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Autism spectrum under study
MELVILLE, N.Y.—Population Diagnostics Inc. (PDx), a private firm known for uncovering the genetic causes of disease, recently announced the results of its collaboration with the Hospital for Sick Children (SickKids) in Toronto on the discovery of a collection of gene variants associated with autism spectrum disorder (ASD).
Their findings, reported Dec. 12 in the journal Genes/Genomes/Genetics (G3), could open the door of early detection diagnostic tests and more personalized treatment for those suffering from the social, behavioral and learning disabilities of autism.
"Both Population Diagnostics and SickKids have been independently engaged for several years in finding genes—and the mutations within them—that cause autism," Peggy S. Eis, chief technology officer at PDx, tells ddn. "We both use the same gene discovery approach, so it was a natural fit to collaborate on autism."
The partners first identified copy number variants (CNVs) that are exclusively found in autism patients, which in subsequent genetic analysis studies enabled them to uncover the full spectrum of mutations within the set of ASD-associated genes.
"We are currently analyzing the data further using additional methods that reveal even smaller sized genetic variants, most of which would likely be missed by other microarray methods," says Eis. "Importantly, because we are using a microarray that screens for CNVs in all regions of the genome, we can discover ASD mutations that occur within introns and in regions between the genes, which often harbor regulatory DNA sequences that can alter gene expression (i.e., can increase or decrease the amount of protein made from the gene)."
In sharp contrast, intronic and intergenic regions are completely missed in exome sequencing studies, says Eis. A subset of the genes described in the published study have already been linked to neurodevelopment (e.g., synapse formation) and neurochemistry (e.g., neurotransmitter receptors). For example, the gene SYAP1 (synapse associated protein 1) that was found to be mutated in three ASD patients is known to impact learning and memory in a fly model for the corresponding gene, she says.
"In order to find genes that are causative or linked to ASD, the ASD data were interpreted using our company's control cohort data, which was generated on genomic DNA samples obtained from 1,000 individuals without ASD or any other major diseases or conditions," Eis says.
Discovering these ASD-associated genes via CNVs that occur only—or almost exclusively—in ASD patients is the critical first step, Eis says. Because there are at least 1,000-fold fewer CNVs in a person's genome compared to single-nucleotide variants (SNVs), it is far more efficient to first assess CNVs in the genomes of ASD cases versus controls.
"Our gene discovery approach can be applied to any disease that has a genetic basis, including Alzheimer's, Parkinson's, schizophrenia, endometriosis, peanut allergy and progressive multifocal leukoencephalopathy (PML), which is a rare but deadly brain disease that occurs in a small percentage of patients on immunosuppressive therapies," Eis says.
In some cases, targeting a biological pathway that is impacted by mutations in one of several genes may be possible, and in other cases drugs will have to be developed that target a single gene, she says.
"While this sounds rather daunting, fortunately, there has been significant progress in drug discovery methods that will enable development of targeted therapeutics," Eis says. "There are a handful of targeted drugs on the market today in other diseases, so the drug development technologies already exist for targeted medicines."
In addition to discovering 16 novel genes associated with autism—many of which are implicated in neurodevelopment—"this study highlights the general importance of analyzing genomes specifically for CNVs, which is a type of genetic variant that can disrupt, delete or generate multiple copies of a gene," says primary investigator Dr. Stephen Scherer of the Hospital for Sick Children.
"Several interesting new autism risk genes have been highlighted in this study," Scherer says. "We now need to go back and perform more validation work in larger case and control cohorts to determine the truly bona-fide autism risk genes. We also need to figure out how they work in brain development."
Unfortunately, there are not yet any effective drugs that treat autism, he says.
"However, with our new gene discoveries, pharmaceutical targets are now known and companies are developing drugs for them," Scherer says. "The progress looks very encouraging."
The discoveries reported in this study "underscore that the genetic landscape for autism involves numerous genes containing many low-frequency genetic variants with large effect, Eis concludes.
"Collectively, these newly discovered genes from our collaboration with SickKids, along with novel genes from our finer-scale analysis that will be reported in a future paper, represent a significant portion of the unexplained genetic contribution to autism and greatly contribute to our understanding of the underlying genetic causes of autism," she says.