Flickr, abbybatchelderIn the not-so-distant past, testing an unborn baby for Down syndrome and other severe genetic disorders required a procedure with a long, gruesome needle and an unnerving risk of miscarriage. But this year, doctors and pregnant women around the country welcomed a new option: a painless genetic screen performed on a sample of the mother-to-be’s blood.

Advances in DNA sequencing have given doctors the power to probe the small fraction of fetal DNA coursing through a pregnant woman’s veins. Approximately 3 to 10 percent of the cell-free DNA in a mother’s blood belongs to her baby, and these fetal blueprints are enough to determine if the baby has the wrong number of certain chromosomes—the cause of some inherited diseases, including Down syndrome. And, instead of an invasive procedure at 15 to 20 weeks of pregnancy, doctors can conduct a genetic screen of the mother’s blood as early as...

Though the technology behind non-invasive prenatal genetic testing officially debuted in October of 2011, this year saw the birth of the first generation of options, with three companies now offering such tests and a fourth on the way. The trending technology has met an expanding market of expecting parents opting for prenatal testing, as well as industry squabbles over patent rights. But perhaps most importantly, the promise of more powerful fetal tests in the near future may breed a new host of ethical questions facing parents and geneticists alike, as they struggle with how much genetic information they want to know and can interpret about an unborn child.  

The birth of an industry

In 2005, the San Diego, California-based biotech company Sequenom licensed technology to detect fetal DNA, building on the results of a 1997 Lancet study that found fetal DNA circulating in maternal blood. But the company stumbled into a messy scandal in 2009 over the first version of a sequence-specific test for fetal trisomy 21—the cause of Down syndrome. Top executives resigned after the company confessed that they had inflated clinical trial results for the test, called SEQureDx, and the Securities and Exchange Commission filed charges against the former head of research.

The company regrouped in 2010, however, and began developing a more accurate sequencing-based test using massively parallel shotgun sequencing (MPSS). MPSS provides blanket sequencing of all the cell-free DNA in maternal blood, which “allows us to estimate the relative amount of each chromosome,” said Dirk van den Boom, executive vice president of research at Sequenom. “So, the theory is that if a pregnant woman has a fetus with, for example, trisomy 21, then the relative amount of chromosome 21 will be elevated.”

After a wave of impressive clinical trial data, the company launched MaterniT21 in October 2011, which tests for trisomy 21, trisomy 18 (Edward’s syndrome), trisomy 13 (Patau syndrome), and determines the sex of the fetus. The results of the Down syndrome test were particularly precise, demonstrating greater than 99 percent accuracy. But, by this point, Sequenom wasn’t alone in the market for long.

In March 2012, Redwood City, California-based biotech company Verinata Health released Verifi—also an MPSS-based test for trisomies 21, 18, and 13. And in May, Ariosa Diagnostics of San Jose, California, introduced Harmony, which detects the same three trisomies using a different method called chromosome-specific sequencing. A fourth company, Natera, also in Redwood City, is preparing to unveil its test, Panorama, which uses a single nucleotide polymorphism (SNP)-based sequencing method to detect the same trisomies, with the addition of sex aneuploidies, which cause diseases such as Turners syndrome (X0).

Nationwide, investors have estimated that the market for these tests could be more than $1 billion, and the competition is getting fierce. Indeed, Sequenom says its test has continued to soar in the past year. “We’ve seen an extraordinarily good adoption rate,” said Ronald M. Lindsay, executive vice president of strategic planning at Sequenom, who predicts that they’ll provide more than 100,000 tests in 2013.

But the other companies are anxious to grab a share of the market, which has led to dizzying legal battles. In the past year, Sequenom, which holds a patent for genetic-based fetal DNA testing, has sent letters warning of patent infringement to Aria Diagnostics, which Sequenom has since sued; Verinata Health, which has since sued Sequenom; and Natera, which also filed a complaint against Sequenom, claiming that their product doesn’t infringe on Sequenom’s patent. Though there’s been no legal resolution yet, the US Patent and Trademark Office did issue a new patent earlier this month (December 6) to Sequenom for detecting fetal aneuploidy using MPSS.

