Genetic Test Reveals More About Potential Birth Defects Than Conventional Methods
December 6, 2012

Genetic Test Reveals More About Potential Birth Defects Than Conventional Methods

Lawrence LeBlond for - Your Universe Online

Two new papers published in the New England Journal of Medicine (NEJM) show that genetic testing in early pregnancy reveals far more about potential birth defects and stillbirth risk than current prenatal testing does, based on a multi-center clinical trial using both methods.

The clinical trials showed that 6 percent of certain fetuses declared normal by conventional prenatal tests were found to have genetic abnormalities using chromosomal microarray testing, according to researchers from Columbia University Medical Center (CUMC). The team found the genetic flaws traditional testing missed were anything from minor defects such as club foot to more serious ones such as mental retardation and heart problems.

The microarray tests used in the prenatal trials are already being used to diagnose problems in newborns that show signs of developmental delays, autism disorders or congenital anomalies, Lorraine Dugoff, an associate professor of obstetrics and gynecology at the University of Pennsylvania, wrote in an editorial accompanying the studies.

“These reports highlight the power and complexity, and some of the pitfalls, of using new genomic technology in clinical practice,” Dugoff wrote. “Chromosomal microarrays can detect almost all the chromosomal imbalances” found with older tests, in addition to much smaller changes, she added.

The downside: these tests are quite expensive. The conventional method--karyotyping--generally runs about $500 to $600; chromosomal microarray testing can be as much as $1,500, or more, according to Ronald Wapner, vice chairman of research at CUMC´s Department of Obstetrics and Gynecology, and lead researcher in the clinical trial.

Still, Wapner said the new genetic test could become standard for women with high-risk pregnancies, and eventually be offered to all pregnant women. But, he warned, these tests are not being done “just so people can terminate pregnancies,” because many choose to continue them even when problems are found.

“We're better able to give lots and lots of women more information about what's causing the problem and what the prognosis is and what special care their child might need,” he explained.

The microarray tests, which are much more precise, can look at specific locations and pick out much smaller changes, as well as spot pieces that are missing or overrepresented, Wapner explained in an interview with Business Week´s Michelle Fay Cortez.

“The biggest advantage of microarray is it can give us a lot more information,” he included. “We are expanding the information a person can get out of prenatal testing, identifying additional and more serious problems.”

For the study, Wapner and associates enrolled more than 4,400 women from 29 centers from around the country; it took four years for data to be compiled. The study involved women with advanced maternal age and those whose fetuses were shown in early screening to be a heightened risk for Down Syndrome, to have structural abnormalities, or to have indications of other problems. This was the first and only study to compare karyotyping to microarray in a blinded head-to-head trial.

The trial showed that microarray analysis, which compares a fetus´s DNA with a normal (control) DNA, performed as well as karyotyping in identifying common abnormalities; it also identified additional abnormalities that went undetected through karyotyping.

Among fetuses in which a growth or structural anomaly was found through ultrasound, microarray found clinically relevant chromosomal deletions or duplications in 6 percent of cases that were not observed with karyotyping. In cases sampled for advanced maternal age or positive screening results, microarray analysis picked up an abnormality in one out of every 60 pregnancies (1.7 percent) that had a normal karyotype.

"Based on our findings, we believe that microarray will and should replace karyotyping as the standard for evaluating chromosomal abnormalities in fetuses," said Dr. Wapner. "These chromosomal micro-deletions and duplications found with microarray are often associated with significant clinical problems."

However, there is a drawback to this type of testing. Currently, microarray requires fetal cells that are obtained through an invasive procedure such as amniocentesis, where fetal cells are taken from amniotic fluid, or through chorionic villus sampling, where cells are taken from the placenta. These tests can prove risky, having the potential to produce procedure-induced miscarriage, but the researchers believe the benefits of the test outweigh the risks. And work is currently underway to develop a non-invasive form of the test using a blood sample instead, though that may be years before becoming a practical option.

"We hope that in the future–when microarray can be done non-invasively–every woman who wishes will be offered microarray, so that she can have as complete information as possible about her pregnancy," said Wapner.

The second paper published in the same issue of NEJM highlighted the use of microarray analysis in stillbirth.

In this study, results showed that microarray analysis produced a clinical relevant result in 87 percent of 532 cases, which were analyzed with both karyotyping and microarray. In contrast, standard methods for analyzing a stillbirth, which include karyotyping, have been shown in previous research to fail to return information in 25 percent of cases.

"Microarray was significantly more successful at returning clinically relevant information because, unlike karyotyping, it does not require cultured cells. Viability does not come into play at all–DNA can be extracted from tissue that is no longer living," said study senior author, Brynn Levy, PhD, associate professor of pathology and cell biology, and co-director of the Division of Personalized Genomic Medicine at CUMC, and director of the Clinical Cytogenetics Laboratory at NewYork-Presbyterian/Columbia. "Not being able to explain why a stillbirth occurred can be very hard for families. These findings are important because they give us a significantly more reliable method to provide information to families and their physicians."

"The primary benefit of using microarray analysis rather than karyotype analysis is the greater likelihood of obtaining results," said Uma Reddy, MD, MPH of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health, first author of the paper. "Microarray analysis is especially useful in stillbirth cases in which the karyotype has failed or there is a birth defect present. However, microarray analysis is currently more expensive than karyotyping — and this may be a barrier to some."

"While the vast majority of abnormalities found with microarray are associated with known conditions, not all are. But with time, knowledge and understanding of what these abnormalities mean will continue to grow," said Wapner. "When we started this study five years ago, the incidence of findings we did not understand was about 2.5%–now, with more information, that has fallen to 1.5%."

Dr. Susan Klugman, director of reproductive genetics at New York's Montefiore Medical Center, which enrolled 300 women into Wapner´s study, said it was a long time coming. The results could pave the way for gene testing becoming a standard of care in cases where initial screening with ultrasound exams show signs of structural defect in the womb.

"We can never guarantee the perfect baby but if they want everything done, this is a test that can tell a lot more," she said in an interview with Marilyn Marchione of The Associated Press.

Wapner is currently leading phase two of his microarray study. With the support of NICHD, he has begun a five-year study to follow children born to mothers who underwent microarray, to learn the clinical implications of micro-deletions or duplications that are not yet understood.

"Unfortunately, it is sometimes difficult to predict the full spectrum of some diseases indicated by a particular deletion or duplication," said Wapner. "Genetic medicine is about obtaining genomic information about an individual and predicting what affect it will have on that person. But we are all different–so genetic abnormality in one person may behave differently than in someone else.”

“For example, an inherited disease could be mild in the mother but severe in her child. We are studying what these mean clinically, and science continues to catch up with our ability to obtain the information," concluded Wapner.