Science Daily — A new model for understanding how autism is acquired has been developed by a team of researchers led by Cold Spring Harbor Laboratory (CSHL) and Albert Einstein College of Medicine. Autism is a developmental disorder, characterized by language impairments, social deficits, and repetitive behaviors. The researchers analyzed data on autism incidence and found a previously unrecognized pattern.
The pattern can be explained by assuming that spontaneous germ-line mutation is a significant cause of the disorder. Parents, especially women, who acquire the mutation – but do not exhibit severe symptoms of the disorder – have a 50% chance of passing the mutation on to their children. Sons often show the most severe symptoms.
Spontaneous mutations are changes in a chromosome that alter genes. Germ-line mutations are newly acquired in a germ cell of a parent, and sometimes are transmitted to offspring at conception. Men and women are equally as likely to acquire a spontaneous mutation that can cause autism, but autism is three times more likely in men, making women the more likely carriers of new mutations. “The fact that germ-line mutations increase with age places older parents at a higher risk of having children with autism, explaining a pattern that has been recently observed,” said CSHL co-author of the study Michael Wigler, Ph.D.
The model proposes two prominent risk classes for families affected by autism. Low risk families give rise to sporadic autism, the more common form, by spontaneous germ-line mutation. The children, mostly female, who receive such a mutation, but do not display the disorder, are the source of the high risk families.
The data show that the transmission pattern to boys in high risk families is often of a dominant pattern that may account for a quarter of autism. Although the data does not answer whether there is a gradation of lower risk, the model builds on recent CSHL findings that spontaneous mutation is frequent in sporadic autism and less frequent in children from high risk families.
Wigler suggests that “what we now know about spontaneous mutations and autism offers an alternative to traditional thinking about genetic disorders as purely heritable from a parent. This has implications for other disorders such as morbid obesity, schizophrenia, and congenital heart disease.”
The full citation of the paper published in the July 31, 2007 print edition of the Proceedings of the National Academy of Sciences is: "A unified theory for sporadic and inherited autism," by Xiaoyue Zhao, Anthony Leotta, Vlad Kustanovich, Clara Lajonchere, Daniel H. Geschwind, Kiely Law, Paul Law, Shanping Qiu, Catherine Lord, Jonathan Sebat, Kenny Ye and Michael Wigler.
The research was funded by the Simons Foundation and utilized databases from the Autistic Resource Exchange (AGRE) Consortium, the University of Michigan, and the Interactive Autism Network (IAN). IAN is an on-line national autism registry and database launched in April by the Kennedy Krieger Institute.
Note: This story has been adapted from a news release issued by Cold Spring Harbor Laboratory.
Wednesday, July 25, 2007
Spontaneous mutation seen as major factor in autism: study
Most apparently random cases of autism may be just that, a function of freak genetic accidents, rather than a product of an inherited genetic predisposition that is passed down through generations, according to a study released Monday.
The authors of the study suggest that spontaneous mutations in the DNA of an afflicted child or their parent may play a much larger role than previously thought in sporadic cases of autism, where there is no family history of the devastating childhood developmental disorder.
The genetic origins of the neurological condition are still unclear, but in a recent paper, US researchers reported that spontaneous mutations, or tiny glitches in the DNA, were common in about 10 percent of the autistic patients they studied.
The pattern was particularly noticeable in cases of sporadic autism which is the most common form.
In the light of this finding, investigators at Cold Spring Harbor Laboratory and Albert Einstein College of Medicine in New York did a mathematical analysis of three databases on the incidence of autism to see if this new theory could account for the distribution of cases.
They concluded that a previously unrecognized pattern could be explained by assuming that spontaneous mutations are a significant cause of the disorder and that parents, especially women, who acquire the DNA glitches, have a 50 percent chance of passing it on to their child.
The researchers suggest that in this way, women who carry these spontaneous mutations, which are in effect missing or duplicate stretches of DNA, while themselves asymptomatic, are the source of high-risk families, which feature one or more autistic children.
