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      Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

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          Abstract

          Evidence for the etiology of autism spectrum disorders (ASD) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity 1, 2 . We sequenced the exomes of 20 sporadic cases of ASD and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, of which 11 were protein-altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4/20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A, and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 mutation and provide functional support for a multihit model for disease risk 3 . Our results demonstrate that trio-based exome sequencing is a powerful approach for identifying novel candidate genes for ASD and suggest that de novo mutations may contribute substantially to the genetic risk for ASD.

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          Most cited references35

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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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              Large recurrent microdeletions associated with schizophrenia.

              Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                17 May 2011
                15 May 2011
                June 2011
                01 December 2011
                : 43
                : 6
                : 585-589
                Affiliations
                [1 ] Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
                [2 ] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
                [3 ] Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
                [4 ] Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands
                [5 ] Howard Hughes Medical Institute, Seattle, WA, USA
                Author notes
                [* ]Corresponding authors: Evan E. Eichler, Ph.D., University of Washington School of Medicine, Howard Hughes Medical Institute, Foege S413C, 3720 15th Ave NE, Box 355065, Seattle, WA 98195, Phone: (206) 543-9526, eee@ 123456gs.washington.edu . Jay Shendure, M.D., Ph.D., Department of Genome Sciences, University of Washington, Foege S210A, 3720 15th Ave NE, Box 355065, Seattle, WA 98195, (206) 685-8543, shendure@ 123456uw.edu
                Article
                nihpa290937
                10.1038/ng.835
                3115696
                21572417
                e24555a8-56ce-4084-af33-46c160641692

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                History
                Funding
                Funded by: National Institute of Child Health & Human Development : NICHD
                Award ID: R01 HD065285-02 || HD
                Funded by: Howard Hughes Medical Institute :
                Award ID: || HHMI_
                Categories
                Article

                Genetics
                Genetics

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