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In March, Sequenom disclosed that it had initiated discussions with the US Food and Drug Administration to try to obtain premarket approval for its sequencing-based prenatal diagnostic test for trisomy 21, SensiGene T21. During a conference call with investors and reporters to discuss its fourth-quarter earnings for 2010, Sequenom also said it expects to offer SensiGene T21 as a lab-developed test to physicians in late 2011, or by early 2012.

Sequenom is not alone in the sequencing-based, non-invasive prenatal diagnostic space. Both the German firm LifeCodexx and Verinata Health — the San Carlos, Calif.-based company formerly known as Artemis Health — have also announced plans for the commercial launch by late this year or early next year of sequencing-based prenatal diagnostics for trisomy 21 — the chromosomal aneuploidy that causes Down syndrome. Many other firms have similar tests in development.

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That the market for non-invasive prenatal diagnostic tests for trisomy 21 — based on sequencing technologies or otherwise — has become increasingly crowded is telling. Today, pregnant women who wish to test their unborn children for Down syndrome have only two options: chorionic villus sampling or amniocentesis. Both invasive procedures carry some risk for miscarriage — 0.5 to 1 percent and 0.25 to 0.5 percent, respectively, according to the US Centers for Disease Control and Prevention.

Because of this, Brian Skotko at Children's Hospital Boston says that "non-invasive prenatal diagnostic testing for Down syndrome has the potential to dramatically change the way that health care is utilized by pregnant females." While women who are now offered invasive testing may forgo it because of the associated risk and opt instead to receive a postnatal diagnosis, Skotko expects non-invasive prenatal diagnostic testing to change that.

He says that at present, about 2 percent of women opt to undergo invasive testing for Down syndrome. "If the sequence-based, non-invasive prenatal diagnostic testing is perfected — the science and the data do pan out — then we might see nearly 100 percent of all pregnant women choosing to get a prenatal diagnosis of Down syndrome," he says. "And so Down syndrome will become a diagnosis that shifts from a postnatal one to almost an exclusively prenatal one."

Benefits and concerns

Beyond minimizing risk, sequencing-based, non-invasive prenatal diagnostic tests for trisomy 21 also provide earlier detection. Taken together, the University of Bristol's Ainsley Newson says these factors make these new tests "undoubtedly attractive." However, she adds, "it is precisely these benefits that also raise concerns. Easier, earlier testing could see an increase in people wanting to test, perhaps without taking the time to think things through."

As such, Newson says that many of the concerns raised by the possibility of non-invasive prenatal diagnostic testing becoming widely used within the next few years — that, by its non-invasive nature, such testing could become normalized, the validity of informed consent could be undermined, there might be a steep increase in the rate of abortions, and there may be a tendency to abuse such testing capabilities to screen for non-medical traits in the future, among others — "certainly ... merit further investigation."

To consider the potential ethical implications of sequencing-based testing for trisomy 21 and other conditions before they make it to market, Newson says that researchers, clinicians, and genetic counselors must thoroughly survey the concerns raised in the literature and by the public to examine the most pressing aspects at greater length.
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Overall, she says, "the questions we need to ask are whether the substance of the concern can be resolved, or whether — even though the concern is significant — it needs to be accepted in order to embrace the benefits of NIPD," or non-invasive prenatal diagnostics.

For her work on the potential consequences of such testing, Newson and her colleagues have placed substantial emphasis on the role of consent. "We need to ensure that this blood test, which could have profound implications, does not get lost in the many blood tests pregnant women are offered. This test may be low risk, but the information received will be the same as it is with invasive testing," she says. "We can … maximize the chance that women provide fully informed consent by structuring a model of offering NIPD [testing] that builds consent into the heart of the process."

The University of Connecticut's Peter Benn says that under the current standard for the prenatal testing for Down syndrome, "amniocentesis and CVS act as sort of a gatekeeper — a control of the number of procedures that get done. People don't want to have those tests, so they're only going to have it if they're perceived as being at very high risk."

If a non-invasive prenatal diagnostic for Down syndrome reaches the broader obstetrics community, Benn expects to see a snowball effect. "If you now have a test then that is very easy and accessible — because it's just a blood test — then you will have a lot more diagnoses," Benn says. "The increased number of diagnoses would presumably result in more pregnancy terminations."

Evidence to suggest whether that is the case will only emerge with time, but so too will additional, increasingly complex quandaries as the capabilities of sequencing-based, non-invasive prenatal diagnostic tests — and findings of the phenotypic consequences for additional genetic variants — expand.

Future possibilities

In a December 2010 Science Translational Medicine paper, the Chinese University of Hong Kong's Dennis Lo and his colleagues reported their discovery that the entire fetal genome is represented in maternal plasma. Given that, Lo et al. also showed that by sequencing the maternal plasma DNA, they could determine the mutational status of the unborn child.

Sequencing the entire fetal genome "has enormous possibilities because … some of those [detectable] polymorphisms are going to be associated with risk factors for late-onset diseases — for cancers and other risks … more complex genetic disorders that we know there's a genetic component," Benn says. "We're only just beginning to sort through which genetic factors are becoming important, but now suddenly you're getting all of this information at the prenatal stage and there's no reason why it need stop at disorders."

He says that given access to the entire fetal genome, researchers could screen for established genetic predispositions to particular phenotypic traits, such as stature, intelligence, or athletic prowess. "The future for all of this is really overwhelming in terms of what we might one day be able to do prenatally, off of a blood test," Benn adds.

Going forward, Bristol's Newson says it will be essential to consider how far parents' rights to obtain information about their unborn children should extend, particularly as they may uncover information that their grown children may not wish to know. Concerns also loom that this type of testing could fuel "wrongful birth" and other lawsuits.

Until widely accepted standards regarding the ethical use of sequencing-based prenatal testing are generated and adopted, both Newson and Benn suggest that researchers, physicians, and genetic counselors consult established ethical guidelines for the applications of genetic testing in children.

At the University of Exeter, Susan Kelly is working to analyze public attitudes toward non-invasive prenatal diagnostic testing before it becomes widespread. In a recent survey of 71 people, Kelly says that, overall, the participants indicated feeling generally receptive toward non-invasive prenatal diagnostic tests, though only "for specific individual medical indications." During the two-year course of her team's study, however, "we did identify concern about how to place limits on testing," she adds.

Still, given the observed resistance to invasive tests, Benn expects that sequencing-based, non-invasive prenatal diagnostic testing will swiftly become accepted as an attractive alternative.

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