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.read more
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References
More filters
Journal ArticleDOI
Childhood autism and associated comorbidities
TL;DR: This review refers to all the genetic syndromes that have been described in children with pervasive developmental disorders (tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Gilles de la Tourette, Williams, etc).
Journal ArticleDOI
Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus.
Rym Benayed,Rym Benayed,Neda Gharani,Ian T. Rossman,Vincent Mancuso,Gloria Lazar,Silky Kamdar,Shannon E. Bruse,Samuel Tischfield,Brett J. Smith,Raymond A. Zimmerman,Emanuel DiCicco-Bloom,Linda M. Brzustowicz,James H. Millonig,James H. Millonig,James H. Millonig +15 more
TL;DR: Together, these data provide further genetic evidence that EN2 might act as an ASD susceptibility locus, and they suggest that a risk allele that perturbs the spatial/temporal expression of EN2 could significantly alter normal brain development.
Journal ArticleDOI
Autism: a world changing too fast for a mis-wired brain?
Bruno Gepner,Francois Feron +1 more
TL;DR: It is argued that TSPDs may result from Multi-system Brain Disconnectivity-Dissynchrony (MBD), defined as an increase or decrease in functional connectivity and neuronal synchronization within/between multiple neurofunctional territories and pathways, and found that slowing down the speed of facial and vocal events enhanced imitative, verbal and cognitive abilities in some ASD children, particularly those with low functioning autism.
Journal ArticleDOI
Research Review: What is the association between the social-communication element of autism and repetitive interests, behaviours and activities?
TL;DR: The approach suggested that the correlation between social-communication impairments and RIBAs has been exaggerated in the current consensus about the autism syndrome, and that these aspects of autism may well share largely independent underlying causes.
Journal ArticleDOI
Rare structural variation of synapse and neurotransmission genes in autism
Xiaowu Gai,Hongbo Xie,Juan C. Perin,Nagahide Takahashi,Kevin Murphy,Adam Wenocur,Monica D’Arcy,R J O'Hara,Elizabeth Goldmuntz,Elizabeth Goldmuntz,Dorothy E. Grice,Tamim H. Shaikh,Hakon Hakonarson,Hakon Hakonarson,Joseph D. Buxbaum,Josephine Elia,Josephine Elia,Peter White,Peter White +18 more
TL;DR: It is shown that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls and suggest a sizable pool of additional potential ASD risk loci.