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Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1 -4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5 -9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11 , 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10 −3 ). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10 −3 ). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10 −6 ). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.ASDs, including autism, are neurodevelopmental disorders characterized by impairments in social and communication skills, as well as stereotyped and repetitive behaviours and/or a restricted range of interests. Current prevalence estimates in the United States are 0.1-0.2% for autism and 0.6% for ASDs 1,2 .Linkage and candidate gene association studies have implicated several chromosomal regions in autism 3,4 . However, positive findings in one study often fail to replicate in other studies, and a consistent picture of susceptibility loci in autism is still lacking. Some telling clues about ASD genetics arose from recent studies on CNVs 5 , including the association of de novo CNVs with ASDs 6 . Although de novo CNVs that disrupt specific genes may contribute to the pathogenesis of ASDs, heritable CNVs are much more common but have been less studied as risk factors of ASDs. A family-based genome-wide linkage and CNV analysis by the Autism Genome Project Consortium using Affymetrix 10K single nucleotide polymorphism (SNP) arrays implicated chromosome 11p12-13 and neurexin 1 (NRXN1) as candidate loci 7 . A study using the Affymetrix 500K SNP array in a Canadian population reported 277 rare CNVs that were only observed in ASD patients but not in 1,652 healthy controls or in the Database of Genomic Variants 8 . Furthermore, 16p11.2 deletions and Glessner et al.Page 2 Nature. Author manuscript; available in PMC 2010 August 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscri...

This study investigated social attention impairments in autism (social orienting, joint attention, and attention to another's distress) and their relations to language ability. Three- to four-year-old children with autism spectrum disorder (ASD; n = 72), 3- to 4-year-old developmentally delayed children (n = 34), and 12- to 46-month-old typically developing children (n = 39), matched on mental age, were compared on measures of social orienting, joint attention, and attention to another's distress. Children with autism performed significantly worse than the comparison groups in all of these domains. Combined impairments in joint attention and social orienting were found to best distinguish young children with ASD from those without ASD. Structural equation modeling indicated that joint attention was the best predictor of concurrent language ability. Social orienting and attention to distress were indirectly related to language through their relations with joint attention. These results help to clarify the nature of social attention impairments in autism, offer clues to developmental mechanisms, and suggest targets for early intervention.

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We are performing whole genome sequencing (WGS) of families with Autism Spectrum Disorder (ASD) to build a resource, named MSSNG, to enable the sub-categorization of phenotypes and underlying genetic factors involved. Here, we report WGS of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible in a cloud platform, and through an internet portal with controlled access. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertion/deletions (indels) or copy number variations (CNVs) per ASD subject. We identified 18 new candidate ASD-risk genes such as MED13 and PHF3, and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (p=6×10−4). In 294/2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried CNV/chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.