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      Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

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      1 , 2 , 3 , * , 4 , 2 , 5 , 5 , 4 , 4 , 6 , 7 , 5 , 2 , 8 , 5 , 5 , 2 , 2 , 7 , 7 , 1 , 1 , 9 , 10 , 3 , 8 , 11 , 12 , 13 , 13 , 12 , 14 , 15 , 1 , 16 , 17 , 18 , 13 , 19 , 20 , 5 , 21 , 22 , 1 , 4 , 6 , 7 , 16 , 5 , 21 , *
      PLoS Genetics
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          Abstract

          The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls ( p = 2.3×10 −5). Less is known about MDGA2, likewise observed to be case-specific ( p = 1.3×10 −4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10 −39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

          Author Summary

          Autism spectrum disorders (ASDs) are common neurodevelopmental syndromes with a strong genetic component. ASDs are characterized by disturbances in social behavior, impaired verbal and nonverbal communication, as well as repetitive behaviors and/or a restricted range of interests. To identify genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. To enrich for variants most likely to interfere with gene function, we restricted our analyses to deletions and gains encompassing exons. Of the many genomic regions highlighted, 27 were seen to harbor rare variants in cases and not controls, both in the first phase of our analysis, and also in an independent replication cohort comprised of 859 cases and 1,051 controls. More work in a larger number of individuals will be required to determine which of the rare alleles highlighted here are indeed related to the ASDs and how they act to shape risk.

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          Most cited references49

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          DAVID: Database for Annotation, Visualization, and Integrated Discovery.

          Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.
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            Structural variation of chromosomes in autism spectrum disorder.

            Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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              Advances in autism genetics: on the threshold of a new neurobiology.

              Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                June 2009
                June 2009
                26 June 2009
                : 5
                : 6
                : e1000536
                Affiliations
                [1 ]Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, California, United States of America
                [2 ]Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [3 ]Penn Center for Bioinformatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [4 ]Department of Neurology, University of California Los Angeles, Los Angeles, California, United States of America
                [5 ]Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
                [6 ]Department of Psychiatry, University of California Los Angeles, Philadelphia, Pennsylvania, United States of America
                [7 ]Center for Autism Research, Semel Institute for Neuroscience and Behavior, University of California Los Angeles, Los Angeles, California, United States of America
                [8 ]Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [9 ]Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America
                [10 ]Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, Maryland, United States of America
                [11 ]Department of Psychiatry, University of Iowa, Iowa City, Iowa, United States of America
                [12 ]Department of Psychiatry, University of Utah, Salt Lake City, Utah, United States of America
                [13 ]Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, United States of America
                [14 ]Department of Psychiatry, Indiana University, Indianapolis, Indiana, United States of America
                [15 ]Department of Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [16 ]Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America
                [17 ]Department of Psychiatry and Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
                [18 ]Center for Molecular Neuroscience and Vanderbilt Kennedy Center, Vanderbilt University, Vanderbilt University, Nashville, Tennessee, United States of America
                [19 ]Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, United States of America
                [20 ]Seaver Autism Center for Research and Treatment, Departments of Psychiatry, Neuroscience, Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
                [21 ]Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [22 ]Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                The University of Queensland, Australia
                Author notes

                Conceived and designed the experiments: MB BSA KW DHG HH. Performed the experiments: BSA LIS CK. Analyzed the data: MB BSA KW JTG EIH MI DH JPB NBG IL JK ML RMC SFAG. Contributed reagents/materials/analysis tools: AIAR TH MS VK CML AS THW WMM TO JAS HC JIN NJM JSS EHC GD JDB GDS. Wrote the paper: MB BSA KW SFAG DHG HH.

                Article
                09-PLGE-RA-0571R3
                10.1371/journal.pgen.1000536
                2695001
                19557195
                c6459cd8-0798-4dd5-9870-3df770bf976b
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 7 April 2009
                : 22 May 2009
                Page count
                Pages: 12
                Categories
                Research Article
                Genetics and Genomics/Genetics of Disease

                Genetics
                Genetics

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