Tuberous Sclerosis (TS) is one of the best established causes of autism spectrum disorder (ASD), with about 50% of children with TS developing ASD. Despite this, there are very few data regarding the architecture of autistic behaviors in TS or the similarities and differences in the manifestations of ASD in TS compared to idiopathic ASD. The data on the risk factors for ASD in TS are also limited, inconsistent and entirely based on retrospective studies. This project will build on the first ever prospective longitudinal study of the natural history of TS (The TS 2000 Study) by undertaking detailed cognitive and behavioral assessments in the cohort of 125 children at 5+ years old. Parallel assessments of the unaffected siblings and extant data from studies of children with ASD due to unknown cause, as well as typically developing children, will be used to answer some key questions about the nature and the basis of the association between TS and ASD. Specifically, the study will determine whether TS carries an increased risk just for ASD or also for the Broader Autism Phenotype and related traits. The pattern of behavioral and cognitive (Theory of Mind, Central Coherence, emotion recognition) impairments in children with TS+ASD will be compared and contrasted to the impairments characterizing idiopathic ASD. In addition, the genetic, neurobiological and cognitive risk factors and markers for ASD in TS will be examined. This study represents the largest most comprehensive and systematic investigation of the association between TS and ASD yet undertaken and it promises to answer key unresolved issues and provide a road map of the risk processes linking the genetic abnormality to the brain changes and cognitive/behavioral impairments. This study will establish the first fully worked out model of the pathways linking gene-brain-mind on the road to ASD. The map and the study methodology will provide the autism research field with a model that can be used to in future investigations to determine the extent to which paths to ASD are shared or different to those leading to ASD in TS.