PROJECT SUMMARY/ABSTRACT Down syndrome (DS) is the most common genetic cause of intellectual disability (ID). Though all individuals with DS have the same underlying etiology, an extra copy of chromosome 21, the severity of ID can vary widely, from mild to severe, across individuals. Specifically, wide individual variation has been shown for intelligence quotient (IQ), language, and adaptive behavior. Given the impact of these domains on learning and daily functioning, it is important to capture and characterize this variability to guide development of interventions that maximize functional ability across the lifespan. This R03 will perform secondary analyses on two existing data resources to address two important aspects of understanding variability in ID across individuals with DS. In Aim 1, we will compile data captured across multiple cohorts with a collective sample size of 561 children with DS to analyze performance on the Kaufman Brief Intelligence Test 2 (KBIT-2), a commonly used instrument to measure IQ. This measure is ideal for large-scale research studies and clinical trials as it only takes about 20 minutes to administer. However, due to floor effects, the KBIT-2 is not a sensitive measure of abilities in children with severe ID. We aim to characterize performance on the KBIT-2 in children with DS to determine the extent of floor effects, including whether floor effects have a bigger impact in subgroups of children with DS defined by domains such as age, as well as calculate norms that could be used for DS-specific standardize scoring. The results of this aim can be used to guide future research and clinical trials. In Aim 2, we will leverage existing whole genome sequencing data in a cohort of children with DS to identify shared genetic variation among subgroups of children with DS defined by similar patterns of cognition and adaptive behavior. The results of the Aim 2 analyses will generate new hypotheses about the biological pathways associated with variability in cognition and behavior across individuals with DS. This proposal completely aligns with the goals of the INLCUDE project. Our goals and those of the INCLUDE project are to identify potential intervention targets in order to facilitate precision medicine approaches to improve quality of life for individuals with DS across the lifespan.