"For the first time, we have a model that explains the sporadic and the inherited forms of autism," said Michael Wigler, a geneticist at Cold Spring Harbor Laboratory.
Given that spontaneous mutations in DNA increase with age, and that many women in industrialized nations are postponing childbirth until the last minute, the theory may also explain why older parents are at greater risk of having autistic children, Wigler said.
The little-understood disorder is characterized by poor social and communication skills and afflicts one in 150 children, most of them boys, according to the latest estimates from US public health authorities.
The study appears in the Proceedings of the National Academy of Sciences.
The authors of the study suggest that spontaneous mutations in the DNA of an afflicted child or their parent may play a much larger role than previously thought in sporadic cases of autism, where there is no family history of the devastating childhood developmental disorder.
The genetic origins of the neurological condition are still unclear, but in a recent paper, US researchers reported that spontaneous mutations, or tiny glitches in the DNA, were common in about 10 percent of the autistic patients they studied.
The pattern was particularly noticeable in cases of sporadic autism which is the most common form.
In the light of this finding, investigators at Cold Spring Harbor Laboratory and Albert Einstein College of Medicine in New York did a mathematical analysis of three databases on the incidence of autism to see if this new theory could account for the distribution of cases.
They concluded that a previously unrecognized pattern could be explained by assuming that spontaneous mutations are a significant cause of the disorder and that parents, especially women, who acquire the DNA glitches, have a 50 percent chance of passing it on to their child.
The researchers suggest that in this way, women who carry these spontaneous mutations, which are in effect missing or duplicate stretches of DNA, while themselves asymptomatic, are the source of high-risk families, which feature one or more autistic children.
"For the first time, we have a model that explains the sporadic and the inherited forms of autism," said Michael Wigler, a geneticist at Cold Spring Harbor Laboratory.
Given that spontaneous mutations in DNA increase with age, and that many women in industrialized nations are postponing childbirth until the last minute, the theory may also explain why older parents are at greater risk of having autistic children, Wigler said.
The little-understood disorder is characterized by poor social and communication skills and afflicts one in 150 children, most of them boys, according to the latest estimates from US public health authorities.
The study appears in the Proceedings of the National Academy of Sciences.
New Theory about Autism Roots
It appears that some boys have as much as a 50 percent risk of developing the mysterious disorder
In work that may one day lead to earlier detection of children at risk of developing autism, a team of scientists has devised a genetic model for the enigmatic disorder. The two-tiered theory integrates families with one or more autistic children.
An estimated one in every 150 children born in the U.S. develops autism, according to the Centers for Disease Control and Prevention (CDC); it is four times more prevalent in boys than in girls. The condition is characterized by cognitive deficiencies and symptoms ranging from antisocial (not responding to one's name and / or avoiding eye contact) to obsessive, repetitive behavior. The most popular theory about its genesis is that there are flaws in several genes passed down through generations of a family that culminate to predispose a child to the disorder, especially if exposed to certain environmental factors such as toxic chemicals or a lack of oxygen at birth.
"People thought there was this uniform risk—if you have an autistic child, then there's some uniform, but fairly low, risk that you'll have another one," says Michael Wigler, a professor of genomics at Cold Spring Harbor Laboratory (CSHL) in Long Island, N.Y., and senior author of the new model described in Proceedings of the National Academy of Sciences USA. "None of the population geneticists, in my experience, had thought that there might be two classes of families: low risk and high risk."
Wigler's rethinking of autism's cause stems from an exhaustive analysis of risk based on a database of families with more than one autistic child. (The Autism Genetic Resource Exchange, or AGRE, manages the database.) The team determined that most cases of autism arise from novel, spontaneous mutations passed down from one or both parents, resulting in large gaps in a person's genome often encompassing several genes, which are then disrupted or inactivated. (This loss of genetic code—known as copy number variation—results in an offspring receiving only one of the standard two copies of a gene, which could cause an insufficient amount of protein to be produced by those genes.) In most instances, this mutation will result in an autistic child. However, in some cases—more likely in girls than boys—the recipient of this mutation will not produce any symptoms.
