About 1% of people with autism have a 500-kilobase region of the short arm of the chromosome either missing or duplicated, according to Mark Daly, Ph.D., of Massachusetts General Hospital, and colleagues.
The discovery of the so-called copy number variation offers a "very direct clue into the biological mechanism underlying autism," Dr. Daly said.
The region involved includes about 25 genes, he said, and the implication is that proteins produced by one or more of them lie at the root of autism. The proteins may also involve other psychiatric and cognitive disorders.
Too little protein or too much, and "you're out of the normal range" of human cognitive abilities, he said.
The next step for researchers, he said, is to determine which particular genes in the region are involved.
However, clinical autism specialists in Boston are already screening for the copy number variations among children whose family histories suggest they might be at increased risk of autism, Dr. Daly said.
Such tests could allow intervention long before the clinical signs of autism become manifest, he said.
The finding -- reported online today by the New England Journal of Medicine -- comes on the heels of a similar report online in Human Molecular Genetics in late December.
And it's a few weeks before another report, set to appear in the American Journal of Human Genetics, gives the same result.
Dr. Daly said the three reports, taken together, offer assurance that the finding is correct. "You never believe a genetic study until it has been confirmed," he said.
The region "is definitely involved in autism," said Steve Scherer, Ph.D., an autism researcher at the Hospital for Sick Children in Toronto and one of the senior authors on the coming report in the American Journal of Human Genetics.
Using a slightly different approach, as well as a different sample of volunteers, Dr. Scherer said, "we found the same thing -- 1% of our families with a copy number variation."
It's now clear that changes in the region are a "significant risk factor for development of autism spectrum disorder," Dr. Scherer said.
But, he noted, autism is a "very complex disorder" and exactly what clinical manifestations arise from the deletions and duplications needs further investigation.
"Autism spectrum disorder is a grab-bag of different disorders with overlapping clinical presentations," Dr. Scherer said.
The Boston researchers found an association between deletions or duplications of the region and autism in three separate cohorts totaling 2,252 patients with autism spectrum disorder, compared with more than 22,200 controls.
In each cohort, the association was highly statistically significant, at P=7.2x10-3 or smaller.
In most cases, the mutations appeared to be de novo, rather than inherited, the researchers found -- a result of errors during duplication of the chromosomes in early development.
But the cases of inheritance suggest some of the complexity of the subject, because parents carrying the mutations were not necessarily autistic. In one case, for instance, the father of an autistic boy carried the same deletion, but the father's problem was attention deficit hyperactivity disorder.
Also, some control volunteers also had deletions and mutations in the region, but without signs of autism spectrum disorder.
Dr. Daly and colleagues said the rate of the mutations appears to be 1% in those with autism, about 0.1% among those with a psychiatric or language disorder, and about 0.01% in the general population.
"It's challenging to put your finger on exactly what that means," Dr. Daly said.
It's likely that the effect of the copy number variations "extends beyond autism," commented Evan Eichler, Ph.D., of the University of Washington, and Andrew Zimmerman, M.D., of Johns Hopkins.
In an accompanying editorial, they noted that other diseases associated with genomic disorders tend to have different clinical manifestations, depending on the genetic background.
They also suggested that copy number variations on chromosome 16 and 15 (previously discovered to be linked to autism) may be "just the tip of the iceberg."
Better genomic techniques may find that copy number variations in a range of other genetic "hot spots" are also significantly associated with autism, they said.
|The study was supported by the Autism Consortium, the National Health and Medical Research Council of Australia, the Ellison Foundation, the Simons Foundation, the National Institute of Mental Health, and by a Ruth L. Kirschstein National Research Service Award. The researchers reported no conflicts.|
Zalman S. Agus, MD Emeritus Professor
University of Pennsylvania School of Medicine
New England Journal of MedicineSource Reference: Weiss LA, et al "Association between microdeletion and microduplication at 16p11.2 and autism" N Engl J Med 2008; DOI: 10.1056/NEJMoa075974.
Eichler E, Zimmerman A, "A hot spot of genetic instability in autism" N Engl J Med 2008; DOI: 10.1056/NEJMe0708756.
Human Molecular GeneticsSource Reference: Kumar RA, et al "Recurrent 16p11.2 microdeletions in autism" Hum Mol Genet 2008; DOI:10.1093/hmg/ddm376.