Elsevier

Behavioural Brain Research

Volume 251, 15 August 2013, Pages 95-112
Behavioural Brain Research

Review
Autism genetics

https://doi.org/10.1016/j.bbr.2013.06.012Get rights and content

Highlights

  • Autism spectrum disorder has strong, complex and heterogeneous genetic underpinnings.

  • The phenotypic expression of these genetic components is also highly variable.

  • All autism genes are also involved in intellectual disability, and several in other disorders like schizophrenia.

  • Autism genetics includes syndromic forms, CNVs or point mutations, mitochondrial forms and polygenic autisms.

  • Genome-wide association studies and whole-exome sequencing have recently provided valuable contributions to the field.

Abstract

Autism spectrum disorder (ASD) is a severe neuropsychiatric disease with strong genetic underpinnings. However, genetic contributions to autism are extremely heterogeneous, with many different loci underlying the disease to a different extent in different individuals. Moreover, the phenotypic expression (i.e., “penetrance”) of these genetic components is also highly variable, ranging from fully penetrant point mutations to polygenic forms with multiple gene–gene and gene–environment interactions. Furthermore, many genes involved in ASD are also involved in intellectual disability, further underscoring their lack of specificity in phenotypic expression. We shall hereby review current knowledge on the genetic basis of ASD, spanning genetic/genomic syndromes associated with autism, monogenic forms due to copy number variants (CNVs) or rare point mutations, mitochondrial forms, and polygenic autisms. Finally, the recent contributions of genome-wide association and whole exome sequencing studies will be highlighted.

Introduction

Since the first description of autism in 1943 by Leo Kanner, who defined “enclosure in one's self” as the distinctive trait shared by a cohort of eleven children [1], extraordinary advances have been achieved in understanding the physiopathology underlying this complex disorder. Autism, the prototypic pervasive developmental disorder (PDD), is characterized by onset prior to 3 years of age and by a triad of behavioral signs and symptoms, including (a) hampered verbal and non-verbal communication, (b) lack of reciprocal social interaction and responsiveness, and (c) restricted, stereotypical, and ritualized patterns of interests and behavior [2], [3]. Autism spectrum disorder (ASD) is a broader diagnostic category, encompassing autistic disorder as well as the less severe Asperger Disorder (AD) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). ASD will be the single diagnostic category adopted by DSM-V, although DSM-V criteria may not consistently detect AD and PDD-NOS as part of ASD [4]. Finally, the “broad autism phenotype” includes individuals with some signs and symptoms of autism, not meeting full criteria for ASD [5]. Collectively, these diagnostic categories and their change over time clearly speak to the difficulty in categorizing deficits in social cognition which are dimensional and quantitative in real life, rather than categorical [6].

ASD is characterized by striking clinical heterogeneity, seemingly underlied by an equally impressive degree of etiological heterogeneity. Researchers have so far aimed to address this great heterogeneity following two complementary strategies, the analysis of endophenotypes and genetic studies. Endophenotypes are familial and heritable quantitative traits associated with a complex disease and able to identify subgroups of patients possibly sharing homogeneous pathophysiological underpinnings [7]. The best established endophenotypes in autism research have been reviewed elsewhere [8]. On the other hand, autism has conclusively been recognized as the neuropsychiatric disorder with the greatest genetic component, due to monozygotic twin concordance rate as high as 73–95%, extraordinary heritability (>90%, as estimated by twin studies), and a noticeable sibling recurrence risk (5–6% for full-blown autistic disorder, approximately 15–25% for broad ASD) [9]. These heritability estimates, obtained mainly in the UK and in Northern Europe in the early 1990s, were recently confuted by a twin study undertaken on a California twin sample, compatible with a larger proportion of variance explained by shared environmental factors as opposed to genetic heritability (55% vs. 37% for strict autism, respectively) [10]. Conceivably, the relative weight of genetic and environmental factors may be region-specific and could be changing over time, as less severe forms of the disease are increasingly diagnosed within the spectrum. However, the related increase in sibling recurrence risk, estimated by recent baby sibling studies at 18.7% (26.2% for males and 9.1% for females) [11], and the presence of mild autistic traits in many first-degree relatives of patients with autism [5] still indicate a strong genetic component in ASD. Linkage and association studies have identified numerous susceptibility genes, located on various chromosomes, especially 2q, 7q, 15q and on the X chromosome. The clinical heterogeneity of ASD is thus believed to at least partly reflect the complexity of its genetic underpinnings, whose general underlying mechanisms include different modes of inheritance and gene–environment interactions. Here we will review the genetics of ASD moving from monogenic forms to the most recent contributions provided by genome-wide association and whole-exome sequencing studies.

