The new findings add to a growing body of evidence that small structural changes in DNA play a significant role in disease. Two studies published in Nature in June linked a deletion in the same region to increased risk of schizophrenia. And a third study identified structural variation in a different part of the genome that appears to be responsible for about 1 percent of autism cases–the largest genetic culprit found to date.
The same technology used in these research studies can be used to screen children with unexplained developmental disorders, and it’s moving rapidly into clinical use. “I expect that within the next year or so, it will become the primary genetic test in the pediatric setting for children with any unexpected developmental abnormality,” says David Ledbetter, a clinical geneticist at Emory University, in Atlanta. Microarray tests have 10 times the sensitivity of the conventional testing, which is based on microscopy and can only identify much larger structural changes, he says.
While it’s not yet clear whether this information will help physicians make treatment decisions, Ledbetter and others say that it plays an important diagnostic role. “It’s important for parents to understand what is causing the phenotype in their child,” says Charles Lee, a cytogeneticist at Brigham and Women’s Hospital, in Boston. Because the variations can either be inherited from a parent or arise de novo–meaning that the mistake occurred in the gametes or early in development–parents are usually tested as well. “If the parent has it, sometimes reexamination shows they are mildly affected,” says Lee. The results can also be used for prenatal counseling. Parents whose children have a de novo variation are at no greater risk of having another affected child than the rest of the population is.
Scientists say that the next step in the research is to identify some of the other factors that modify the ultimate effect of the deletion–explaining why some people who carry it are unaffected and others severely mentally retarded. (While none of the healthy people in the study’s control group had the deletion, follow-up testing revealed that some parents with no known cognitive problems did.) Sebat’s group, for example, is searching for epigenetic changes–nongenetic factors that influence gene expression–that might impact a variety of deletions.