_______________________________________________________________

_______________________________________________________________

Report Information from ProQuest

December 17 2014 01:44
_______________________________________________________________

17 December 2014

ProQuest

Table of contents
1. Autism; Sweeping studies vindicate genetic theory of autism...................................................................... 1

17 December 2014

ii

ProQuest

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 of
Columbia University, suggests further that despite the genetic diversity of autism, the myriad of genome regions
identified by the microarray scans are not all functionally independent, and in many cases appear to perturb a
common molecular network. The implicated network is primarily related to synapse development, axon targeting
and neuron mobility. "We believe that our functional analysis signifies an important transition between studies of
individual rare mutations to analyses of the underlying molecular networks and pathways," Vitkup says. "This
analysis," his team writes, "strongly supports the hypothesis that perturbed synaptogenesis is likely to be at the
heart of autism."
While most previous genetic studies of families with autism have focused on data from 'multiplex' families, in
which more than one family member has an autism spectrum disorder, most cases of autism in fact occur in
simplex families. A growing body of evidence suggests that in these families the disorder typically arises from
highly deleterious 'de novo' mutations - mutations that the affected child did not inherit from a parent. Most of
these mutations are believed to be extremely rare, appearing in at most one percent of the population on the
autism spectrum.
Since the CNVs involved in autism are rare variants, most of the CNVs discovered by the two research groups
appeared just once in the entire study population. A handful of CNVs, however, appeared in more than one
individual. To assess the importance of these 'recurrent' CNVs, both teams developed rigorous approaches to
evaluating their statistical significance. They found that the association of autism with region 7q11.23 was highly
significant; even more significant was a region called 16p11.2. While CNVs at 16p11.2 had been eyed in
previous studies as a possible autism risk factor, the region's relevance to autism is now established beyond
doubt, both groups agree.
Full text: 2011 JUN 20 - (NewsRx.com) -- With autism affecting close to one percent of children in the U.S., the
urgency to find some sort of explanation for the disorder has never been greater. This week, three studies
published 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 genetic
variants that are likely to increase the risk of developing an autism spectrum disorder. Combined, the two
studies - one by a group at Cold Spring Harbor Laboratory in New York led by Michael Wigler, and the other by
a consortium of researchers at multiple institutions, headed by Matthew State at Yale University - paint a portrait
of autism as a highly genetically diverse disorder, whose risk of occurrence may by increased by a mutation at
any 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 the
microarray scans are not all functionally independent, and in many cases appear to perturb a common
molecular network. The implicated network is primarily related to synapse development, axon targeting and
neuron mobility. "We believe that our functional analysis signifies an important transition between studies of
individual rare mutations to analyses of the underlying molecular networks and pathways," Vitkup says. "This
analysis," his team writes, "strongly supports the hypothesis that perturbed synaptogenesis is likely to be at the
heart of autism."
The Vitkup team's analysis of this network may also contribute to an understanding of why autism spectrum
17 December 2014

Page 1 of 3

ProQuest

disorders are more than four times as likely to be diagnosed in males as in females. "Our network analysis and
the sizes of observed genetic mutations suggest that significantly stronger functional perturbations are required
to 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 parents
and unaffected siblings. The study population was drawn from the Simons Simplex Collection (SSC), a
repository of genetic, phenotypic and biological data from simplex families, which was launched by the Simons
Foundation several years ago with the express purpose of facilitating the search for rare mutations linked to
autism. The SSC now numbers close to 3,000 families, so additional, follow-up studies are expected in the near
future.
While most previous genetic studies of families with autism have focused on data from 'multiplex' families, in
which more than one family member has an autism spectrum disorder, most cases of autism in fact occur in
simplex families. A growing body of evidence suggests that in these families the disorder typically arises from
highly deleterious 'de novo' mutations - mutations that the affected child did not inherit from a parent. Most of
these mutations are believed to be extremely rare, appearing in at most one percent of the population on the
autism spectrum.
Identifying these mutations in individuals affected by autism may eventually allow researchers to design
customized 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 a
significant fraction of autism."
Among the studies' most tantalizing findings is the identification of a region of the human genome that appears
to be connected with two disorders involving opposite social tendencies. Mutations that produce extra copies of
this 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, which
is 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," State
says.
In the new work, the two microarray studies found that the children with autism are about four times as likely as
their unaffected siblings to have de novo 'copy number variants' (CNVs), mutations in which a region of the
genome, sometimes as long as several million base pairs, is either duplicated or deleted. What's more, the
research teams found that typically, the CNVs in the children with autism both are larger and contain a higher
density 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 which
the groups feel that the evidence is quite strong. Based on their data, the researchers project that there are
potentially 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 groups
appeared just once in the entire study population. A handful of CNVs, however, appeared in more than one
individual. To assess the importance of these 'recurrent' CNVs, both teams developed rigorous approaches to
evaluating their statistical significance. They found that the association of autism with region 7q11.23 was highly
significant; even more significant was a region called 16p11.2. While CNVs at 16p11.2 had been eyed in
previous studies as a possible autism risk factor, the region's relevance to autism is now established beyond
doubt, both groups agree.
"This is a clear and convincing replication, and in this field that's a cause for real celebration," says Yale's
17 December 2014

Page 2 of 3

ProQuest

Stephan Sanders, lead author of the multi-site study. "Once we know something with certainty from a genetic
standpoint, that opens the door to a whole range of biological studies."
Keywords: Autism, Developmental Disabilities, Genetics, Neurology, Pediatrics, Risk and Prevention, Simons
Foundation, 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

_______________________________________________________________
Contact ProQuest

Copyright 2014 ProQuest LLC. All rights reserved. - Terms and Conditions

17 December 2014

Page 3 of 3

ProQuest