This application seeks to renew our highly productive and interdisciplinary UCLA Autism Center of Excellence (ACE III). Over the last decade, our group has made significant advances in the field, identifying risk genes, candidate brain based biomarkers of treatment response and early risk markers of Autism Spectrum Disorder (ASD) beginning in the first few weeks of life. We developed new interventions for toddlers with social communication delays, identified an intervention with the most robust effects on repetitive behaviors to date, and we showed how genetic risk influences brain structure and function in ASD. Most unique and impactful is our Center's integration of genetics, early biomarkers and behavioral assays with intervention In parallel with growing awareness in the field, we recognize the profound clinical and genetic heterogeneity in ASD, which poses a significant challenge to identifying diagnostic biomarkers and to developing effective interventions that target individual profiles. In order to move from a “one size fits all” to a “precision medicine” approach, we must better understand the biological and clinical basis of this heterogeneity. Our ACE application takes a multidisciplinary, integrative approach to study the relationship between genetic, neural and phenotypic heterogeneity in ASD, to determine whether this heterogeneity reflects unique biological mechanisms underlying autism, and to identify predictors of developmental trajectories and treatment outcome. In four interacting projects, we will focus on three areas of heterogeneity that our work suggests has unique neural, genetic and behavioral signatures: sensorimotor processing social attention/motivation, and social communication/language. Project I aims to determine how differences in genetic risk for autism (familial risk, 22q11deletion, and Tuberous Sclerosis Complex (TSC) affect early brain development, neuroimaging and EEG biomarkers in the first year of life and identifying predictors of ASD diagnosis at age 3; P. II examines heterogeneity in treatment response using a SMART design, 3-phase adaptive treatment intervention for very young children at risk for ASD; P. III uses MRI in youth with ASD to determine how behavioral phenotypes and genetic risk differentially affect brain activation, structural and functional connectivity. P. IV conducts a proof-of- mechanism pharmacological trial aimed to increase social interest and social reward responsivity with the dopamine precursor L-DOPA in adolescents and young adults enrolled in a social skills intervention.. All projects examine these target phenotypes using at least one biological marker, in addition to standardized and observational tests. This will allow us to integrate biomarkers, genetics and behavior across projects and across ages. A well-established core infrastructure centralizes diagnostics, genetics, imaging, and EEG acquisition, with a common database built for cross project and core collaboration, an...