Studies: New Clues to the Genetic Roots of Autism

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Random changes in genes, rather than changes handed down from parents, may be responsible for some cases of autism, say scientists who report in three new papers a major breakthrough in understanding where those genetic changes may lie.

The findings suggest that autism is a genetically complex disorder, involving perhaps hundreds of spontaneous changes in genes. The discoveries should help researchers gain a better understanding of the biology of the disorder and find targets for better treatments. It’s latest in a steady stream of good news from autism researchers recently, who have reported on innovative ways to diagnose the disorder earlier (as we reported here, here and here) and on new genes that contribute to it (which we described here).

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For the new studies, published in the journal Neuron, researchers focused on about 1,000 families in which only one child was affected with autism. Much of the past research on the genetic roots of autism has looked at families with at least two affected siblings; these families may represent cases in which inherited genetic mutations may play a more prominent role in the disorder, but researchers wanted to understand the genetic factors involved in children whose condition cannot be traced back to their parents. Most cases of autism involve children whose other family members remain unaffected.

Two groups of scientists, working independently, focused their attention on these families, and compared the genetic differences between autistic and non-autistic members within each. What they found was that children with autism were about four times more likely than their unaffected siblings to have copy number variants (CNVs), mutations in which a part of the genome is either duplicated or deleted. The CNVs in children with autism were also larger and contained a higher density of genes than the CNVs in unaffected siblings. These differences may account for anywhere from 5% to 10% of autism in families with only one autistic child, the researchers said.

“These genetic studies open the door to understanding the biology and pathophysiology of the disorder,” says Dr. Matthew State, professor of child psychiatry, psychiatry and genetics at Yale University School of Medicine and one the study authors. “It lays an important foundation for the next step, which is to identify better treatments for folks with autism.”

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The CNVs involved in autism are rare. Many occurred in only one child. But some occurred more frequently: State’s group found four areas of the genome in which CNVs occurred in the autistic children, but not in unaffected children; one of those regions, on chromosome 7, is of particular interest in behavioral and developmental disorders. It’s known that people with deletions in this part of their genome have a condition called Williams syndrome, which causes them to be highly sociable, empathetic and excessively engaged with others. Too much DNA in this same area, however, is associated with autism spectrum disorders, in which people may be more withdrawn and antisocial and unable to interpret social cues.

Learning more about the effects of variations in that region of the genome may offer important insights to autism, says State, and “suggests that one of the relatively small number of genes in that interval is playing a critical role in the development of affiliation and social capacity. It could be a really important clue to understand what the underlying mechanisms of autism are.”

In another of the three new studies, led by Dennis Vitkup at Columbia University, scientists discovered hints as to why boys are more likely to have autism than girls. The researchers found that girls with autism had more CNVs and that their CNVs involved more genes, compared with boys with autism. That suggests that girls may have a higher threshold of tolerating CNVs in their genome than boys do — in other words, that girls need a higher number of genetic changes in order to develop autism. It sheds light on why autism spectrum disorders are four times more common in boys than in girls.

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The findings represent an important advance in the understanding of what drives autism spectrum disorders. And while it may be years before researchers can exploit the new information and translate it into effective therapies for the disorder, it’s an important first step. “The advances and new information are coming fast and furious now,” says State. And that’s a good thing.