Developing a new method for noninvasive diagnosis of Down syndrome and other chromosomal abnormalities

By Sathya Achia Abraham

Virginia Commonwealth University is part of an international research team that has developed a noninvasive diagnostic method for Down syndrome that uses a sample of blood from a pregnant woman.

The results may one day lead to a fast, accurate and noninvasive method for prenatal testing for Down syndrome, which occurs when an individual has three, instead of two, copies of chromosome 21. As a result of the additional genetic material, individuals with Down syndrome experience developmental difficulties.

In the United States, Down syndrome affects 1 in 800 newborns. Those odds increase to about 1 in 350 when the mother is age 35 or older.

Current methods available to test for Down syndrome, as well as to detect other genetic disorders prenatally, include amniocentesis and chorionic villus sampling, or CVS. Both are invasive tests that pose a risk of miscarriage.

The study, published online in December 2008 in the Proceedings of the National Academy of Sciences, is a collaboration between researchers based at The Chinese University of Hong Kong (CUHK) in China and VCU. Using a new approach known as massively parallel DNA sequencing to detect fetal trisomy 21, or Down syndrome, the team developed a prenatal maternal blood-based test. The blood test measured small amounts of fetal DNA found in the mother's blood. Each blood sample from the mother was about 10 to 20 milliliters, and the cell-free plasma DNA was examined by the team. Through the blood test, the team was able to correctly identify cases of normal fetuses and cases of Down syndrome fetuses.

While the paper was under review, similar findings were reported in October 2008 by researchers at Stanford University in California. Both teams independently used massively parallel sequencing of plasma DNA to identify the fetal chromosomal abnormalities, however there were several differences. The Stanford study involved 18 pregnant women, of which 17 had undergone an invasive prenatal diagnostic procedure 15 to 30 minutes prior to blood sampling. It is known that such invasive procedures may increase the levels of fetal DNA in maternal plasma, thus potentially making fetal DNA measurement easier. All Down syndrome cases in the Stanford study were from the second trimester.

In contrast, the new study included a sample of 28 women in the first and second trimesters of pregnancy and included 14 cases of fetuses with trisomy 21 and 14 cases of normal fetuses with matched gestational ages; in most of the cases, no invasive diagnostic procedure had been performed prior to blood sampling.

“As more and more couples marry and have children later and later in life, a testing for Down syndrome is becoming increasingly more important. Most parents choose not to undergo amniocentesis or CVS screening due to the invasive nature along with the small associated risk of miscarriage,” said Yuan Gao, Ph.D., an assistant professor in the Department of Computer Science in VCU’s School of Engineering and in VCU Life Sciences’ Center for the Study on Biological Complexity. Gao was a key collaborator on the study.

“Our work suggests that we can do this diagnosis by using circulating cell-free fetal DNA in the pregnant mother's blood. The test is noninvasive for the unborn baby, has no related risk of miscarriage,” he said.

This work was supported by University Grants Committee of the Government of the Hong Kong Special Administration Region, China, under the Areas of Excellence Scheme and a sponsored research agreement with Sequenom, a molecular diagnostic company in San Diego, Calif.

Bin Xie, a senior research associate in Gao's lab also contributed to this work. Dennis Lo, M.D., Ph.D., the Li Ka Shing Professor of Medicine at CUHK, was the study's principal investigator, and Rossa Chiu, Ph.D., a professor at CUHK was the first author of the paper.