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Getting into the genetics of autism
January 2015
by Kelsey Kaustinen  |  Email the author
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NEW YORK—According to the U.S. Centers for Disease Control, roughly 1 percent of the world’s population presents with autism spectrum disorder (ASD), with the numbers in the United States standing at one in 68 children. That number is on the rise—two years ago, U.S. statistics reported one in 88 children had autism—but thankfully, scientific and genetic knowledge of autism is increasing as well.
 
A recent international study involving researchers from 37 institutions is one of the latest contributors to that knowledge base. The study, which appeared in Nature, has reported that genetic differences in the top 107 genes were found to impact an individual’s risk of autism. This study is the largest in autism to date, with data collected and analyzed from 3,871 autism cases, 2,270 sets of mothers, fathers and affected children and additional control samples. The scope is thanks to the Autism Sequencing Consortium, which was originally funded by the Beatrice and Samuel A. Seaver Foundation and the Seaver Autism Center within the Icahn School of Medicine at Mount Sinai.
 
The study looked at data on several types of rare genetic differences in more than 14,000 DNA samples from parents, affected children and unrelated individuals, which resulted in a multitude of new genes linked with ASD. Where until recently only nine genes have been closely linked to autism risk, this study nearly quadrupled the number of genes definitively associated with autism to 33. More than 70 additional likely ASD genes were also identified, with each one mutated in more than 5 percent of autistic individuals. The researchers used DNA sequencing techniques that can determine the order of the genetic “letters” in DNA to reveal variations, with whole-exome sequencing utilized as well.
 
“The steps we added to our analysis over past studies provide the most complete theoretical picture to date of how many genetic changes pile up to affect the brains of children with autism. Beyond autism, we think this work will yield insights into what makes us social beings,” said Dr. Joseph D. Buxbaum, professor of psychiatry, neuroscience and genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai and director of the Seaver Autism Center.
 
This study found that three pathways required for healthy development are linked to increased autism risk when mutations are present. One of the key discoveries for this study was the association discovered between autism risk and mutations in genes responsible for controlling chromatin remodeling, which plays a key role in DNA processes.
 
“What was novel was that we saw for the first time, on large scale, that chromatin remodeling is a major area for autism risk. Synaptic formation and turnover happens over our lifetime, but chromatin remodeling is especially important in development,” says Buxbaum, who, along with Dr. Mark J. Daly, co-director of the Program in Medical and Population Genetics at the Broad Institute of MIT and Harvard, is senior author of the study.
 
Along those lines, one of the groups of genes this study has linked to autism codes for an enzyme that regulates histones by attaching or removing methyl groups to one of their building blocks, thereby influencing when certain genes are turned on or off. This aligns with the theory that these mechanisms are altered in autism, with the result that developing brain cells might not mature, divide or migrate in the same way.
 
Other variations were seen in genes that govern synapses, as well as in another group of genes that regulate basic steps that turn genes into proteins.
 
While past studies regarding genetic autism risk have focused only on de-novo loss-of-function mutations, this Nature study examined inherited and de-novo loss-of-function mutations, as well as de-novo missense mutations, in which a protein is present but does not work properly.
 
“Until now, nobody’s looked formally at missense mutations. So we’re able to show very clearly that missense mutations, the more deleterious ones, are a major part of risk and actually can be equally deleterious as the loss-of-function mutations,” Buxbaum tells DDNews.
 
“While we have very strong findings in these genetic analyses, newfound genetic discoveries must next be moved into molecular, cell and animal studies to realize future benefits for families,” he adds. “A study like this creates an industry for years to come, with labs worldwide checking the brain changes linked to each new genetic finding and searching for drugs to counter them.”
 
Another recent Nature study shed further light on autism risk and the contribution genetic mutations play in that sphere. The study, “The contribution of de novo coding mutations to autism spectrum disorder,” was co-led by investigators from Cold Spring Harbor Laboratory, Yale University, the University of Washington and the University of California, San Francisco.
 
