Amniocentesis and chorionic villus sampling remain the gold standard for detecting genetic abnormalities such as Down syndrome in a developing fetus. But because these procedures are invasive and can cause miscarriage, their use is normally only advised for women with known risk factors. Now a handful of emerging tests suggest that in the near future, it may be possible to detect genetic defects with a simple blood draw from the mother.
“The holy grail all along is to give women a diagnosis without having an invasive procedure,” says Joe Leigh Simpson, executive associate dean for academic affairs at the Florida International University College of Medicine and a pioneer in the field of noninvasive prenatal testing.
While the placenta serves to separate the fetus’s circulatory system from the mother’s, a minuscule amount of free-floating fetal nucleic acid and a small number of fetal cells can be found circulating in the mother’s bloodstream. For decades, scientists have been searching for ways to isolate and characterize these potential clues to the genetic status of a developing fetus.
It’s relatively straightforward to purify circulating snippets of DNA and RNA and analyze their sequences, but distinguishing fetal nucleic acids from those of the mother remains a challenge. Particularly in the case of Down syndrome, in which the defining feature is an extra copy of chromosome 21, it’s tough to tally how many copies the fetus has without an intact fetal cell.
To get around this roadblock, Dennis Lo, professor of chemical pathology and medicine at the Chinese University of Hong Kong, takes advantage of SNPs–commonly occurring single-letter differences in a given gene. A normal fetus with two copies of chromosome 21 might have two different spellings of a particular gene on that chromosome, expressed in a one-to-one ratio. A Down syndrome fetus would have an extra copy of one version, yielding a two-to-one ratio.
By analyzing the ratios of RNA produced by SNP-containing genes, researchers can indirectly count fetal copies of chromosome 21. The more SNPs included in the analysis, the more accurate the outcome. Sequenom, a molecular diagnostics company based in San Diego, is currently working to adapt Lo’s work into a clinical test for Down syndrome.
Other genetic disorders, such as Rh incompatibility syndrome, are more readily amenable to an analysis of fetal nucleic acids from the maternal bloodstream. Rh is a protein found sticking out of the red blood cells of individuals with Rh-positive blood. If a mother is Rh-negative, her immune system may react violently to an Rh-positive fetus. In this case, scanning the mother’s bloodstream for the presence of the Rh-encoding gene or its corresponding RNA provides a simple way to determine whether preventative treatment will be necessary. Traditionally, all Rh-negative pregnant women are treated–unless the father is known to be Rh-negative as well–even though only a fraction of them carry an Rh-positive baby.
Although Rh tests based on this approach have been in use in Europe for years, the first U.S. version, developed by Lo in conjunction with Sequenom and implemented by Lenetix Medical Screening Laboratory, just hit the market last December.
Diana Bianchi, a professor of pediatrics, obstetrics, and gynecology at the Tufts University School of Medicine, says that Sequenom’s Rh test is promising but not perfect. “It will be interesting to see whether obstetricians in the United States are willing to take the risk of a false negative,” she says.