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A Simpler Test for Detecting Down’s Syndrome

A new blood test uses scraps of fetal DNA to piece together a prenatal diagnosis.

In January, the American College of Obstetricians and Gynecologists recommended that all pregnant women have access to Down’s syndrome screening, which in the past was advised only for women age 35 and older. But prenatal tests for Down’s syndrome and other genetic abnormalities can be problematic. Initial screening can be done with ultrasound or a blood test, but a definitive diagnosis requires more-invasive procedures: amniocentesis or chorionic villus sampling, both of which carry a small risk of causing miscarriage. What’s more, the screening tests have a 5 percent false-positive rate, which results in many unnecessary procedures.

A new prenatal test uses fetal DNA from a pregnant woman’s blood. Scientists first separate the fetal DNA from the mother’s DNA, then compare the amount of DNA from two different chromosomes. They’re looking for an extra copy of chromosome 21, which causes Down’s syndrome.

Now researchers at a Columbia, MD-based biotech company are reporting encouraging preliminary results using a new experimental method for detecting Down’s syndrome. The blood test takes advantage of small pieces of fetal DNA floating in a pregnant woman’s bloodstream. The development of the method, reported in the current issue of Lancet, is still in early stages, but this represents a first step toward a long-sought goal of a quick, safe, and effective way to perform prenatal genetic tests.

In Down’s syndrome, each cell has an extra copy of chromosome 21. To detect this defect, scientists at Ravgen examined fetal-DNA fragments in the blood of pregnant women and looked for a disproportionate level of DNA from chromosome 21. In a study on 60 patients, the research group was able to identify the number of chromosomes correctly in 58 cases. Three patients carried a fetus with Down’s syndrome. The test was able to detect two of the three. There was also one false positive among the 57 samples without the extra chromosome 21.

Farideh Bischoff, a molecular cytogeneticist at Baylor College of Medicine, says that the study provides “proof of concept” for the technique. “Conceptually, it all makes sense; scientifically, there’s a lot of development to be done.” In particular, the sensitivity and accuracy of the test must be improved before it can function as a diagnostic test, and it must be tested on a larger scale.

Several years ago, researchers discovered that a mother’s blood contains cells from her baby, as well as fragments of fetal DNA. But Bischoff says that one of the major challenges in the field is distinguishing a mother’s DNA from her baby’s. Sorting through the scattered DNA fragments is like listening to a radio station playing two channels at once; the trick is to separate the two signals.

Part of the problem, says Ravgen’s founder and CEO, Ravinder Dhallan, is that the baby’s signal is so low: previous studies had estimated that fetal DNA accounts for a mere 3 percent of DNA in the blood. So the Ravgen group developed a simple way to boost the signal. It believes the mother’s DNA is much more abundant because maternal blood cells burst when a blood sample is processed, spilling the woman’s DNA into the surrounding plasma. But if the blood sample is treated immediately with formaldehyde, which causes cells to harden, the proportion of fetal DNA in the plasma jumps to about 25 percent.

The scientists at Ravgen then scan the DNA samples for common variations in genetic sequence, called single nucleotide polymorphisms (SNPs). “We look at many variable sites in the mother’s DNA and compare it to variable sites in the fetal DNA, and we find sites where mother and the baby differ,” Dhallan says. This allows the researchers to piece together two separate genetic signals. They can then compare the level of the fetal signal at chromosome 21 to another chromosome; an abnormally high level indicates an extra copy of chromosome 21.

Dennis Lo, a scientist at the Chinese University of Hong Kong who first discovered fetal-DNA fragments in maternal blood, says that this method and the company’s results must be reproduced by other groups, but that the research bodes well for the prospects of a noninvasive prenatal test. He is developing a competing technique that uses pieces of fetal RNA to detect Down’s syndrome.

Deborah Driscoll, a reproductive geneticist at University of Pennsylvania who authored the revised guidelines for Down’s syndrome testing, says that while current diagnostic tests are accurate, they cannot be performed until 15 weeks into a pregnancy. “People are looking for technological advances that will provide a high detection rate, will be noninvasive, and can be done early in pregnancy,” she says.

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