Autism spectrum under study

Population Dx, Toronto’s Hospital for Sick Children discover gene variants for autism spectrum disorder

Lori Lesko
MELVILLE, N.Y.—Population Diagnostics Inc. (PDx), a privatefirm known for uncovering the genetic causes of disease, recently announced theresults of its collaboration with the Hospital for Sick Children (SickKids) inToronto on the discovery of a collection of gene variants associated withautism spectrum disorder (ASD).
Their findings, reported Dec. 12 in the journal Genes/Genomes/Genetics (G3), could openthe door of early detection diagnostic tests and more personalized treatmentfor those suffering from the social, behavioral and learning disabilities ofautism.
"Both Population Diagnostics and SickKids have beenindependently engaged for several years in finding genes—and the mutationswithin them—that cause autism," Peggy S. Eis, chief technology officer at PDx,tells ddn. "We both use the same genediscovery 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 geneticanalysis studies enabled them to uncover the full spectrum of mutations withinthe set of ASD-associated genes.
"We are currently analyzing the data further usingadditional methods that reveal even smaller sized genetic variants, most ofwhich would likely be missed by other microarray methods," says Eis."Importantly, because we are using a microarray that screens for CNVs in allregions of the genome, we can discover ASD mutations that occur within intronsand in regions between the genes, which often harbor regulatory DNA sequencesthat 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 arecompletely missed in exome sequencing studies, says Eis. A subset of the genesdescribed in the published study have already been linked to neurodevelopment (e.g., synapse formation) andneurochemistry (e.g.,neurotransmitter receptors). For example, the gene SYAP1 (synapse associatedprotein 1) that was found to be mutated in three ASD patients is known toimpact 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, whichwas generated on genomic DNA samples obtained from 1,000 individuals withoutASD or any other major diseases or conditions," Eis says.
Discovering these ASD-associated genes via CNVs that occuronly—or almost exclusively—in ASD patients is the critical first step, Eissays. Because there are at least 1,000-fold fewer CNVs in a person's genomecompared to single-nucleotide variants (SNVs), it is far more efficient tofirst assess CNVs in the genomes of ASD cases versus controls.
"Our gene discovery approach can be applied to any diseasethat 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 smallpercentage of patients on immunosuppressive therapies," Eis says. 
In some cases, targeting a biological pathway that isimpacted by mutations in one of several genes may be possible, and in othercases drugs will have to be developed that target a single gene, she says.
"While this sounds rather daunting, fortunately, there hasbeen significant progress in drug discovery methods that will enabledevelopment of targeted therapeutics," Eis says. "There are a handful oftargeted drugs on the market today in other diseases, so the drug developmenttechnologies already exist for targeted medicines."
In addition to discovering 16 novel genes associated withautism—many of which are implicated in neurodevelopment—"this study highlightsthe general importance of analyzing genomes specifically for CNVs, which is atype of genetic variant that can disrupt, delete or generate multiple copies ofa gene," says primary investigator Dr. Stephen Scherer of the Hospital for SickChildren.
"Several interesting new autism risk genes have beenhighlighted in this study," Scherer says. "We now need to go back and performmore validation work in larger case and control cohorts to determine the truly bona-fide autism risk genes. We alsoneed to figure out how they work in brain development."
Unfortunately, there are not yet any effective drugs thattreat autism, he says.
"However, with our new gene discoveries, pharmaceuticaltargets are now known and companies are developing drugs for them," Scherersays. "The progress looks very encouraging." 
The discoveries reported in this study "underscore that thegenetic landscape for autism involves numerous genes containing manylow-frequency genetic variants with large effect, Eis concludes.
"Collectively, these newly discovered genes from ourcollaboration with SickKids, along with novel genes from our finer-scaleanalysis that will be reported in a future paper, represent a significantportion of the unexplained genetic contribution to autism and greatlycontribute to our understanding of the underlying genetic causes of autism,"she says.

Lori Lesko

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