To define the clinical and neurodevelopmental profile of Latinos with Down syndrome. Although Latinos are the fastest growing segment of the population with DS in the USA, little is known about potential differences in their developmental and clinical profiles. Therefore, we propose to complete a comprehensive annotation of demographic information, social determinants of health, co-occurring conditions, and lifestyle factors. 3. To identify biosignatures associated with differential features of Latinos with Down syndrome. We will complete a multi-omics investigation of the variable pathophysiology of DS in the Latino population, including analyses of the genome, transcriptome, proteome, metabolome, immune system, and microbiome to define associations between differential developmental and clinical features and underlying biological processes. Altogether, our efforts will provide unmatched diversity to the INCLUDE Project in terms of the ...