Section snippets

Monogenic autisms

Autism can be part of a known genetic syndrome. This instance occurs in approximately 10% of all ASD cases, it is typically associated with malformations and/or dysmorphic features (“syndromic” autism) and, unlike “idiopathic” or “primary” ASD, it shows an equal male:female sex ratio [12], [13], [14].

Well-known genetic or genomic disorders can encompass autistic features in their clinical presentation, such as fragile X syndrome, tuberous sclerosis, neurofibromatosis, untreated phenylketonuria,

Non-syndromic autism: the role of common variants

In a complex disease like autism, it is conceivable that functional common polymorphisms can confer vulnerability or protection. Thus, according to Falconer's threshold model [141], a host of unfavourable common variants could even cause a disease phenotype, either directly, or by lowering the sensitivity threshold to the point of conferring pathogenicity to widespread environmental agents. This scenario is supported by several recent studies, demonstrating, for example, a moderate to high

Recent advances in the genetics of autism spectrum disorder: the impact of whole-exome sequencing

Traditional approaches for gene mapping from candidate gene studies to positional cloning strategies have been applied for Mendelian disorders. Since 2005, next-generation sequencing (NGS) technologies are improving as rapid, high-throughput and cost-effective approaches to fulfil medical sciences and research demands [163]. Whole-exome sequencing (WES) has recently been introduced to identify rare or novel genetic defects from genetic disorders. Particularly, ASD is a model disease to apply

Conclusions

The latest advances in the field of autism genetics highlight the striking complexity of its underlying pathophysiology. It is expected that high-throughput molecular screenings, such as high resolution array-CGH, whole-exome and whole-genome sequencing, as well as transcriptomic analysis, will further increase our understanding of the genetic underpinnings of ASD. Specific rare genetic variants have been convincingly shown to cause autism, at least in some cases. However, genotype–phenotype

Acknowledgments

The authors gratefully acknowledge all the patients and families who participated in our studies, and financial support by the Italian Ministry for University, Scientific Research and Technology (PRIN n.2006058195 and n.2008BACT54_002), the Italian Ministry of Health (RFPS-2007-5-640174 and RF-2011-02350537), the Fondazione Gaetano e Mafalda Luce (Milan, Italy), Autism Aid ONLUS (Naples, Italy), Autism Speaks (Princeton, NJ), the Autism Research Institute (San Diego, CA), and the Innovative

References (276)

  • S.J. Sanders et al.

    Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism

    Neuron

    (2011)
  • D. Levy et al.

    Rare de novo and transmitted copy-number variation in autistic spectrum disorders

    Neuron

    (2011)
  • S.R. Gilman et al.

    Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses

    Neuron

    (2011)
  • C. Betancur et al.

    The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders

    Trends in Neurosciences

    (2009)
  • A.M. Craig et al.

    Neurexin–neuroligin signaling in synapse development

    Current Opinion in Neurobiology

    (2007)
  • I.P. Fabrichny et al.

    Structural analysis of the synaptic protein neuroligin and its β-neurexin complex: determinants for folding and cell adhesion

    Neuron

    (2007)
  • P. Scheiffele et al.

    Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons

    Cell

    (2000)
  • K. Gerrow et al.

    A preformed complex of postsynaptic proteins is involved in excitatory synapse development

    Neuron

    (2006)
  • A.A. Chubykin et al.

    Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism

    Journal of Biological Chemistry

    (2005)
  • R. Moessner et al.

