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CHOP Team Identifies CNVs, Pathways Linked to Autism

NEW YORK (GenomeWeb News) – Researchers have uncovered about two dozen novel copy-number variants strongly linked to autism-spectrum disorders, while also confirming the association of a further 31 known CNVs with the disorders, they reported in PLOS One yesterday.

The team, led by Hakon Hakonarson, the director of the Center for Applied Genomics at Children's Hospital of Philadelphia, examined whether families with a high risk of autism harbored CNVs that could also contribute to raising disease risk in the broader autism population. Many of the CNVs they found are located near genes involved in neurological functions and implicated in other neurological disorders.

"Many of these gene variants may serve as valuable predictive markers," Hakonarson said in a statement. "If so, they may become part of a clinical test that will help evaluate whether a child has an autism spectrum disorder."

The researchers turned to 55 people from families in Utah with multiple family members that had an autism-spectrum disorder. Using Affymetrix Genome-Wide Human SNP arrays, they identified 153 CNVs linked to the disorders.

With that as a basis, Hakonarson and his team developed a custom Illumina iSelect array containing probes for those CNVs as well as probes for an additional 185 autism CNVs that had previously been reported in the literature. Then, they used that array to analyze 1,544 cases and 5,762 controls. To call CNVs, the researchers used both PennCNV and Golden Helix's CNAM.

Using TaqMan copy number assays, the researchers focused on validating CNVs that had an odds ratio greater than 2.0, or that was quite rare but seen in at least two cases. This, the researchers noted, meant that they would likely have clinical significance. About 60 CNVs were validated in that way.

Interestingly, the researchers noted that CNVs called by both PennCNV and CNAM were more likely to be validated.

Of the 153 CNVs found in the families, 139 were present in the larger study and 15 of them were then validated. Those CNVs included a deletion near the 5' end of the NRXN1 gene as well as a CNV affecting the LINGO2 gene, which has a known role in Parkinson's disease.

An additional 25 CNVs were identified in the high-risk families using SNV probes, and nine of those were also validated. A further 31 CNVs identified in the literature or from unpublished work at CHOP were also validated in this study.

Hakonarson and his team noted that a number of the CNVs they validated are located near genes involved in neural function, such as GABRA5, LINGO2, and IL1RAPL1. Four of the genes they pointed out — E2F1, AADAT, NECAB3, and IL1RAPL1 — may be novel autism risk genes.

"Many of these gene pathways active in ASDs overlap with those in other nervous system disorders, such as schizophrenia and epilepsy," Hakonarson said. "At the same time, our results are consistent with other studies suggesting that many different biological pathways, when disrupted, can lead to ASDs."

Researchers from Salt Lake City-based molecular diagnostics firm Lineagen also participated in the study. The company said that this study validates the ASD markers it uses in its FirstStepDx Plus test for diagnostic evaluation of individuals with ASDs, developmental delay, and intellectual disability.