Collaborators at the University of Oxford aim to carry out pilot genetic testing trial.

A major international study investigating the genetic basis of autism spectrum disorder (ASD) has identified a number of genes linked to risk of developing the disorder. The three-year Autism Genome Project, funded by Autism Speaks, claims the findings support the growing consensus that autism is caused in part by many rare genetic variants that are generally found in less than 1% of the population.

One of the study’s lead research teams at the Wellcome Trust Centre for Human Genetics at the University of Oxford now hopes to carry out a pilot study to investigate the potential use of genetic testing for diagnosing new cases of autism.

The study is published in Nature in a paper titled “Functional impact of global rare copy number variation in autism spectrum disorders.”

The Autism Genome Project involved the analysis of high-density genotyping data from 1,000 children with ASD and 1,300 children without the condition. “We know that 10 million gene variants consistently exist in every individual’s genome,” explains Rita Cantor, Ph.D., professor of human genetics at the University of California, Los Angeles, whose scientists co-led the study.  “We used DNA chips to collect and analyze data on 1 million of these variations to shed light on how autism develops.”

The results identified new autism susceptibility genes including SHANK2, SYNGAP1, DLGAP2, and the X-lined DDX53-PTCHD1 locus. Importantly, the study found that children with autism carried about 19% more gene-disrupting copy number variants (CNVs) than children in the control group, especially for loci previously implicated in either ASD and/or intellectual disability. Among the CNVs were numerous de novo and inherited genetic glitches, which were sometimes combined in a given family. While some of the affected genes have been linked with synapse-related pathways, others appear to represent functional targets.

“We found a number of disruptions that are new, or de novo,” comments Daniel Geschwind, Ph.D., Gordon and Virginia MacDonald distinguished chair in Human Genetics and UCLA professor of neurology and psychiatry. “The autistic child is the first in their family to carry that variant. This suggests that tiny genetic errors may occur during formation of the parents’ eggs and sperm. The finding parallels what takes place in chromosomal disorders like Down syndrome.”

The authors do stress that their findings won’t explain every case of autism. “This study’s larger sample size enabled us to pinpoint rare variations that we could not have detected in a smaller group,” says co-author Stanley Nelson, Ph.D., UCLA professor of human genetics and psychiatry. “Yet these findings explain only 3.3 percent of the genetic origins of autism. In order to identify all of autism’s genetic causes, we need tens of thousands of families to volunteer their DNA samples for sequencing.”

The researchers hope in the meantime to go one step further and identify groups of disrupted genes implicated in key functions or biological processes. They hope the results will provide new insights into the genetic basis of autism risk and provide potential new therapeutic avenues. 

“Our findings provide strong support for the involvement of multiple rare genetic CNVs, both genome-wide and at specific loci, in ASD,” they conclude. “The combined identification of higher-penetrance rare variants and new biological pathways, including those identified in this study, may broaden the targets amenable to genetic testing and therapeutic intervention.”

The study’s collaborators at the University of Oxford are separately applying for funding to carry out a pilot study assessing the use of DNA microarray testing for CNVs in children who have been newly diagnosed with autism. Such tests are already available to help in the diagnosis of learning disability, they point out.

“Just knowing about these genetic changes can help the families involved come to terms with why their child has autism, but it can also be important where there are siblings too in determining future risk,” remarks Tony Monaco, M.D., professor at the Wellcome Trust Centre for Human Genetics.

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