Meanwhile, all four companies are continuing to improve their technologies and push their tests onto the market. Verinata announced this month that it’s expanding its test to include sex-based aneuploidies. And Natera plans to release its test—which can be done at 9 weeks, instead of 10 and includes sex chromosome aneuploidies—early next year. “We’re confident that nothing is going to get in our way,” said Gautam Kollu, vice president of marketing for Natera.

Early adopters

Genetics postdoc and expecting mother Erin Osborne Nishimura is one of the many patients trying out the new tests. “We decided to do [a sequencing-based] test the day we talked to the genetic counselor,” said Osborne Nishimura, who works in Jason Lieb’s lab at the University of North Carolina at Chapel Hill (UNC). “Being in an ’omics lab, it’s really exciting to get in on that action early on.”

At 36, Osborne Nishimura is considered to be of “advanced maternal age,” so she and her husband (a plant biologist at UNC) began sifting through the options for prenatal tests. The standard lineup of options includes invasive diagnostics, such as amniocentesis and chorionic villus sampling (CVS)—which take samples of fetal tissues for a direct look at the baby’s DNA, but carry risks of birth defects and miscarriages—as well as blood-based hormonal tests, which are safer but less accurate. The couple also considered that one test might lead to more tests: any positive results from an indirect blood test would need to be followed up with an invasive test, upping the time, number of procedures, and medical bills.

There are also the costs of the individual tests to consider. Like many new tests, most insurance companies, which typically take at least 2 years to cover new technologies, do not yet pay for the genetic-based tests. But this month, the American College of Obstetricians and Gynecologist endorsed such tests, paving the way for insurance companies to expedite the process. In the meantime, Sequenom capped the cost of MaterniT21—usually around $2,000—at $235 for women who have health insurance.

In the end, Osborne Nishimura and her husband decided to take the plunge and purchase a genetic test for their unborn child. They went with the MaterniT21—the only genetics-based test offered by their doctor’s office—because they trusted the technology and were impressed by the clinical trial data. But they then delved into the unavoidable ethical implications of taking such a test. Though their results raised no red flags about the baby’s health—thankfully—the couple was forced to consider how they might handle undesirable results, including whether to continue the pregnancy if the test returns an undesirable report, or how to begin planning for lifelong care of a child with a severe disorder. While these weighty questions come with all prenatal testing options, as genetic technologies continue to advance, they may allow parents to test for a wider swath of genetic diseases, which will only make considerations dicier.

The first pressing new dilemma revolves around the ability to detect sex chromosome abnormalities, which is offered by Verinata’s test and will soon be offered by Natera. “This will affect the complexity of genetic counseling tremendously,” said Emily Hardisty, a certified genetic counselor and coordinator of reproductive genetic counseling at UNC hospitals, which now offers tests from Sequenom and Verinata and counsels 2,000 to 3,000 expecting mothers a year. “There’s a lot of educational material about Down syndrome and trisomy 13 and 18, which we’re currently routinely screening for, but there’s not a lot of information about the sex chromosome abnormalities,” Hardisty said. “And they’re not all that well understood.” Thus, if a baby is given a diagnosis of a sex chromosome disorder—some of which have no treatments—it will not clarify what a child’s life would be like 30 years later, or even directly after birth, she explained.

Moreover, Sequenom and Verinata’s tests detect chromosomal abnormalities by sequencing the entire fetal genome. “At this point in time, there’s so much information to filter through,” Hardisty said. “And some of it may have clear clinical implications and some of it may not.” Indeed, while the companies offering the tests insist they will continue to only provide information on relevant medical conditions, genomic data could potentially reveal additional information as more is understood about the genetics that underlie rare diseases and cosmetic traits.

And beyond the screen results, the data itself opens new questions. Genetic privacy regulations that may one day guide such tests are still in their infancy. Mothers like Osborne Nishimura will have to grapple with how to tell her child that his or her genome has been sequenced, and, she added, “they’re not just sequencing fetal DNA, they’re sequencing my DNA, too.”

But for Osborne Nishimura, the ethical unknowns were worth not having to worry about the “what if”s of genetic disorders for the rest of the pregnancy. “Because, lord knows I can make up all sorts of other things to worry about.”

Correction, 12.19.2012: The original article incorrectly identified Natera's upcoming non-invasive prenatal test as preNatus. The correct test name is Panorama, while the name of the clinical trial in which Panorama is being tested is called PreNatus. The Scientist regrets the error. 

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