Expectant mothers are used to fuzzy images on ultrasound monitors and blood tests to screen for potential health problems in their unborn babies. But what if one of those blood tests came back with a readout of the baby’s entire genome? What if a simple test gave parents every nuance of a baby’s genetic makeup before birth?
Recent studies show that it’s possible to decode an entire fetal genome from a sample of the mother’s blood (see “Using Parents’ Blood to Decode the Genome of a Fetus”). In the future, doctors may be able to divine a wealth of information about genetic diseases or other characteristics of a fetus from the pregnant mother’s blood. Such tests will raise ethical questions about how to act on such information. But they could also lead to research on treating diseases before birth, and leave parents and their doctors better prepared to care for babies after birth.
It’s been about 15 years since Dennis Lo, a chemical pathologist at the Chinese University of Hong Kong, first discovered that fragments of DNA from a fetus could be found in a pregnant woman’s blood. The work was a breakthrough, since obtaining fetal DNA from the amniotic fluid, placenta, or directly from the fetus’s blood requires an invasive procedure and carries a risk of miscarriage. A noninvasive test would make genetic testing safer and much more widely accessible.
Since then, several labs have worked to analyze this fetal DNA and exploit it for noninvasive prenatal tests. The field has progressed rapidly in the past couple of years as genetic sequencing technologies have become vastly cheaper and faster, and methods to analyze genetic data have improved (see “Analyzing the Unborn Genome”).
One of the first tests to be developed is for RhD factor, a type of blood protein that can lead to fetal disease or death if the mother is RhD negative and her fetus is RhD positive. Sequenom, a San Diego, California-based company that licensed Lo’s research, began offering a noninvasive RhD test in 2010 (prior tests required invasive procedures such as amniocentesis or chorionic villus sampling, which carry a small risk of miscarriage). Several companies have also offered tests for sex determination and paternity.
But what has gained more attention in the United States is a recent wave of tests that detect Down syndrome, which is caused by an extra copy of chromosome 21. Because women in the United States are routinely offered testing for Down syndrome, the market for such a test is large.
The test for Down syndrome could, in particular, have an enormous beneficial impact. Typically, a pregnant woman receives an initial screening test for substances in her blood associated with Down syndrome. Jacob Canick, a professor of pathology and laboratory medicine at Brown University, explains that the tests will detect 90 percent of Down syndrome cases, but have a false positive rate of 2 to 5 percent. That may sound small, but given that Down syndrome affects only one in 500 pregnancies, the number of women with a false positive is much higher than those who are truly carrying an affected fetus. The only definitive diagnosis is through amniocentesis or chorionic villus sampling. “That means that 19 out of 20 women that undergo an invasive procedure will find out that they don’t have the genetic abnormality,” Canick says.
With those low odds, many women choose not to undergo an invasive procedure at all. But new noninvasive tests could make screening much more widespread. “It looks, from our data and other data, that these tests are very, very good,” says Canick, who led a trial, funded by Sequenom, on one these tests. They are still not definitive, but could ensure that far fewer women unnecessarily undergo invasive tests.
A number of startups have begun offering fetal tests for Down syndrome and other health problems caused by extra copies or missing chromosomes. Diana Bianchi, executive director of the Mother Infant Research Institute at Tufts Medical Center, who is on the advisory board of a startup called Verinata Health that is developing such fetal tests, says it’s been surprising how quickly the tests have made their way into the clinic.
That speed has some people concerned. “There’s not a minimum standard of accuracy that’s required before they go to market,” says Mildred Cho, a bioethicist at Stanford University. She says that the tests are being adopted even as their accuracy is being evaluated in clinical studies. Whereas most prenatal genetic tests have been developed through academic laboratories, this technology was quickly commercialized and disseminated through companies. Sequenom has claimed broad intellectual property rights and has sued other companies for patent infringement. Cho worries that such a monopoly, if upheld, will prevent other companies from improving the technology.
Meanwhile, recent studies suggest that noninvasive testing could expand in the coming years beyond simply counting chromosomes to hunting for smaller genetic aberrations, including mutations in single genes. A study published this June by a group at the University of Washington in Seattle decoded a fetus’s genome using a blood sample from the mother and saliva sample from the father. Meanwhile, Stanford University researchers have accomplished a similar feat using only a blood sample from the mother.
That means parents could soon receive a comprehensive test that could screen for all kinds of genetic abnormalities and characteristics. “When you open it up to whole-genome analysis, that brings up the possibility of testing for traits that are not diseases,” says Cho, and for complex diseases that are not as genetically determined as Down syndrome. “People may be making decisions about terminating a pregnancy based on these very tiny risk factors,” she says. “They may misunderstand that the tests are not predictive.”
But more knowledge could also help women and doctors anticipate a risky birth, or better prepare for treatable health problems that are not currently diagnosed until birth. Bianchi hopes that the ability to uncover disease in fetuses will also spur a new interest in treating disease before birth. “Things that are treatable are really going to change the landscape,” she says. “That’s where it’s going to be transformative.”
Fetal medicine, she says, has been confined largely to surgeries for anatomical abnormalities that are visible with ultrasound. But many diseases may be treatable medically—even genetically determined ones. Bianchi’s lab is studying fetal Down syndrome to see if it’s possible to alleviate some of the effects of the disease while the baby is still in the womb. “If we can improve the biochemical environment at a time when the brain is developing,” she says, “perhaps we can improve learning and memory.”