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
Citations
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Functional annotation of genes overlapping copy number variants in autistic patients: focus on axon pathfinding.
TL;DR: The results suggest that the autism’s “connectivity genes” in some patients affect very early phases of neurodevelopment, i.e., earlier than synaptogenesis.
Journal ArticleDOI
Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.
Petya D. Radoeva,Ioana L. Coman,Cynthia A. Salazar,Karen L. Gentile,Anne Marie Higgins,Frank A. Middleton,Kevin M. Antshel,Wanda Fremont,Robert J. Shprintzen,Bernice E. Morrow,Wendy R. Kates +10 more
TL;DR: The results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS.
Journal ArticleDOI
Altered modulation of gamma oscillation frequency by speed of visual motion in children with autism spectrum disorders
Tatiana A. Stroganova,Anna V. Butorina,Olga V. Sysoeva,Andrey O. Prokofyev,Anastasia Yu. Nikolaeva,Marina M. Tsetlin,Elena V. Orekhova +6 more
TL;DR: Findings suggest that abnormal velocity-related gamma frequency modulation in ASD may constitute a potential biomarker for reduced excitability of fast-spiking inhibitory neurons in a subset of children with ASD.
Journal ArticleDOI
Copy number variants in autism spectrum disorders
Stefano Vicari,Eleonora Napoli,Viviana Cordeddu,Deny Menghini,Viola Alesi,Sara Loddo,Antonio Novelli,Marco Tartaglia +7 more
TL;DR: The accumulated evidence concerning the genetic events associated with ASD is described, current knowledge about the clinical relevance of CNVs in these disorders is summarized, and several lines of evidence support the view that structural genomic variation contributes to the pathogenesis of ASD.
Journal ArticleDOI
Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families
Thomas W. Frazier,Eric A. Youngstrom,Antonio Y. Hardan,Stelios Georgiades,John N. Constantino,Charis Eng +5 more
TL;DR: Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis.
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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.