Previously unknown chromosomal abnormalities play substantial role in autism

Jan 18 2008

Genome-wide scans of families affected by autism spectrum disorder (ASD) have revealed new evidence that previously unknown chromosomal abnormalities have a substantial role in the prevalent developmental disorder, according to a report published online Jan. 17th in the American Journal of Human Genetics, a publication of Cell Press.

Structural variants in the chromosomes were found to influence ASD with sufficiently high frequency to suggest that genomic analyses be considered in routine clinical workup, according to the researchers.

“Historical studies in identical twins and their families have provided strong evidence for a genetic basis of autism,” said Stephen Scherer of The Hospital for Sick Children and the University of Toronto. “Last year, with the Autism Genome Project Consortium, we did an initial study to look at the rate of chromosomal changes in autism. Now, we've really pinned down those numbers.”

Autism is a complex developmental disorder found in about one in every 165 children, making it one of the most common forms of developmental disability of childhood. Individuals with ASD have deficits in social interaction and communication and show a preference for repetitive, stereotyped activities. Structural changes, including gains and losses of genes as well as chromosomal translocations (in which a chromosomal segment ends up in the wrong place) or inversions (in which a portion of the genome is oriented backwards) have been previously identified in some individuals with ASD, but their causal role hasn't been clear.

In the new study, the researchers examined structural abnormalities in 427 unrelated ASD cases using both microarray analysis and karyotyping. Microarrays can detect “unbalanced” genetic changes that alter the number of copies of a particular gene. Karyotyping, in which chromosomes are viewed under the microscope, can identify “balanced” translocations or inversions that might otherwise be missed by microarrays.

While most chromosomal abnormalities were inherited, the researchers found that seven percent of children with autism carry structural changes in the genome that are not found in their parents. The rate of such de novo changes in the general population is typically less than one percent, Scherer said.

The researchers detected 13 regions of the genome with overlapping or recurrent chromosomal changes in unrelated people with autism, suggesting that genes located at these sites may cause or add to the complexity of the condition. The most prevalent change, occurring in one percent of ASD cases, was found on chromosome 16, they reported. The altered portion of chromosome 16 has structural characteristics that make it more prone to errors, Scherer noted.

In a subset of ASD cases, the researchers found abnormalities in several genes known to be involved in neuron function. They also identified at least two sites that have previously been linked to mental retardation.

“Our understanding of the full etiologic role of structural variation in ASD will require genomic and phenotypic analyses of more cases (and their families) and population controls,” the researchers concluded. As a first step toward achieving the desired numbers, the researchers have established a new Autism Chromosome Rearrangement Database, which allows integration of their new data and all other molecular information with the wealth of karyotypic data gathered over the years.

In light of the new findings, Scherer's team also calls for new testing in the clinic.

“From our current data it is already apparent that for a proportion of individuals, it will be possible to describe their ASD based on the underlying structural characteristics of their genome,” they wrote.

“If we found certain changes, we could then watch those children closer,” Scherer added, noting the critical importance of early diagnosis for autism.