Chromosomal abnormality linked to autism disorders

Researchers have fitted another piece into the complex genetic puzzle that is autism, finding DNA deletions and duplications on a specific chromosome that they say explains one to two percent of the 1.5 million cases of autism and related disorders in the United States today.

The genetic changes were discovered in DNA scans of more than 3,000 people, both with and without autism spectrum disorder, a category of developmental disability that includes autism disorder, Asperger’s syndrome, and a broad category called “pervasive developmental disorder not otherwise specified.”

Autism spectrum disorders, which typically begin before age three, are characterized by impaired abilities to communicate and interact socially, as well as unusual behaviors and interests. Those with the disorder can range in mental ability from severely challenged to gifted, according to the Centers for Disease Control and Prevention (CDC). CDC statistics indicate that autism spectrum disorders affect roughly one in 150 children under the age of three.

The work, published online Wednesday (Jan. 9) by the New England Journal of Medicine, was conducted by the Autism Consortium, a group of 14 Boston-area universities and medical centers that, together with families, researchers, and clinicians, aims to accelerate research and advance care for those with autism spectrum disorders. The consortium includes several Harvard-affiliated institutions, including Massachusetts General Hospital, Children’s Hospital Boston, Harvard Medical School, Beth Israel Deaconness Medical Center, the Cambridge Health Alliance, McLean Hospital, and the Broad Institute of MIT and Harvard.

The work identified a region on chromosome 16 where a section of DNA 600 kilobases long was either deleted or duplicated. Though about 15 percent of autism cases are caused by known inherited genetic factors, these changes are thought not to be inheritable, rather occurring in the embryo during development. Researchers said the results were particularly robust because they were replicated by three research groups using different populations.

Harvard Medical School Assistant Professor Mark Daly, of Massachusetts General Hospital’s Center for Human Genetic Research and the Broad Institute, led the research team. Though the findings apply just to a small portion of all autism-related cases, Daly said that autism is such a complex condition that it is unlikely researchers will ever find a single cause for most cases.

“We know that for complex human diseases we’re not going to find a gene that explains it. We’re going to find 10 or 100 genes that interact to cause it,” Daly said. “This is likely a very strong causal factor in one to two percent of autism. That makes it a small piece of a larger puzzle. The hope going forward is that this may help us find other pieces.”

Daly said the research has been made possible by very recent advances in genetic screening technology that allow the analysis of far more material. As recently as 10 years ago, a similar study would have been impossible and, just two years ago, such a study would have been just “a shadow” of the current work, Daly said.

DNA, the long, coiled molecules that hold the blueprint for life, are present in almost every cell in the body. During normal times, they are dispersed in the cell nucleus, but during cell division they form compact bodies called chromosomes, arranged in pairs. Different species have characteristic numbers of chromosome pairs. Humans have 23.

The region on chromosome 16 where the deletions and duplications appear holds 25 genes, some of whose functions are related to the brain, according to Yiping Shen, director of research and development at Children’s Hospital’s Genetics Diagnostic Laboratory. The functions of other genes in the region are unknown.

The work consisted of an initial scan of 3,000 individuals, including 1,441 with autism spectrum disorders. That scan turned up five with deletions in this region. Further investigation at Children’s Hospital turned up another five deletions among 512 children who had undergone genetic testing because of developmental delays. Additional investigation by Iceland-based deCODE genetics found three individuals among a database of 299 people with autism-related disorders.

The investigation also found duplications in the same region, seven in the scan of 3,000 people and four in the Children’s Hospital group, all in people who showed signs of autism spectrum disorders. David Miller, assistant director of Children’s Genetics Diagnostic Laboratory, said that though it may seem that a genetic deletion and duplication would have opposite effects, it is a sign of the delicate balance needed for normal development that they don’t. It may be that the genes involved control some part of a complex process in brain development that requires precise balance, so a deletion or duplication can throw the process out of whack in similar ways.

Though the work was completed in October 2007, the knowledge is already being applied. At Children’s Hospital, which conducts routine genetic screening of children with developmental delays, researchers are devising a less expensive test for the chromosome 16 deletions and duplications.

Miller said identifying autism and related disorders early in life is important, as early interventions in the form of speech and other therapies can make a large difference in a child’s outcome. Further, with knowledge of whether a child’s disorder is inherited or not, physicians can better counsel parents about the risks of having a second child with autism.

“Making a diagnostic test available to a broader range of children is important because early intervention is important,” Miller said.