    Contribution of SHANK3 mutations to autism spectrum disorder

    American Journal of Human Genetics

    (2007)
  • D. Sato et al.

    SHANK1 deletions in males with autism spectrum disorder

    American Journal of Human Genetics

    (2012)
  • K. Ichtchenko et al.

    Neuroligin 1: a splice site-specific ligand for beta-neurexins

    Cell

    (1995)
  • T. Vrijenhoek et al.

    Recurrent CNVs disrupt three candidate genes in schizophrenia patients

    American Journal of Human Genetics

    (2008)
  • A.K. Vaags et al.

    Rare deletions at the neurexin 3 locus in autism spectrum disorder

    American Journal of Human Genetics

    (2012)
  • M. Chahrour et al.

    The story of Rett syndrome: from clinic to neurobiology

    Neuron

    (2007)
  • L. Kanner

    Autistic disturbances of affective contact

    Nervous Child

    (1943)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders

    (1994)
  • A. Bailey et al.

    Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives

    Journal of Child Psychology and Psychiatry

    (1996)
  • J. Piven et al.

    Broader autism phenotype: evidence from a family history study of multiple-incidence autism families

    American Journal of Psychiatry

    (1997)
  • J.N. Constantino et al.

    Autistic traits in the general population: a twin study

    Archives of General Psychiatry

    (2003)
  • I.I. Gottesman et al.

    The endophenotype concept in psychiatry: etymology and strategic intentions

    American Journal of Psychiatry

    (2003)
  • A.M. Persico et al.

    Endophenotypes in Autism Spectrum Disorders

  • J. Hallmayer et al.

    Genetic heritability and shared environmental factors among twin pairs with autism

    Archives of General Psychiatry

    (2011)
  • S. Ozonoff et al.

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

    Pediatrics

    (2011)
  • C. Lintas et al.

    Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist

    Journal of Medical Genetics

    (2009)
  • J.D. Buxbaum

    Multiple rare variants in the etiology of autism spectrum disorders

    Dialogues in Clinical Neuroscience

    (2009)
  • D.D. Krueger et al.

    Toward fulfilling the promise of molecular medicine in fragile X syndrome

    Annual Review of Medicine

    (2011)
  • P. Curatolo et al.

    Autism spectrum disorders in tuberous sclerosis: pathogenetic pathways and implications for treatment

    Journal of Child Neurology

    (2010)
  • E. Santini et al.

    Exaggerated translation causes synaptic and behavioural aberrations associated with autism

    Nature

    (2013)
  • C. Bagni et al.

    From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome

    Nature Reviews Neuroscience

    (2005)
  • F. Rousseau et al.

    Prevalence of carriers of premutation-size alleles of the FMR1 gene and implications for the population genetics of the fragile X syndrome

    American Journal of Human Genetics

    (1995)
  • R. Hagerman et al.

    Fragile X and autism: intertwined at the molecular level leading to targeted treatments

    Molecular Autism

    (2010)
  • W.E. Kaufmann et al.

    Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors

    American Journal of Medical Genetics

    (2004)
  • A. McDuffie et al.

    Autism spectrum disorder in children and adolescents with fragile X syndrome: within-syndrome differences and age-related changes

    American Journal on Intellectual and Developmental Disabilities

    (2010)
  • M. Losh et al.

    Social communication and theory of mind in boys with autism and fragile x syndrome

    Front Psychology

    (2012)
  • V. Napolioni et al.

    Genetics and molecular biology of tuberous sclerosis complex

    Current Genomics

    (2008)
  • G.C. Gutierrez et al.

    Autism in tuberous sclerosis complex

    Journal of Autism and Developmental Disorders

    (1998)
  • P.B. Crino et al.

    The tuberous sclerosis complex

    New England Journal of Medicine

    (2006)
  • D.D. Hatton et al.

    Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP

    American Journal of Medical Genetics Part A

    (2006)
  • P. Chaste et al.

    High-functioning autism spectrum disorder and fragile X syndrome: report of two affected sisters

    Molecular Autism

    (2012)
  • Cited by (214)

    View all citing articles on Scopus
    View full text