PROJECT SUMMARY. Individuals with Down syndrome (DS), the condition caused by trisomy 21 (T21), display an increased risk of developing co-occurring conditions such as congenital heart defects, autism spectrum disorders, seizure disorders, autoimmune conditions, and Alzheimer’s disease. Despite many research efforts, the mechanisms by which T21 causes these effects are yet to be defined. The clinical presentation of DS is highly heterogeneous, which could be driven by differences in genetic makeup, epigenetic mechanisms, or variations in the pathophysiology of DS revealed in multi-omics signatures. Furthermore, the impacts of T21 are likely modulated by sex, race/ethnicity, socio-economic status, lifestyle, and cultural background. Therefore, there is a clear need to develop a research infrastructure that could support a wide range of investigations by a multidisciplinary team of researchers. Accordingly, we propose to develop a Down Syndrome Biorepository (DS-Biorepository) by leveraging the infrastructure and expertise developed through well-established cohort studies of DS: the Human Trisome Project (HTP), the Alzheimer Biomarkers Consortium – Down Syndrome (ABC-DS), and the Down Syndrome Biobank Consortium (DSBC). In collaboration with other key stakeholders in the DS research community, we will accomplish the following Specific Aims: 1. Serve as the primary biorepository for biospecimens generated from INCLUDE-funded research. Building upon the infrastructure and available biospecimens obtained by the HTP, ABC-DS, and DSBC, we will develop a primary biorepository for all DS research funded by the NIH INCLUDE Project including blood-derived biospecimens, oral biospecimens, biopsies, urine, stool, amniotic fluid, cord blood, and post-mortem tissues, including brain tissue. These efforts will be informed by the proven pan-omics pipelines of the HTP and ABC-DS studies and by decades of collective experience in biobanking for DS research by all team members. 2. Coordinate the implementation of standard processes, protocols, and practices for biospecimen collection. Building upon the comprehensive catalogs of standard operating procedures developed by the HTP, ABC-DS, and DSBC studies, and in collaboration with other key stakeholders in the community, we will implement common protocols for biospecimen collection and processing across a vast network of research sites. 3. Develop a web-based interface to facilitate the search of publicly accessible biospecimens. Building upon the first-ever virtual biorepositories for DS research developed by our team members, we will develop a web-based interface to facilitate the identification of biospecimens based on sample type, demographic, and clinical information of participants, as well as existing datasets from the same samples. Together, these efforts will accelerate the pace of discoveries that benefit people with DS, while creating a high- quality lasting resource for future generations of DS researchers.

PROJECT NARRATIVE. People with Down syndrome display increased risk of developing diverse co-occurring conditions, but the mechanisms driving this unique clinical profile are yet to be defined. This project will develop a biobanking research infrastructure that could support a wide range of investigations by a multidisciplinary team of researchers through the collection of diverse biospecimens using harmonized protocols. These activities will greatly accelerate the pace of discoveries benefiting persons with Down syndrome.