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      Genetic research in autism spectrum disorders

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Purpose of review

          The recent explosion of genetic findings in autism spectrum disorder (ASD) research has improved knowledge of the disorder's underlying biology and etiologic architecture. This review introduces concepts and results from recent genetic studies and discusses the manner in which those findings can influence the trajectory of ASD research.

          Recent findings

          Large consortium studies have associated ASDs with many types of genetic risk factors, including common polygenic risk, de novo single nucleotide variants, copy number variants, and rare inherited variants. In aggregate, these results confirm the heterogeneity and complexity of ASDs. The rare variant findings in particular point to genes and pathways that begin to bridge the gap between behavior and biology.

          Summary

          Genetic studies have the potential to identify the biological underpinnings of ASDs and other neuropsychiatric disorders. The data they generate are already being used to examine disease pathways and pathogenesis. The results also speak to ASD heterogeneity and, in the future, may be used to stratify research studies and treatment trials.

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          De novo gene disruptions in children on the autistic spectrum.

          Ivan Iossifov, Michael Ronemus, Dan Levy … (2012)
          Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Association between microdeletion and microduplication at 16p11.2 and autism.

            Lauren A Weiss, Yiping Shen, Joshua M. Korn … (2008)
            Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Copyright 2008 Massachusetts Medical Society.
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              The role of de novo mutations in the genetics of autism spectrum disorders.

              Dan Levy, Michael Ronemus, Michael Wigler … (2014)
              The identification of the genetic components of autism spectrum disorders (ASDs) has advanced rapidly in recent years, particularly with the demonstration of de novo mutations as an important source of causality. We review these developments in light of genetic models for ASDs. We consider the number of genetic loci that underlie ASDs and the relative contributions from different mutational classes, and we discuss possible mechanisms by which these mutations might lead to dysfunction. We update the two-class risk genetic model for autism, especially in regard to children with high intelligence quotients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Curr Opin Pediatr
                Journal ID (iso-abbrev): Curr. Opin. Pediatr
                Journal ID (publisher-id): COPED
                Title: Current Opinion in Pediatrics
                Publisher: Lippincott Williams and Wilkins
                ISSN (Print): 1040-8703
                ISSN (Electronic): 1531-698X
                Publication date (Print): December 2015
                Publication date (Electronic): 11 November 2015
                Volume: 27
                Issue: 6
                Pages: 685-691
                Affiliations
                [a ]Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston
                [b ]Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT
                [c ]Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA
                Author notes
                Correspondence to Elise B. Robinson, Stanley Center for Psychiatric Research, Broad Institute, 75 Ames Street, Cambridge, MA 02142, USA. Tel: +1 617 714 7543; fax: +1 617 800 1764; e-mail: erob@ 123456broadinstitute.org
                Article
                Accession ID: 00006
                DOI: 10.1097/MOP.0000000000000278
                PMC ID: 4650984
                PubMed ID: 26371945
                SO-VID: fbb0801a-4934-421a-8e8e-adc81eb6f633
                Copyright © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
                License:

                This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by-nc-nd/4.0

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                Subject: GENETICS: Edited by Nathaniel H. Robin
                Custom metadata
                OPEN-ACCESS TRUE

                Keywords: autism,exome sequencing,genetics,gwas
                Data availability:
                Keywords: autism, exome sequencing, genetics, gwas

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