Understanding the Roots of Autism

Specific cellular pathways, along which genetic mutations occur, appear to play a key role in the development of autism spectrum disorders (ASD), according to new research from Icahn School of Medicine at Mount Sinai.

The findings, published online in the April 24, 2014, issue of The American Journal of Human Genetics, provide scientists with a better understanding of the complex genetic architecture involved in ASD, which has its roots in early brain development.

The study was led by Dalila Pinto, PhD, Assistant Professor of Psychiatry, and Genetics and Genomic Sciences at Icahn School of Medicine, as part of the Autism Genome Project Consortium, and examined 2,446 individuals with ASD and their parents in the United States, Canada, and Europe. The team isolated DNA from the participants’ blood samples or cell lines genotyped with high-resolution microarrays, and examined the copy-number variation (CNV)—or deletions or duplications in sections of DNA—in the samples.

The team’s results confirmed previous findings that people with autism have an excess of rare genetic deletions and duplications affecting genes, when compared with people who do not have the disorder. In addition, the investigators reported that some of these genetic changes were inherited, while others were de novo and not observed in the parents.

ASD is estimated to occur in 1 out of every 68 births, according to the U.S. Centers for Disease Control and Prevention. It is a host of complex disorders characterized by difficulties in communication and social interaction, and repetitive behaviors.

Dr. Pinto says her team began to analyze the pathways in which genetic activity occurs after asking the following question: “If different genes can be altered in different individuals with ASD, why does it manifest itself so similarly in individuals?”

She says, “We found that changes can affect different genes but always the same interconnected pathways. Some nodes of the pathway or network are more important than others. But when the hubs are dysregulated, the system gets disturbed, and the result will determine the clinical phenotype of the child.”

In a number of individuals with ASD, the researchers discovered that their respective CNVs involved a gene that indicated greater risk for developing epilepsy, demonstrating that identifying genetic alterations for ASD may indicate other medical conditions.

The recent findings expanded upon an earlier study led by Dr. Pinto in 2010. The next step, she says, will be an even larger study that enables her team to find more genes and additional sections of the pathways.

Her lab is searching for genetic overlaps between ASD, epilepsies, and intellectual disabilities. Understanding the biology behind autism, she adds, will help scientists improve early diagnosis and intervention.

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