A technology guru may have solved a problem that has long vexed obstetricians: how to test for Down syndrome without poking a needle into the womb. By sequencing the fetal DNA floating in a mother's blood, bioengineer Stephen Quake's team at Stanford University in Palo Alto, California, detected nine cases of the disease with 100% accuracy. If this small study holds up in larger trials, the test could become routine for expectant mothers.
Down syndrome is caused by an extra copy of chromosome 21. It results in mental retardation and other health problems, and some women choose to abort Down syndrome fetuses. Although there is a noninvasive screening test that indicates the likelihood a fetus has Down syndrome, pregnant women who want a definitive answer currently have two choices: amniocentesis, which involves inserting a needle into the uterus to withdraw fluid, or another procedure that extracts a piece of placental tissue. These tests, done at about 10 to 16 weeks, are 99% accurate but cost about $1000 and in rare cases can cause miscarriage. As a result, usually only women over 35 who are at higher risk for carrying a Down baby get tested.
In the past decade, researchers have developed prenatal tests for gender and Rh blood group based on testing for mutations in fragments of fetal DNA circulating in the blood of pregnant women (Science, 2 September 2005, p. 1476). But detecting disorders such as Down syndrome using maternal blood has been tougher because the test has to spot an extra chromosome, and the mother's DNA swamps out the fetus's DNA. In the most advanced approach, the company Sequenom, based in San Diego, California, is using messenger RNA produced by the placenta to detect Down's. However, the test is only a screen because it relies on DNA markers on chromosome 21 that vary by ancestry, and it misses about 7% of cases in the U.S. population.
Quake's team tried a brute-force approach to circumvent this problem: They put maternal blood samples through a DNA-sequencing machine. Although the researchers only sequenced about 2% of the mother's and fetus's genome, this was enough data to distinguish levels of chromosome 21 in mothers carrying a Down syndrome baby from those with a normal fetus as early as 14 weeks. In all nine Down syndrome cases tested but not six normal cases, this ratio was greater than one--indicating that the condition was present. The technique also detected three cases of other chromosomal disorders that lead to abnormal development, Quake's group reports online today in the Proceedings of the National Academy of Sciences.
The test cost $700 per sample, but that price should come down with newer sequencing technologies, notes Quake, who hopes to see the approach commercialized. "I think it's going to get better and better," agrees Department of Energy medical geneticist Edward Rubin, who says Quake's paper was the talk of a recent genome meeting in Boston.
Fetal testing experts are also impressed: "The results are astonishing," says molecular biologist Sinuhe Hahn of Basel University Hospital in Switzerland. Hahn and others say it's too soon to know, however, whether the test will prove superior to Sequenom's. It needs to be studied on a much larger scale to be sure it can pick up all of the one in 1000 Down syndrome births in the general population, says Diana Bianchi of Tufts University in Boston. Even so, she says, the study is "a significant advance."