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Book ChapterDOI

The Genetics of Autism Spectrum Disorders

TL;DR: 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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Citations
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Journal ArticleDOI
27 Oct 2011-Nature
TL;DR: The generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains, finds that 86 per cent of the genes analysed were expressed, and that 90 per cent were differentially regulated at the whole-transcript or exon level acrossbrain regions and/or time.
Abstract: Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.

1,760 citations

Journal ArticleDOI
27 Jul 2010-Brain
TL;DR: The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes.
Abstract: Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

1,115 citations


Cites background from "The Genetics of Autism Spectrum Dis..."

  • ...…in CNTNAP2 (which encodes Caspr2) are associated with epilepsy and cognitive decline as well as peripheral nerve involvement (Strauss et al., 2006), and have also been identified in various forms of schizophrenia, epilepsy and autism spectrum disorders (reviewed in Kumar and Christian, 2009)....

    [...]

  • ...It is interesting that mutations in genes encoding both these proteins are found in hereditary epilepsy and other disorders (reviewed by Morante-Redolat et al., 2002; Kumar and Christian, 2009), reflecting the fact that genetic and autoimmune conditions often target the same proteins....

    [...]

Journal ArticleDOI
TL;DR: Clinicians can make a difference by providing timely and individualised help to families navigating referrals and access to community support systems, by providing accurate information despite often unfiltered media input, and by anticipating transitions such as family changes and school entry and leaving.

1,023 citations

Journal ArticleDOI
TL;DR: Current understanding of the genetic architecture of ASD is reviewed and genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology are integrated.
Abstract: Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

650 citations

Journal ArticleDOI
TL;DR: It is argued that deficits in executive functioning, theory of mind, and central coherence can all be understood as the consequence of a core deficit in the flexibility with which people with autism spectrum disorder can process violations to their expectations.
Abstract: There have been numerous attempts to explain the enigma of autism, but existing neurocognitive theories often provide merely a refined description of 1 cluster of symptoms. Here we argue that deficits in executive functioning, theory of mind, and central coherence can all be understood as the consequence of a core deficit in the flexibility with which people with autism spectrum disorder can process violations to their expectations. More formally we argue that the human mind processes information by making and testing predictions and that the errors resulting from violations to these predictions are given a uniform, inflexibly high weight in autism spectrum disorder. The complex, fluctuating nature of regularities in the world and the stochastic and noisy biological system through which people experience it require that, in the real world, people not only learn from their errors but also need to (meta-)learn to sometimes ignore errors. Especially when situations (e.g., social) or stimuli (e.g., faces) become too complex or dynamic, people need to tolerate a certain degree of error in order to develop a more abstract level of representation. Starting from an inability to flexibly process prediction errors, a number of seemingly core deficits become logically secondary symptoms. Moreover, an insistence on sameness or the acting out of stereotyped and repetitive behaviors can be understood as attempts to provide a reassuring sense of predictive success in a world otherwise filled with error. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

542 citations


Cites background from "The Genetics of Autism Spectrum Dis..."

  • ...Although ASD has a strong polygenetic component with heritability around 70% (Geschwind, 2011), no biological marker is available yet and thus, diagnosis mainly relies on behavioral assessment....

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  • ...This imbalance in the brain’s handling of prediction errors could result from different genetic and neurophysiological pathways, thus highlighting that different pathogenetic factors could in fact contribute to a common information processing imbalance (Geschwind, 2011)....

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References
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Journal ArticleDOI
13 Sep 1996-Science
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.
Abstract: The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult. In their Perspective, Risch and Merikangas propose that we can best accomplish this goal by combining the power of the human genome project with association studies, a method for determining the basis of a genetic disease.

5,143 citations

Journal ArticleDOI
20 Apr 2007-Science
TL;DR: Findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Abstract: We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

2,770 citations

Journal ArticleDOI
TL;DR: The findings indicate that autism is under a high degree of genetic control and suggest the involvement of multiple genetic loci.
Abstract: Two previous epidemiological studies of autistic twins suggested that autism was predominantly genetically determined, although the findings with regard to a broader phenotype of cognitive, and possibly social, abnormalities were contradictory. Obstetric and perinatal hazards were also invoked as environmentally determined aetiological factors. The first British twin sample has been re-examined and a second total population sample of autistic twins recruited. In the combined sample 60% of monozygotic (MZ) pairs were concordant for autism versus no dizygotic (DZ) pairs; 92% of MZ pairs were concordant for a broader spectrum of related cognitive or social abnormalities versus 10% of DZ pairs. The findings indicate that autism is under a high degree of genetic control and suggest the involvement of multiple genetic loci. Obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors. Few new cases had possible medical aetiologies, refuting claims that recognized disorders are common aetiological influences.

2,378 citations

Journal ArticleDOI
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.

2,033 citations

Journal ArticleDOI
Dalila Pinto1, Alistair T. Pagnamenta2, Lambertus Klei3, Richard Anney4  +178 moreInstitutions (46)
15 Jul 2010-Nature
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.
Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

1,919 citations