"When that child matures and becomes a parent, they have a 50 percent chance of transmitting … [their mutation] … to a child that might not be as lucky as they were, especially if … [its] … a boy," Wigler says. "So, they will be transmitting this with close to a 50 percent frequency—and that is the source of the high-risk families."
Wigler says that the team will continue to update its model as new figures are added to the AGRE database and try to gain new insight into the mechanism that gives girls greater resistance than boys. "To understand that [disparity] at a molecular or genetic level would be very important, because you could theoretically treat kids … you could detect something early and intervene," Wigler says. "I view it as the most important thing to understand."
Maja Bucan, an associate professor of genetics and gene variation at the University of Pennsylvania, says that the new autism model is a creative way to interpret the familial data. "It's important to come up with new theories and then just test them once we have more data," she explains. "I don't think we have enough data [yet] to say whether this theory is right or wrong."
According to Wigler, the new model "certainly changes the way you think about autism. The paradigm shift is … something can be genetic without being heritable. The field has ignored the contribution of spontaneous mutation for a whole range of things that matter a lot to society," which, he adds, includes schizophrenia and morbid childhood obesity.
In work that may one day lead to earlier detection of children at risk of developing autism, a team of scientists has devised a genetic model for the enigmatic disorder. The two-tiered theory integrates families with one or more autistic children.
An estimated one in every 150 children born in the U.S. develops autism, according to the Centers for Disease Control and Prevention (CDC); it is four times more prevalent in boys than in girls. The condition is characterized by cognitive deficiencies and symptoms ranging from antisocial (not responding to one's name and / or avoiding eye contact) to obsessive, repetitive behavior. The most popular theory about its genesis is that there are flaws in several genes passed down through generations of a family that culminate to predispose a child to the disorder, especially if exposed to certain environmental factors such as toxic chemicals or a lack of oxygen at birth.
"People thought there was this uniform risk—if you have an autistic child, then there's some uniform, but fairly low, risk that you'll have another one," says Michael Wigler, a professor of genomics at Cold Spring Harbor Laboratory (CSHL) in Long Island, N.Y., and senior author of the new model described in Proceedings of the National Academy of Sciences USA. "None of the population geneticists, in my experience, had thought that there might be two classes of families: low risk and high risk."
Wigler's rethinking of autism's cause stems from an exhaustive analysis of risk based on a database of families with more than one autistic child. (The Autism Genetic Resource Exchange, or AGRE, manages the database.) The team determined that most cases of autism arise from novel, spontaneous mutations passed down from one or both parents, resulting in large gaps in a person's genome often encompassing several genes, which are then disrupted or inactivated. (This loss of genetic code—known as copy number variation—results in an offspring receiving only one of the standard two copies of a gene, which could cause an insufficient amount of protein to be produced by those genes.) In most instances, this mutation will result in an autistic child. However, in some cases—more likely in girls than boys—the recipient of this mutation will not produce any symptoms.
"When that child matures and becomes a parent, they have a 50 percent chance of transmitting … [their mutation] … to a child that might not be as lucky as they were, especially if … [its] … a boy," Wigler says. "So, they will be transmitting this with close to a 50 percent frequency—and that is the source of the high-risk families."
Wigler says that the team will continue to update its model as new figures are added to the AGRE database and try to gain new insight into the mechanism that gives girls greater resistance than boys. "To understand that [disparity] at a molecular or genetic level would be very important, because you could theoretically treat kids … you could detect something early and intervene," Wigler says. "I view it as the most important thing to understand."
Maja Bucan, an associate professor of genetics and gene variation at the University of Pennsylvania, says that the new autism model is a creative way to interpret the familial data. "It's important to come up with new theories and then just test them once we have more data," she explains. "I don't think we have enough data [yet] to say whether this theory is right or wrong."
According to Wigler, the new model "certainly changes the way you think about autism. The paradigm shift is … something can be genetic without being heritable. The field has ignored the contribution of spontaneous mutation for a whole range of things that matter a lot to society," which, he adds, includes schizophrenia and morbid childhood obesity.
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