Autism spectrum disorders ASDs) are characterized by many differences in their presentation, severity, and comorbidities. ASDs have also been associated with several different types of genetic risk factors. The purpose of this project is to link differences in case presentation to differences in genetic architecture, with the ultimate goal of identifying more homogeneous groups of individuals with ASDs for research and treatment studies. We focus on two types of genetic variation that have been associated with ASDs. First, de novo variants, genetic variants that occur spontaneously and are not seen in an affected individual's parents. Second, inherited genetic risk for schizophrenia, bipolar disorder, and depressive disorders, psychiatric conditions that have been linked to ASDs through genetic or family history analyses. Using the Simons Simplex Collection SSC) data set, we will test whether behavioral and medical traits that are sometimes seen with ASDs predict: a) the rate of de novo variation in ASD cases and b) the role of inherited risk for psychiatric disease, assessed both through family history and directly measured genetic risk. We will also examine whether individuals with de novo mutations in genes that are particularly sensitive to mutation have average differences in case presentation. These analyses will capitalize on the SSC's unique combination of detailed medical and behavioral data, in conjunction with its advanced genetic profiling of its participants and their families. Taken together, the project aims to provide important clarification regarding diversity in ASDs and create a path towards more targeted research and treatment strategies.