Autism in some boys linked to missing DNA
TORONTO - Researchers are a step closer to understanding why autism spectrum disorder affects four times as many boys as girls.
A study led by a team of Toronto scientists has discovered that males who carry specific genetic alterations on their X-chromosome have an elevated risk for developing autism spectrum disorder, or ASD.
“The male gender bias in autism has intrigued us for years and now we have an indicator that starts to explain why this may be,” said co-principal investigator Stephen Scherer, director of the Centre for Applied Genomics at Toronto's Hospital for Sick Children.
The researchers, whose work is published this week in the journal Science Translational Medicine, found that about one per cent of boys with ASD had mutations related to the PTCHD1 gene on the X-chromosome.
"Hearing that it's in one per cent doesn't get a lot of people excited," conceded Scherer. "But it gets geneticists really excited because there's a lot of genes involved (in ASD)."
Boys inherit one X-chromosome from their mother and one Y-chromosome from their father, explained Scherer. "If a boy's X-chromosome is missing the PTCHD1 gene or other nearby DNA sequences, they will be at high risk of developing ASD or intellectual disability.
"Girls are different in that, even if they are missing one PTCHD1 gene, by nature they always carry a second X-chromosome, shielding them from ASD. While these women are protected, autism could appear in future generations of boys in their families."
Autism spectrum disorder affects an estimated one in every 165 children. The neurological disorder ranges in severity, but often includes problems communicating and interacting with others, unusual patterns of behaviour and intellectual disability.
An estimated 190,000 Canadians have ASD, which is on the rise worldwide, says Autism Society Canada.
The isolation of genetic alterations on the X-chromosome within a percentage of individuals with autism follows a number of recent genetic discoveries by Scherer and others that are moving science slowly but surely towards a better understanding of the causes of this baffling disorder.
To conduct this study, researchers analyzed the gene sequences of 2,000 individuals with ASD, along with others with an intellectual disability, and compared the results to DNA sequencing from thousands of healthy control subjects.
While the PTCHD1 mutation occurred in one per cent of males with ASD, it was not present in the DNA of thousands of healthy male controls — and sisters of males carrying the same mutation seemed unaffected by autism symptoms.
"The deletions and other mutations seem to be related only to disease in the boys," said co-principal researcher John Vincent. "They have sisters who have the same mutation but are healthy."
Vincent, head of the molecular neuropsychiatry and development lab at Toronto's Centre for Addiction and Mental Health, isn't surprised to find another gene on the X-chromosome involved in autism.
"It's another one in the list and I think it will be one of the most common ones, so parents will be able to have their children tested," he said. "Particularly if they have a son affected, it will be important for them to know if it's caused by a mutation at or around PTCHD1."
"And if it is, they'll know that future (male) children would be at risk."
"There are lots of women in the population," added Scherer, "who are carrying this (genetic variation) that are predisposed to having boys with autism."
The scientists believe the PTCHD1 gene plays a role in a neurobiological pathway that delivers information to cells during brain development, and this specific mutation could disrupt crucial processes and contribute to the onset of autism, said Vincent.
Having a test for the altered DNA would mean children could be diagnosed at a younger age, allowing behavioural therapies to be started sooner, he said. "So the earlier you can catch it, the more effective the therapies can be."
Calling the discovery "incredibly important," Suzanne Lanthier of Autism Speaks said the research provides solid evidence about what's behind ASD prevalence rates being skewed towards males.
"This is the first time we're seeing some hard science findings to start to explain why boys are more affected than girls," said Lanthier, executive director of the research fundraising organization and mother of an 11-year-old boy with ASD.
Asked if such genetic links to autism put an end to the contentious notion that childhood vaccines — in particular, the measles-mumps-rubella inoculation — may trigger autism, Lanthier responded that ASD is manifested in many ways "and it doesn't lay to rest potential environmental causes."
"And what the research is pointing to more and more is that there are some genetic underpinnings and in some cases environmental triggers that set off what we know genetically."
"It certainly doesn't mean that we should stop doing research on environmental causes. By no means."
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