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Document 1 of 1 Autism; Sweeping studies vindicate genetic theory of autism Author: Anonymous ProQuest document link Abstract (Abstract): A gene network analysis in the third paper, by a team headed by Dennis Vitkup ofColumbia University, suggests further that despite the genetic diversity of autism, the myriad of genome regionsidentified by the microarray scans are not all functionally independent, and in many cases appear to perturb acommon molecular network. The implicated network is primarily related to synapse development, axon targetingand neuron mobility. "We believe that our functional analysis signifies an important transition between studies ofindividual rare mutations to analyses of the underlying molecular networks and pathways," Vitkup says. "Thisanalysis," his team writes, "strongly supports the hypothesis that perturbed synaptogenesis is likely to be at theheart of autism." While most previous genetic studies of families with autism have focused on data from 'multiplex' families, inwhich more than one family member has an autism spectrum disorder, most cases of autism in fact occur insimplex families. A growing body of evidence suggests that in these families the disorder typically arises fromhighly deleterious 'de novo' mutations - mutations that the affected child did not inherit from a parent. Most ofthese mutations are believed to be extremely rare, appearing in at most one percent of the population on theautism spectrum. Since the CNVs involved in autism are rare variants, most of the CNVs discovered by the two research groupsappeared just once in the entire study population. A handful of CNVs, however, appeared in more than oneindividual. To assess the importance of these 'recurrent' CNVs, both teams developed rigorous approaches toevaluating their statistical significance. They found that the association of autism with region 7q11.23 was highlysignificant; even more significant was a region called 16p11.2. While CNVs at 16p11.2 had been eyed inprevious studies as a possible autism risk factor, the region's relevance to autism is now established beyonddoubt, both groups agree. Full text: 2011 JUN 20 - (NewsRx.com) -- With autism affecting close to one percent of children in the U.S., theurgency to find some sort of explanation for the disorder has never been greater. This week, three studiespublished in the 9 June issue of Neuron offer a definitive vindication of the theory that spontaneous, or de novo,genetic mutations underlie the development of autism in many families with no history of the disorder. Two of the new papers, independent microarray studies of unprecedented scale, point to an array of geneticvariants that are likely to increase the risk of developing an autism spectrum disorder. Combined, the twostudies - one by a group at Cold Spring Harbor Laboratory in New York led by Michael Wigler, and the other bya consortium of researchers at multiple institutions, headed by Matthew State at Yale University - paint a portraitof autism as a highly genetically diverse disorder, whose risk of occurrence may by increased by a mutation atany one of several hundred different sites in the human genome. A gene network analysis in the third paper, by a team headed by Dennis Vitkup of Columbia University,suggests further that despite the genetic diversity of autism, the myriad of genome regions identified by themicroarray scans are not all functionally independent, and in many cases appear to perturb a commonmolecular network. The implicated network is primarily related to synapse development, axon targeting andneuron mobility. "We believe that our functional analysis signifies an important transition between studies ofindividual rare mutations to analyses of the underlying molecular networks and pathways," Vitkup says. "Thisanalysis," his team writes, "strongly supports the hypothesis that perturbed synaptogenesis is likely to be at theheart of autism." The Vitkup team's analysis of this network may also contribute to an understanding of why autism spectrum

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disorders are more than four times as likely to be diagnosed in males as in females. "Our network analysis andthe sizes of observed genetic mutations suggest that significantly stronger functional perturbations are requiredto trigger the autistic phenotype in females compared to males," Vitkup says. Each of the two microarray teams used a different type of platform to examine the genomes of more than 1,000'simplex' families: families with just one child with an autism spectrum disorder, as well as unaffected parentsand unaffected siblings. The study population was drawn from the Simons Simplex Collection (SSC), arepository of genetic, phenotypic and biological data from simplex families, which was launched by the SimonsFoundation several years ago with the express purpose of facilitating the search for rare mutations linked toautism. The SSC now numbers close to 3,000 families, so additional, follow-up studies are expected in the nearfuture. While most previous genetic studies of families with autism have focused on data from 'multiplex' families, inwhich more than one family member has an autism spectrum disorder, most cases of autism in fact occur insimplex families. A growing body of evidence suggests that in these families the disorder typically arises fromhighly deleterious 'de novo' mutations - mutations that the affected child did not inherit from a parent. Most ofthese mutations are believed to be extremely rare, appearing in at most one percent of the population on theautism spectrum. Identifying these mutations in individuals affected by autism may eventually allow researchers to designcustomized drug therapies that can take on the roles of the damaged genes. "These studies are the culmination of a several-year effort to understand the role of genetic variants in autism,"says Gerald Fischbach, scientific director at the Simons Foundation, which funded the State and Wigler studies."The microarray studies have shown beyond doubt that there are indeed rare genetic variants that account for asignificant fraction of autism." Among the studies' most tantalizing findings is the identification of a region of the human genome that appearsto be connected with two disorders involving opposite social tendencies. Mutations that produce extra copies ofthis region, called 7q11.23, are associated with autism spectrum disorders, the State and Wigler teams report.Conversely, deletions of this region are known to be responsible for a disorder called Williams syndrome, whichis characterized in part by a highly sociable, empathetic personality. "This region of the genome could be a Rosetta Stone for studying the development of the social brain," Statesays. In the new work, the two microarray studies found that the children with autism are about four times as likely astheir unaffected siblings to have de novo 'copy number variants' (CNVs), mutations in which a region of thegenome, sometimes as long as several million base pairs, is either duplicated or deleted. What's more, theresearch teams found that typically, the CNVs in the children with autism both are larger and contain a higherdensity of genes than the CNVs found in unaffected siblings. The analyses identified a total of about 75 CNVs worthy of further study, including between 4 and 6 for whichthe groups feel that the evidence is quite strong. Based on their data, the researchers project that there arepotentially several hundred different regions of the genome where a CNV can increase the risk of autism,meaning that the current findings represent "not even the tip of the iceberg," Wigler says. Since the CNVs involved in autism are rare variants, most of the CNVs discovered by the two research groupsappeared just once in the entire study population. A handful of CNVs, however, appeared in more than oneindividual. To assess the importance of these 'recurrent' CNVs, both teams developed rigorous approaches toevaluating their statistical significance. They found that the association of autism with region 7q11.23 was highlysignificant; even more significant was a region called 16p11.2. While CNVs at 16p11.2 had been eyed inprevious studies as a possible autism risk factor, the region's relevance to autism is now established beyonddoubt, both groups agree. "This is a clear and convincing replication, and in this field that's a cause for real celebration," says Yale's

Stephan Sanders, lead author of the multi-site study. "Once we know something with certainty from a geneticstandpoint, that opens the door to a whole range of biological studies." Keywords: Autism, Developmental Disabilities, Genetics, Neurology, Pediatrics, Risk and Prevention, SimonsFoundation, Yale University. This article was prepared by Health &Medicine Week editors from staff and other reports. Copyright 2011,Health &Medicine Week via NewsRx.com. People: Wigler, Michael, Vitkup, Dennis Publication title: Health & Medicine Week First page: 3636 Publication year: 2011 Publication date: Jun 20, 2011 Year: 2011 Publisher: NewsRx Place of publication: Atlanta Country of publication: United States Publication subject: Medical Sciences ISSN: 15316459 Source type: Trade Journals Language of publication: English Document type: Expanded Reporting ProQuest document ID: 871777552 Document URL: http://search.proquest.com/docview/871777552?accountid=15533 Copyright: (c)Copyright 2011, Health & Medicine Week via NewsRx.com Last updated: 2011-06-15 Database: ProQuest Central

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