Genetic mutations, environmental factors linked to autism

After years of struggling to identify genetic factors that contribute to autism spectrum disorder, scientists have identified several gene mutations that likely increase a person’s risk of developing the condition.

Using clinical sequencing, researchers estimate that there probably are 1,000 genes or more linked to the development of ASD. They also confirmed certain mutations often are linked to a child’s father.

The findings were published online April 4 in three separate studies in the journal Nature. Each study included lead investigators from the Autism Sequencing Consortium, an international group of autism genetics researchers working to identify additional genetic causes of autism through sequencing.

“We now have a good sense of the large number of genes involved in autism and have discovered about 10% of them,” said Joseph D. Buxbaum, PhD, a study author and director of the Seaver Autism Center for Research and Treatment at Mount Sinai School of Medicine in New York. The center leads research studies on ASD and cares for people with the condition.

As more of these genes are identified, “it will lead to earlier diagnosis [of ASD] and novel drug development. This work is crucial for advancing autism treatment,” said Buxbaum, professor of psychiatry, genetics and genomic sciences, and neuroscience at Mount Sinai. He also is a founder of the Autism Sequencing Consortium.

Though the findings are a significant step toward better understanding and treatment of ASD, they do not yet have much implication for primary care, said Jeremy Veenstra-VanderWeele, MD, assistant professor of psychiatry, pediatrics and pharmacology at Vanderbilt University School of Medicine in Nashville, Tenn.

Within a few years, physicians might be able to order genetic tests that comprehensively identify gene mutations linked to ASD, he said. In the meantime, doctors can tell parents whose child has ASD that scientists have identified some likely genetic causes of the neurodevelopmental condition and continue to search for more.

“This will help families emotionally to have an explanation of why their child has autism,” said Benjamin Neale, PhD, an author of one of the studies in Nature and assistant in genetics at Massachusetts General Hospital and Harvard Medical School in Boston.

Autism diagnoses increasing

Childhood autism diagnoses are rising in the United States, according to a study of 8-year-olds showing that about one in 88 has some form of ASD. In 2006, the rate was one in 110, said a study in the March 30 issue of the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report.

One potential factor contributing to the increase could be the growing prevalence of diabetes, hypertension and obesity among pregnant women, according to a study of more than 1,000 children and their mothers published online April 9 in Pediatrics. The study found that those three metabolic conditions were more common among mothers of children with ASD and other developmental disorders than in mothers whose children had typical development.

In addition to potential environmental factors in ASD, it long has been known that there is a genetic component to the condition.

For the three studies in Nature, researchers analyzed the genetic material of parents who do not have autism and the DNA of their children with the condition. They focused on de novo mutations, which are gene mutations that occur spontaneously at conception or shortly after it.

“It is important to point out that in each generation there is, on average, one new coding mutation per child, and not all of these will cause developmental problems,” said Brian J. O’Roak, PhD, one of the study authors and a senior fellow in the Dept. of Genome Sciences at the University of Washington School of Medicine in Seattle. “However, in the case of children with autism, [there] are disruptions in many genes that are known to directly interact and also look similar to genes previously associated with autism.”

De novo mutations were about four times more common in DNA from fathers than from mothers, according to one study’s analysis of 51 such mutations. The risk of having these genetic changes increased with age.

Genes identified as autism risk factors

Researchers have identified mutations in three genes that are risk factors for autism. Those genes are: KATNAL2, a gene whose function is unknown; SCN2A, which encodes a brain protein that forms a channel for sodium ions; and CHD8, which regulates gene transcriptions and modifies the network of proteins that surround DNA.

Together, these genes help explain only a small percentage of the genetic risk of autism, study authors said. But they said the findings are significant, because they represent a step toward understanding the biological process of ASD, which could help improve diagnosis and treatment of the condition.

“These results clearly demonstrate the potential of DNA sequencing to articulate specific risk factors for autism,” said Mark Daly, PhD, one of the study authors and chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital. “We have only scratched the surface, but with continued collaborative efforts, these gene discoveries will point us to the underlying biological roots of autism.”