No abstract

SUMMARY Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

We provide a systematic review of epidemiological surveys of autistic disorder and pervasive developmental disorders (PDDs) worldwide. A secondary aim was to consider the possible impact of geographic, cultural/ethnic, and socioeconomic factors on prevalence estimates and on clinical presentation of PDD. Based on the evidence reviewed, the median of prevalence estimates of autism spectrum disorders was 62/10 000. While existing estimates are variable, the evidence reviewed does not support differences in PDD prevalence by geographic region nor of a strong impact of ethnic/cultural or socioeconomic factors. However, power to detect such effects is seriously limited in existing data sets, particularly in low‐income countries. While it is clear that prevalence estimates have increased over time and these vary in different neighboring and distant regions, these findings most likely represent broadening of the diagnostic concets, diagnostic switching from other developmental disabilities to PDD, service availability, and awareness of autistic spectrum disorders in both the lay and professional public. The lack of evidence from the majority of the world's population suggests a critical need for further research and capacity building in low‐ and middle‐income countries. Autism Res 2012, 5: 160–179. © 2012 International Society for Autism Research, Wiley Periodicals, Inc.

Summary Given prior evidence for the contribution of rare copy number variations (CNVs) to autism spectrum disorders (ASD), we studied these events in 4,457 individuals from 1,174 simplex families, composed of parents, a proband and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, featuring a highly social personality. We identify rare recurrent de novo CNVs at five additional regions including two novel ASD loci, 16p13.2 (including the genes USP7 and C16orf72) and Cadherin13, and implement a rigorous new approach to evaluating the statistical significance of these observations. Overall, we find large de novo CNVs carry substantial risk (OR=3.55; CI =2.16-7.46, p=6.9 × 10−6); estimate the presence of 130-234 distinct ASD-related CNV intervals across the genome; and, based on data from multiple studies, present compelling evidence for the association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin1.