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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The Behavioral Phenotype in MECP2 Duplication Syndrome: A Comparison With Idiopathic Autism
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References
More filters
Journal ArticleDOI
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
Strong Association of De Novo Copy Number Mutations with Autism
Jonathan Sebat,B. Lakshmi,Dheeraj Malhotra,Jennifer Troge,Christa Lese-Martin,Tom Walsh,Boris Yamrom,Seungtai Yoon,Alexander Krasnitz,Jude Kendall,Anthony Leotta,Deepa Pai,Ray Zhang,Yoon-ha Lee,James W. Hicks,Sarah J. Spence,Annette Lee,Kaija Puura,Terho Lehtimäki,David H. Ledbetter,Peter K. Gregersen,Joel D. Bregman,James S. Sutcliffe,Vaidehi Jobanputra,Wendy K. Chung,Dorothy Warburton,Mary Claire King,David Skuse,Daniel H. Geschwind,T. Conrad Gilliam,Kenny Ye,Michael Wigler +31 more
TL;DR: Findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Journal ArticleDOI
Autism as a strongly genetic disorder: evidence from a British twin study.
Anthony J. Bailey,A. Le Couteur,Irving I. Gottesman,Patrick Bolton,Emily Simonoff,E. Yuzda,Michael Rutter +6 more
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).
Gillian Baird,Emily Simonoff,Andrew Pickles,Susie Chandler,Tom Loucas,David Meldrum,Tony Charman +6 more
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,Alistair T. Pagnamenta,Lambertus Klei,Richard Anney,Daniele Merico,Regina Regan,Judith Conroy,Tiago R. Magalhaes,Tiago R. Magalhaes,Catarina Correia,Catarina Correia,Brett S. Abrahams,Joana Almeida,Elena Bacchelli,Gary D. Bader,Anthony J. Bailey,Gillian Baird,Agatino Battaglia,Tom Berney,Nadia Bolshakova,Sven Bölte,Patrick Bolton,Thomas Bourgeron,Sean Brennan,Jessica Brian,Susan E. Bryson,Andrew R. Carson,Guillermo Casallo,Jillian P. Casey,Brian H.Y. Chung,Lynne E Cochrane,Christina Corsello,Emily L. Crawford,Andrew Crossett,Cheryl Cytrynbaum,Geraldine Dawson,Maretha de Jonge,Richard Delorme,Irene Drmic,Eftichia Duketis,Frederico Duque,Annette Estes,Penny Farrar,Bridget A. Fernandez,Susan E. Folstein,Eric Fombonne,Christine M. Freitag,John Gilbert,Christopher Gillberg,Joseph T. Glessner,Jeremy Goldberg,Andrew Green,Jonathan Green,Stephen J. Guter,Hakon Hakonarson,Elizabeth A. Heron,Matthew Hill,Richard Holt,Jennifer L. Howe,Gillian Hughes,Vanessa Hus,Roberta Igliozzi,Cecilia Kim,Sabine M. Klauck,Alexander Kolevzon,Olena Korvatska,Vlad Kustanovich,Clara Lajonchere,Janine A. Lamb,Magdalena Laskawiec,Marion Leboyer,Ann Le Couteur,Bennett L. Leventhal,Anath C. Lionel,Anath C. Lionel,Xiao-Qing Liu,Catherine Lord,Linda Lotspeich,Sabata C. Lund,Elena Maestrini,William M. Mahoney,Carine Mantoulan,Christian R. Marshall,Helen McConachie,Christopher J. McDougle,Jane McGrath,William M. McMahon,Alison K. Merikangas,Ohsuke Migita,Nancy J. Minshew,Ghazala Mirza,Jeff Munson,Stanley F. Nelson,Carolyn Noakes,Abdul Noor,Gudrun Nygren,Guiomar Oliveira,Katerina Papanikolaou,Jeremy R. Parr,Barbara Parrini,Tara Paton,Andrew Pickles,Marion Pilorge,Joseph Piven,Chris P. Ponting,David J. Posey,Annemarie Poustka,Fritz Poustka,Aparna Prasad,Jiannis Ragoussis,Katy Renshaw,Jessica Rickaby,Wendy Roberts,Kathryn Roeder,Bernadette Rogé,Michael Rutter,Laura J. Bierut,John P. Rice,Jeff Salt,Katherine Sansom,Daisuke Sato,Ricardo Segurado,Ana Filipa Sequeira,Lili Senman,Lili Senman,Naisha Shah,Val C. Sheffield,Latha Soorya,Inês Sousa,Olaf Stein,Nuala Sykes,Vera Stoppioni,Christina Strawbridge,Raffaella Tancredi,Katherine E. Tansey,Bhooma Thiruvahindrapduram,Ann P. Thompson,Susanne Thomson,Ana Tryfon,John Tsiantis,Herman Van Engeland,John B. Vincent,Fred R. Volkmar,Simon Wallace,Kai Wang,Zhouzhi Wang,Thomas H. Wassink,Caleb Webber,Rosanna Weksberg,Kirsty Wing,Kerstin Wittemeyer,Shawn Wood,Jing Wu,Brian L. Yaspan,Danielle Zurawiecki,Lonnie Zwaigenbaum,Joseph D. Buxbaum,Rita M. Cantor,Edwin H. Cook,Hilary Coon,Michael L. Cuccaro,Bernie Devlin,Sean Ennis,Louise Gallagher,Daniel H. Geschwind,Michael Gill,Jonathan L. Haines,Joachim Hallmayer,Judith Miller,Anthony P. Monaco,John I. Nurnberger,Andrew D. Paterson,Margaret A. Pericak-Vance,Gerard D. Schellenberg,Peter Szatmari,Astrid M. Vicente,Veronica J. Vieland,Veronica J. Vieland,Ellen M. Wijsman,Stephen W. Scherer,James S. Sutcliffe,Catalina Betancur +181 more
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.