Genetic architecture in autism spectrum disorder

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Autism spectrum disorder (ASD) is characterized by impairments in reciprocal social interaction and communication, and by restricted and repetitive behaviors. Family studies indicate a significant genetic basis for ASD susceptibility, and genomic scanning is beginning to elucidate the underlying genetic architecture. Some 5–15% of individuals with ASD have an identifiable genetic etiology corresponding to known chromosomal rearrangements or single gene disorders. Rare (<1% frequency) de novo or inherited copy number variations (CNVs) (especially those that affect genes with synaptic function) are observed in 5–10% of idiopathic ASD cases. These findings, coupled with genome sequencing data suggest the existence of hundreds of ASD risk genes. Common variants, yet unidentified, exert only small effects on risk. Identification of ASD risk genes with high penetrance will broaden the targets amenable to genetic testing; while the biological pathways revealed by the deeper list of ASD genes should narrow the targets for therapeutic intervention.

Section snippets

Autism spectrum disorder (ASD)

Autism spectrum disorder (Figure 1) is a lifelong developmental condition that affects about 1 in 110 individuals [1], with onset before the age of three years. It is characterized by abnormalities in communication, impaired social function, repetitive behaviors and restricted interests [2]. The presentation of autistic features is variable, with symptoms ranging from mild to severe, sometimes with poor clinical outcomes. These individuals vary greatly in cognitive development, with some who

ASD: genetically heterogeneous

As we shall discuss, various genes certainly have an important role in ASD, and there has been incremental progress toward their identification, enhancing clinical definition and diagnostic tools [3, 15, 16, 17, 18].

Future investigation

As documented above, de novo genetic variation has an important role in risk for an ASD phenotype. From an evolutionary perspective, this is unsurprising because interest in reproductive success is typically low in individuals with autism, such that genetic variants would be subject to negative selection. If inherited variation were to contribute significantly in ASD risk, it would need to be shielded, at least partly, from this selection [90]. Possible mechanisms include sex-differential

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors wish to thank Anath C. Lionel for assistance. BD is supported by MH057881. SWS holds the GlaxoSmithKline Canadian Institutes of Health Research (CIHR) Endowed Chair in Genome Sciences.

References (100)

  • C.S. Leblond et al.

    Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders

    PLoS Genet

    (2012)
  • A.K. Vaags et al.

    Rare deletions at the neurexin 3 locus in autism spectrum disorder

    Am J Hum Genet

    (2012)
  • B.H. Chung et al.

    Severe intellectual disability and autistic features associated with microduplication 2q23.1

    Eur J Hum Genet

    (2012)
  • A.T. Pagnamenta et al.

    Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability

    J Med Genet

    (2011)
  • Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN,...
  • R. Anney et al.

    A genome-wide scan for common alleles affecting risk for autism

    Hum Mol Genet

    (2010)
  • A.A. Scott-Van Zeeland et al.

    Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2

    Sci Transl Med

    (2010)
  • Y. Sakai et al.

    Protein interactome reveals converging molecular pathways among autism disorders

    Sci Transl Med

    (2011)
  • Autism and Developmental Disabilities Monitoring Network

    Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, 2006

    MMWR Surveill Summ

    (2009)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition—Text Revision (DSMIV-TR)

    (2000)
  • J.H. Miles et al.

    Autism spectrum disorders

  • C. Gillberg et al.

    Brief report: “the autism epidemic”. The registered prevalence of autism in a Swedish urban area

    J Autism Dev Disord

    (2006)
  • S. Steffenburg et al.

    A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden

    J Child Psychol Psychiatry

    (1989)
  • A. Bailey et al.

    Autism as a strongly genetic disorder: evidence from a British twin study

    Psychol Med

    (1995)
  • A. Le Couteur et al.

    A broader phenotype of autism: the clinical spectrum in twins

    J Child Psychol Psychiatry

    (1996)
  • P. Szatmari et al.

    Genetics of autism: overview and new directions

    J Autism Dev Disord

    (1998)
  • J.N. Constantino et al.

    Sibling recurrence and the genetic epidemiology of autism

    Am J Psychiatry

    (2010)
  • R.E. Rosenberg et al.

    Characteristics and concordance of autism spectrum disorders among 277 twin pairs

    Arch Pediatr Adolesc Med

    (2009)
  • S. Ozonoff et al.

    Recurrence risk for autism spectrum disorders: a baby siblings research consortium study

    Pediatrics

    (2011)
  • J. Hallmayer et al.

    Genetic heritability and shared environmental factors among twin pairs with autism

    Arch Gen Psychiatry

    (2011)
  • S. Folstein et al.

    Infantile autism: a genetic study of 21 twin pairs

    J Child Psychol Psychiatry

    (1977)
  • M. Losh et al.

    Defining key features of the broad autism phenotype: a comparison across parents of multiple- and single-incidence autism families

    Am J Med Genet B Neuropsychiatr Genet

    (2008)
  • D.T. Miller et al.

    Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies

    Am J Hum Genet

    (2010)
  • P. Walsh et al.

    In search of biomarkers for autism: scientific, social and ethical challenges

    Nat Rev Neurosci

    (2011)
  • M.W. State et al.

    The conundrums of understanding genetic risks for autism spectrum disorders

    Nat Neurosci

    (2011)
  • C. Betancur

    Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting

    Brain Res

    (2011)
  • J. Xu et al.

    Molecular cytogenetics of autism

    Curr Genomics

    (2004)
  • C.R. Marshall et al.

    Structural variation of chromosomes in autism spectrum disorder

    Am J Hum Genet

    (2008)
  • Y. Shen et al.

    Clinical genetic testing for patients with autism spectrum disorders

    Pediatrics

    (2010)
  • B.A. Nowakowska et al.

    Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies

    Eur J Hum Genet

    (2012)
  • P. Baker et al.

    Brief report: duplication of chromosome 15q11–13 in two individuals with autistic disorder

    J Autism Dev Disord

    (1994)
  • B.S. Abrahams et al.

    Advances in autism genetics: on the threshold of a new neurobiology

    Nat Rev Genet

    (2008)
  • E.H. Cook et al.

    Copy-number variations associated with neuropsychiatric conditions

    Nature

    (2008)
  • A.K. Merikangas et al.

    Copy-number variants in neurodevelopmental disorders: promises and challenges

    Trends Genet

    (2009)
  • C. Lee et al.

    The clinical context of copy number variation in the human genome

    Expert Rev Mol Med

    (2010)
  • P. Szatmari et al.

    Mapping autism risk loci using genetic linkage and chromosomal rearrangements

    Nat Genet

    (2007)
  • S.L. Christian et al.

    Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder

    Biol Psychiatry

    (2008)
  • J.T. Glessner et al.

    Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

    Nature

    (2009)
  • M. Bucan et al.

    Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes

    PLoS Genet

    (2009)
  • J.A. Rosenfeld et al.

    Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders

    Genet Med

    (2010)
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