Recent studies have indicated that humans have an exceptionally high per-generation mutation rate of 7.6 × 10–9 to 2.2 × 10–8. These spontaneous germline mutations can have serious phenotypic consequences when affecting functionally relevant bases in the genome. In fact, their occurrence may explain why cognitive disorders with a severely reduced fecundity, such as mental retardation, remain frequent in the human population, especially when the mutational target is large and comprises many genes. This would explain a major paradox in the evolutionary genetic theory of these disorders. In this presentation, I will describe our recent work on using a family-based exome sequencing approach to test this de novo mutation hypothesis in ten patients with unexplained mental retardation [1]. Unique nonsynonymous de novo mutations were identified and validated in nine genes. Six of these, identified in different patients, were likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. The clinical relevance of these novel genes, and the ultimate proof that they cause disease, lies in the identification of de novo mutations in additional patients with a similar phenotype. As such, we are currently screening approximately 1,200 patients with unexplained mental retardation for mutations in YY1, which is one of these newly identified genes. In addition, we are extending our family-based exome sequencing approach to 100 patients to establish the diagnostic yield for de novo mutations in patients with unexplained mental retardation. These findings, when replicated, provided strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population. In my presentation, I will explain this work, as well as related work on autism [2] and schizophrenia [3].