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CHOP-Led Study IDs Pathways Impacted by Rare, Inherited CNVs in Autism

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a paper appearing online today in Molecular Psychiatry, a research group led by investigators at The Children's Hospital of Philadelphia reported that rare, inherited copy number variants associated with autism often fall in pathways involved in brain communication and other processes that seem to be consistent with autism-associated behaviors and phenotypes.

The team used array-based analyses to track down CNVs in hundreds of families affected by autism spectrum disorders, comparing these to copy number patterns in thousands of unaffected individuals. In so doing, they found evidence that autism-specific copy number changes frequently affect genes in pathways related to synaptic function, neurotransmission, and other intriguing processes.

"This large study is the first to demonstrate a statistically significant connection between genomic variants in autism and both synaptic function and neurotransmission," senior author Peter White, director of CHOP's Center for Biomedical Informatics, said in a statement.

Although autism spectrum disorders are often inherited within families, the researchers explained, past studies have shown that autism's genetic underpinnings are complicated and likely involve many small changes across the genome.

Because previous research has hinted at a role for CNVs in a range of neuropsychiatric conditions, including autism and schizophrenia, the team decided to home in on these CNVs for the current study, looking at pathways that were affected in individuals with autism but not unaffected controls.

"Our approach considered whether groups of genes with common biological functions collectively accounted for a greater percentage of autism risk," lead author Xiaowu Gai, a researcher with CHOP's Center for Biomedical Informatics, said in a statement.

For the initial stage of the study, researchers used the Illumina Infinium II Human-Hap550 BeadChip to genotype 631 children with autism spectrum disorders and 1,162 parents recruited through the Autism Genetic Resource Exchange. They then compared CNV patterns in these families with those detected in 1,775 unaffected children. All of the individuals included in their analyses were of European descent.

Although the team didn't detect any obvious differences in the overall number or size of CNVs in the case and control groups, they did track down 395 rare, inherited CNVs that only turned up in families affected by autism. Of the 382 non-olfactory genes affected by these changes, they noted, just 14 genes were altered in five or more individuals not related to one another.

When the researchers started scrutinizing the predicted functions of these CNV-affected genes, though, they found an over-representation of genes involved in processes such as cell signaling, synapse function, and neurotransmission.

The team unearthed another 392 inherited, autism-related CNVs affecting 387 non-olfactory genes when they used the same approach to look for copy number alterations in a second group of individuals of European descent, also recruited through AGRE. This replication group included 593 individuals with autism, 1,109 of their parents, and 2,026 controls.

Despite identifying hundreds of CNVs in the replication group, the researchers noted that just 11 percent of the affected non-olfactory genes overlapped with those found in the initial analysis.

Nevertheless, when they combined their data on all 1,224 children with autism spectrum disorders from both cohorts, the researchers found CNV patterns similar to those detected in the discovery group: again, genes harboring copy number changes in the affected children frequently fell in synapse- and neurotransmission-related pathways.

"This suggested to us that there may be many different — possibly even hundreds — of genetic paths to autism, with only a few gene alterations relevant to each individual patient," White said. "But if those hundreds of genes have similar roles in the nervous system, the end result may lead to the same diagnosis: an autism spectrum disorder."

Moreover, by bringing information from the autism-related CNV gene set together with phenotypic data from mouse models, the team found clues that several genes detected in the CNV analysis might also be tied to autism-related behaviors and phenotypes, including movement, coordination, and spatial learning.

"These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of [autism spectrum disorder] pathophysiology and suggest a sizeable pool of additional potential ASD risk loci," the team wrote.

Though the findings suggest it may be difficult to come up with diagnostic tests for autism based on individual genes, those involved in the study argue that such pathway analyses could help uncover previously unappreciated processes underlying autism and related conditions, perhaps leading to other treatment and diagnostic options down the road.

"Because the gene alterations that we found influence brain development, our hope is that they may eventually provide clues to developing diagnostic tests as well as treatments for children with autism," co-author Josephine Elia, a child psychiatrist at CHOP, said in a statement.

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