What’s missing may be key to understanding genetics of autism

Each person with autism may have their own genetic version of the developmental disorder, a new large-scale study finds.

Rare variations in which some parts of a person’s genetic blueprints have been erased or repeated are responsible for some cases of autism, the study shows. Such missing or duplicated stretches of DNA are known as copy number variations and have been implicated in schizophrenia and other diseases (SN: 4/25/09, p. 16).

The new study, published online June 9 in Nature, shows that some people with autism may be missing all or parts of one or several genes involved in the development and function of the brain. The findings could lead to improved diagnosis of the disorder, perhaps even in infants, and may give new direction to research on drug treatments.

“The exciting thing about the findings of this study is that it highlights biological pathways that can be targets for therapy,” says Geraldine Dawson, chief science officer of Autism Speaks, a national organization that helped to fund the new study.

Autism is a group of developmental disorders that impairs social interactions and often language development. Researchers don’t know the exact causes of the disorder, but genetic factors are strong suspects. Studies of identical twins show that when one twin has autism, about 90 percent of the time the other twin will too. Autism affects about one in every 100 children in the United States and is more common in boys.

Previous studies have indicated people with autism may have more copy number variants overall than healthy people do. But the new study shows that people with autism had the same number of deletions as people in a healthy control group did. However, people with autism tend to have deletions that remove parts or all of genes, while healthy people carry deletions on stretches of DNA that don’t contain genes.

“You and I may have just as many deletions in our genomes, but since they don’t hit genes, we don’t have autism” or other diseases, says Anthony Wynshaw-Boris, a medical geneticist at the University of California, San Francisco, who was not part of the new study. “This is a natural part of being a human being. We get mutations. Most of the time it’s not a problem, but sometimes it hits a gene involved in autism.”

In the new study, an international consortium of researchers analyzed the genetic makeup of 996 people with autism and 1,287 people without autism to discover genetic factors that contribute to the disorder. The researchers found more than 5,000 copy number variants in people with autism, usually places where DNA was missing. Many of the people with autism had more than one spot in the genome where they were missing large chunks of DNA, each about 30,000 base pairs long.

Each of the specific variants was rare on its own, with even the most common found in less than 1 percent of people in the study. Often, people with autism inherited the rare variants from their parents, but just under 6 percent of them had new deletions not found in their parents. Such new mutations may account for some sporadic cases of autism, the researchers say.

“Most individuals with autism are genetically unique,” says Stephen Scherer, a genome scientist at the Hospital for Sick Kids in Toronto and one of the leaders of the study. He says that researchers are likely to find even more copy number variants involved in autism. Some people may have larger or smaller deletions than were examined in the study.

The new work may also help settle a scientific debate about whether common diseases and disorders are caused by genetic variations present in many people, or if rare variants contribute more to these diseases. “This definitely suggests a role for rare variations in autism,” says Charles Lee, a clinical cytogeneticist at Brigham and Women’s Hospital in Boston and Harvard Medical School.

Although each person with autism appears to have a distinct set of genetic variations, the genes affected by the variants tend to affect similar biological processes. Further studies of the genes involved promise to give researchers a better picture of what causes autism, Wynshaw-Boris says.

Study coauthor Louise Gallagher of Trinity College in Dublin adds, “There’s a whole new definition of the underlying genetic mechanisms of autism.”

Some of the deleted genes had a strong link to autism, meaning that missing just a single copy is enough to push a person across the autism threshold, Scherer says. Other genes had to be inherited along with more deletions or other genetic factors for autism to develop.

One gene strongly linked to autism in the new study is called DDX53-PTCHD1, and is located on the X chromosome. Women — who have two X chromosomes — may carry a deletion of the gene on one of their X chromosomes, but a healthy copy of the gene on the other X chromosome is enough to cover for the missing copy. Problems may arise if a woman passes the X chromosome with the deleted gene on to a son. With no healthy copy of the gene (the Y chromosome doesn’t carry the gene) to compensate, he will get autism.

Researchers also identified several genes involved in forming connections, called synapses, between brain cells. The genes, SHANK2, SYNGAP1, and DLGAP2, had not been linked to autism before. Genes involved in a cell-to-cell communications system known as the Ras/GTPase pathway were also found to play a role in autism.

All together, the new study identified 25 places in the genome that may help in diagnosing autism. New genetic tests would probably focus on these markers, Lee says. If a person has a deletion in one of these places, he or she may have autism, but until scientists understand more about how genetic factors work together to cause disease, no one will be able to make a definitive diagnosis, he says.

Even with the new findings, scientists are able to explain genetic causes for only about 10 percent of autism cases, says Steven McCarroll, a geneticist at Harvard Medical School. “What causes autism in the other 90 percent of cases is still on the table,” he says. “Every little victory is important, but it’s still amazing how little we know.”