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Researchers Develop Screen for Autism-Linked Copy Number Variants

NEW YORK (GenomeWeb News) – Researchers have developed a new method for detecting copy number variants associated with autism spectrum disorder — and, in the process, uncovered new chromosomal duplications linked to ASD.
In a paper appearing online today in BMC Medical Genomics, a team of researchers led by Joseph Buxbaum, a psychiatry researcher at the Seaver and NY Autism Center of Excellence at New York’s Mount Sinai School of Medicine, screened nearly 300 children with ASD for micro-duplications and -deletions in suspicious regions of the genome: those linked to other cognitive conditions.
They detected several known and previously unrecognized duplications associated with ASD, raising the possibility that the approach could eventually help diagnose autism and related conditions early on, so that children can receive appropriate behavioral interventions as soon as possible, researchers say.
Autism and ASD are a group of developmental conditions affecting an estimated three to six children in every thousand. Males are about four times as likely as females to develop ASD, a group of conditions characterized by impaired communication and social interactions, stereotypical and repetitive behaviors, and, in some cases, cognitive impairment.
Even so, the nature and severity of ASD varies dramatically. In addition, some cases are linked to known genetic conditions such as Fragile X syndrome, while others aren’t, leaving researchers hunting for new genetic targets.
For the latest study, Buxbaum and his colleagues used an approach called multiplex ligation-dependent probe amplification, or MLPA, to look for gene dosage abnormalities already known to have a role in cognitive impairment. The approach relies on two probes that are homologous to the sequence of interest. If the probes bind, researchers can join the probes with a ligase and evaluate the stretch of DNA using qPCR.
Although a significant number of larger duplications and deletions have been detected, Buxbaum told GenomeWeb Daily News, it is now increasingly obvious that there are copy number variations at every level. MLPA is advantageous, he said, because it is cheap and easy way to target both large and small duplications and deletions. It can also be used to detect methylation abnormalities easily, Buxbaum noted.
The researchers screened 279 unrelated children with ASD using four different MLPA panels targeted parts of the genome previously linked to cognitive impairment. The subjects, who were around 8 years old, were not pre-selected based on dysmorphism or cognitive defects, Buxbaum said.
After weeding out copy number variants that were found in healthy controls and validating micro-deletions or -duplications using fluorescence in situ hybridization, quantitative PCR, or direct sequencing, the researchers found that about one to two percent of those with ASD also had a chromosomal abnormality associated with cognitive impairment.
For instance, they found subjects with duplications in a chromosome 15 region known to be involved in Prader-Willi/Angelman syndrome, a region of chromosome 22 that’s linked to DiGeorge syndrome, and a region of the X-chromosome that’s associated with X-linked non-specific mental retardation. The team also detected subjects with a partial duplication in the ASMT gene, which is found in the pseudoautosomal region 1 of sex chromosomes and has been previously linked to ASD.
Although the approach is quick and easy, Buxbaum cautioned, MLPA can’t be used to find new, unknown mutations — a situation that may occur in autism. That means it could miss private mutations that could be caught using array CGH with a dense chip.
But array CGH is very expensive and time consuming, Buxbaum said. So while array CGH may be the wave of the future, he said, it will take time to catch on. In the meantime, researchers noted, new genetic abnormalities can be incorporated into future MLPA-based autism tests as they are detected.
Although it’s increasingly clear that autism encompasses many different subgroups with different genetic underpinnings, unraveling the individual mutations still provides important clues about autism’s biology. Eventually, Buxbaum said, such studies could pave the way for a more individualized, targeted approach to treating autism and related conditions.
For now, though, Buxbaum envisions the screen as a quick way to provide an etiological diagnosis for children suspected of having autism. That, in turn, could help autistic children get appropriate behavioral therapies.
But, he emphasized, it would be unrealistic and undesirable to think of applying this sort of test in a prenatal setting, particularly because the individual mutations associated with autism are often incredibly rare, often with a vast range of expressivity. In cases where there is a family-member with a known genetic condition, Buxbaum noted, genetic testing for that specific condition can sometimes be desirable.
“Every time you say genetic testing, some people automatically think of pre-natal testing,” Buxbaum said. “This is more about giving an etiological diagnosis to children with autism.”

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