There is definitive evidence that rare mutations, including spontaneous, or de novo, structural variations, contribute to autism spectrum disorders. However, recent findings highlight important remaining areas for investigation. Approximately six to ten percent of families in the Simons Simplex Collection (SSC) carry large multi-genic de novo copy-number variants (CNVs), those most clearly associated with autism risk. This suggests that higher-resolution detection of de novo point mutations and insertions or deletions may lead to discovery of multiple additional bona fide autism risk genes. The findings also highlight the question of whether these CNVs carry risk as a consequence of being large and therefore more likely to encompass a critical gene, or because they simultaneously disrupt multiple coding or regulatory units. Whole-exome sequencing is an ideal way to pursue these questions: to explore the genome for rare autism-related de novo and transmitted mutations that disrupt proteins, to evaluate whether multiple de novo events in the same individual increase risk, and to determine whether de novo and transmitted point mutations begin to clarify the nature of the risk posed by large multi-genic CNVs. This project represents a collaboration among the labs of Matthew State, Evan Eichler and Daniel Geschwind. The goal is to carry out whole-exome sequencing and analysis of 400 SSC families. The researchers plan to evaluate 200 SSC trios — including parents and affected child — at the University of Washington in Seattle, and 200 SSC quartets, including an unaffected sibling in each pedigree, at Yale University. Geschwind’s team at the University of California, Los Angeles, aims to develop bioinformatics tools for integrated analysis with other types of genomic and transcriptomic data.