The researchers report that based on their work, at least 30 percent of all autism cases are the result of de- novo mutations—and that is likely a conservative estimate. There are three major contributors to that number: missense mutations, likely gene- disrupting (LGD) mutations and large-scale copy number variations. Missense mutations were noted as the cause of 12 percent of autism cases, and LGD mutations as the cause of 9 percent.
NEW YORK—According to the U.S. Centers for Disease Control, roughly 1 percent of the world’s population presents with autism spectrum disorder (ASD), with the numbers in the United States standing at one in 68 children. That number is on the rise—two years ago, U.S. statistics reported one in 88 children had autism—but thankfully, scientific and genetic knowledge of autism is increasing as well.
 
A recent international study involving researchers from 37 institutions is one of the latest contributors to that knowledge base. The study, which appeared in Nature, has reported that genetic differences in the top 107 genes were found to impact an individual’s risk of autism. This study is the largest in autism to date, with data collected and analyzed from 3,871 autism cases, 2,270 sets of mothers, fathers and affected children and additional control samples. The scope is thanks to the Autism Sequencing Consortium, which was originally funded by the Beatrice and Samuel A. Seaver Foundation and the Seaver Autism Center within the Icahn School of Medicine at Mount Sinai.
 
The study looked at data on several types of rare genetic differences in more than 14,000 DNA samples from parents, affected children and unrelated individuals, which resulted in a multitude of new genes linked with ASD. Where until recently only nine genes have been closely linked to autism risk, this study nearly quadrupled the number of genes definitively associated with autism to 33. More than 70 additional likely ASD genes were also identified, with each one mutated in more than 5 percent of autistic individuals. The researchers used DNA sequencing techniques that can determine the order of the genetic “letters” in DNA to reveal variations, with whole-exome sequencing utilized as well.
 
“The steps we added to our analysis over past studies provide the most complete theoretical picture to date of how many genetic changes pile up to affect the brains of children with autism. Beyond autism, we think this work will yield insights into what makes us social beings,” said Dr. Joseph D. Buxbaum, professor of psychiatry, neuroscience and genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai and director of the Seaver Autism Center.
 
This study found that three pathways required for healthy development are linked to increased autism risk when mutations are present. One of the key discoveries for this study was the association discovered between autism risk and mutations in genes responsible for controlling chromatin remodeling, which plays a key role in DNA processes.
 
“What was novel was that we saw for the first time, on large scale, that chromatin remodeling is a major area for autism risk. Synaptic formation and turnover happens over our lifetime, but chromatin remodeling is especially important in development,” says Buxbaum, who, along with Dr. Mark J. Daly, co-director of the Program in Medical and Population Genetics at the Broad Institute of MIT and Harvard, is senior author of the study.
 
Along those lines, one of the groups of genes this study has linked to autism codes for an enzyme that regulates histones by attaching or removing methyl groups to one of their building blocks, thereby influencing when certain genes are turned on or off. This aligns with the theory that these mechanisms are altered in autism, with the result that developing brain cells might not mature, divide or migrate in the same way.
 
Other variations were seen in genes that govern synapses, as well as in another group of genes that regulate basic steps that turn genes into proteins.
 
While past studies regarding genetic autism risk have focused only on de-novo loss-of-function mutations, this Nature study examined inherited and de-novo loss-of-function mutations, as well as de-novo missense mutations, in which a protein is present but does not work properly.
 
“Until now, nobody’s looked formally at missense mutations. So we’re able to show very clearly that missense mutations, the more deleterious ones, are a major part of risk and actually can be equally deleterious as the loss-of-function mutations,” Buxbaum tells DDNews.
 
“While we have very strong findings in these genetic analyses, newfound genetic discoveries must next be moved into molecular, cell and animal studies to realize future benefits for families,” he adds. “A study like this creates an industry for years to come, with labs worldwide checking the brain changes linked to each new genetic finding and searching for drugs to counter them.”
 
Another recent Nature study shed further light on autism risk and the contribution genetic mutations play in that sphere. The study, “The contribution of de novo coding mutations to autism spectrum disorder,” was co-led by investigators from Cold Spring Harbor Laboratory, Yale University, the University of Washington and the University of California, San Francisco.
 
The researchers report that based on their work, at least 30 percent of all autism cases are the result of de-novo mutations—and that is likely a conservative estimate. There are three major contributors to that number: missense mutations, likely gene-disrupting (LGD) mutations and large-scale copy number variations. Missense mutations were noted as the cause of 12 percent of autism cases, and LGD mutations as the cause of 9 percent.
 
Code: E011506

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