Copy number linked to autism

Copy number variation could be an important factor in autism, according to a new study published in Science today (March 15).

The largest percentage of copy number mutations occurred in families with one autistic child, the so-called sporadic, or spontaneously occurring cases -- not in families with multiple autistic children, indicating genetic inheritance.

Autism is widely recognized to be a genetic disorder, but this study focused on de novo genetic mutations (those present in the child but not the parents), rather than inherited mutations. "The majority of genetic studies to date have focused on the minority of families with multiple affected kids," study author Jonathan Sebat of Cold Spring Harbor Laboratory in New York told The Scientist. Until recently it hadn't been recognized that "the sporadic cases might be a rich source of genetic information," he said.

This study is part of a growing shift in the focus of study in genetics, according to James R. Lupski at Baylor College of Medicine, who did not participate in the research. Instead of looking at single nucleotide mutations of single genes, advances in microarray technology are letting researchers zoom out to look at the whole genome. And what they are finding is that structural genomic mutations can cause major phenotypic changes, according to Lupski.

Sebat and his colleagues analyzed the DNA from 264 families using either blood, immortalized B-cells, or both. They used ROMA, a type of microarray that relies on comparative genomic hybridization, to compare the children's genomes to the parents'. Each potential copy number variation, or CNV, was re-tested with a fresh blood sample from the same person for confirmation.

The study found that 10% of children (12 out of 118) with sporadic autism had de novo copy number variations, whereas only 1% of controls (2 out of 196), who had no history of autism, showed CNVs. Among families with multiple autistic children, only 2% (2 out of 77) autistic children showed differences in copy number from their parents.

The frequency of de novo mutations in children with sporadic autism "is high," said Charles Lee of Brigham and Women's Hospital at Harvard Medical School, who did not participate in the research. Lee has surveyed CNVs in the general population and found rates of de novo mutation in the general population on the order of 0.2%.

Most of the mutations seen in the autistic children overall were deletions, whereas the two CNV cases in the control group were gene duplications. The finding isn't necessarily surprising, said Sebat, who said that human bodies are "less tolerant" of deletions. "When you're down to only your back-up copy for a gene, you're at greater risk for whatever minor defects may exist in that that gene."

Lupski noted that one of the paper's limitations is that it falls short of describing the exact gene, or set of genes, that cause autism. "But I don't care what the gene is right now," he said, "because I know that this will lead us to a better chance at finding that gene."

Finding the genes responsible for autism is one of the goals that Sebat and his colleagues have set for their next project. "We'll be screening at least 2,000 families over the next three years using a much higher resolution platform," Sebat said. He added that he hopes the data will provide a better estimate of the frequency of CNV in sporadic autism, as well as a view of a larger array of genes involved than when researchers restricted their studies to inherited cases. "I think this will be a study that really tips the balance in the field towards using technologies that can directly detect mutations, [and] focusing on the majority of cases that are sporadic."

Edyta Zielinska
mail@the-scientist.com

Links within this article

I. Ganguli, "Copy number a major source of variation,"The Scientist, May 2006.
http://www.the-scientist.com/article/display/23372

J. Sebat et al, "Strong association of de novo copy number mutations with autism," Sciencexpress, March 16, 2007.
http://www.sciencemag.org

Jonathan Sebat
http://gradschool.cshl.edu/sebat_.html

James Lupski
http://imgen.bcm.tmc.edu/molgen/lupski/lupski_james.html

JR Lupski and PP Stankiewicz, "Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes," PLoS Genet. December 2005
http://www.the-scientist.com/pubmed/16444292

Charles Lee
http://labmed.bwh.harvard.edu/pathology/Faculty/Charles_Lee.htm

Richard Redon, et al. Global variation in copy number in the human genome. Nature. November 2006.
http://www.the-scientist.com/pubmed/17122850

JP Roberts, "Looking at variation in numbers," The Scientist, March 14, 2005.
http://www.the-scientist.com/article/display/15302/