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The Genetics of Autism Spectrum Disorders

TLDR
Three approaches to identifying genetic factors that contribute to the pathogenesis of ASDs are reviewed: common variants and genome-wide association studies (GWAS); 2) rare variants and copy number variation (CNV) studies, and 3) familial forms of autism and the role of next-generation sequencing (NGS) methods.
Abstract
Autism is a neurodevelopmental disorder of complex etiology and is amongst the most heritable of neuropsychiatric disorders while sharing genetic liability with other neurodevelopmental disorders such as intellectual disability (ID). Autism spectrum disorders (ASDs) are defined more broadly and include autism, Asperger syndrome, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. Under the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Revised (DSM-IVTR), these disorders are grouped together with Rett syndrome (“Rett’s disorder”) as pervasive developmental disorders. However, Rett syndrome has a reportedly distinct pathophysiology, clinical course, and diagnostic strategy (Levy & Schultz, 2009) and will likely be removed in the impending publication of DSM-V (APA, 2010). The new diagnostic manual will formally adopt the single diagnostic category “ASDs”, which is used here. Reported prevalence rates for ASDs range from 20 (Newschaffer et al. 2007) to 116 (Baird et al., 2006) per 10,000 children, and vary in accordance with diagnostic, sampling, and screening criteria. The Centers for Disease Control and Prevention (CDC) suggest that in the United States, the prevalence of ASDs is 1 in 110 (1/70 in boys and 1/315 in girls) (ADDM, 2009). The three primary characteristics of ASDs are communication impairments, social impairments, and repetitive/stereotyped behaviors. The DSM-IVTR, ICD-10, and many other diagnostic instruments require impairment in each of these domains for a diagnosis of autistic disorder. Within the last decade, a number of major technological developments have transformed our understanding of the genetic causes of autism, and the field continues to evolve rapidly. In this chapter, we will review three approaches to identifying genetic factors that contribute to the pathogenesis of ASDs: 1) common variants and genome-wide association studies (GWAS); 2) rare variants and copy number variation (CNV) studies, and 3) familial forms of autism and the role of next-generation sequencing (NGS) methods. Data from all three approaches underscores the conclusion that autism is a highly complex and heterogeneous disorder, involving a multifactorial etiology. Moreover, it is becoming increasingly apparent that autism is not a unitary disorder, and that the spectrum may consist of any number of different autisms that share similar symptoms or phenotypes. This conclusion has important implications for evaluation and treatment, which are discussed in the conclusion.

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The Behavioral Phenotype in MECP2 Duplication Syndrome: A Comparison With Idiopathic Autism

TL;DR: Direct comparisons of ASD profiles revealed that a majority of boys with MECP2 duplication syndrome are similar to idiopathic ASD; they have impairments in social affect and similar severity in restricted/repetitive behaviors.
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Epigenetics, Copy Number Variation, and Other Molecular Mechanisms Underlying Neurodevelopmental Disabilities: New Insights and Diagnostic Approaches

TL;DR: A number of the molecular genetic mechanisms that play a role in disorders leading to ID/NDD are described and the categories and technologies for diagnostic testing of these conditions are discussed.
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Leo Kanner and autism: a 75-year perspective.

TL;DR: Leo Kanner concluded that this was a neurodevelopmental disorder and that ‘these children have come into the world with an innate inability to form the usual, biologically provided contact with people’.
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Adult zebrafish in CNS disease modeling: a tank that's half-full, not half-empty, and still filling.

TL;DR: Recent findings using zebrafish CNS assays are summarized, model limitations and the existing challenges are discussed, as well as future directions of research in this field are outlined.
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Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength

TL;DR: It is shown that Shank3 is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic transmission, and an autism-associated mutation in Shank3 partially impairs this signaling system.
References
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The Future of Genetic Studies of Complex Human Diseases

TL;DR: The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult as mentioned in this paper, and Risch and Merikangas proposed that they can best accomplish this goal by combining the power of the human genome project with association studies.
Journal ArticleDOI

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

TL;DR: The findings indicate that autism is under a high degree of genetic control and suggest the involvement of multiple genetic loci.
Journal ArticleDOI

Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP).

TL;DR: Prevalence of autism and related ASDs is substantially greater than previously recognised and services in health, education, and social care will need to recognise the needs of children with some form of ASD, who constitute 1% of the child population.
Journal ArticleDOI

Functional impact of global rare copy number variation in autism spectrum disorders

Dalila Pinto, +181 more
- 15 Jul 2010 - 
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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