Autism impairs the early development of social, emotional and communication functions, but the early neural defects that cause this disorder remain a mystery due to the near absence of genetic, molecular and cellular studies of the young autistic brain. Because prefrontal cortex plays an important role in these early developmental functions and displays abnormal growth and function during the first years of life in autism, we performed a detailed analysis of the structural organization of prefrontal cortex in the youngest postmortem autistic cases available. We discovered that young autistic males consistently display abnormal architecture in prefrontal cortex that occurs in discrete patches (roughly 1cm by 1cm), this is undeniably of very early developmental origin, and is likely to be the neural defect that causes autism. Moreover, using whole genome analyses of gene expression of prefrontal cortex in these same young autistic cases we also discovered evidence of dysregulation of early developmental processes, including cell proliferation, cell death, cell cycle regulation and DNA damage repair. This suggests that autism may result from alterations in these early developmental processes that can lead to the formation of patches of abnormally organized cortex. We propose several next steps to further investigate cortical patches in autism and test this theory that local alterations can lead to a cortical patch phenotype. We will (1) determine how common these abnormalities are across ages, gender and level of functioning in autism, (2) determine if they are commonly found in multiple cortical regions, (3) analyze the structural and genetic properties of cells in these abnormal regions, and (4) develop animal models that replicate these changes. Understanding the mechanisms that cause these patches will lead to new methods for determining early risk and prognosis and may lead to new therapies for autism.