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GenomeWeb Feature: Prenatal Testing, Carrier Screening Emerge as Early Markets for Widespread Sequencing


While much ado has been made about the plummeting costs of next-generation sequencing and how the $1,000 genome will revolutionize healthcare, the days of ubiquitous whole-genome sequencing are still years away. The technology, though, is already changing reproductive medicine, particularly how physicians perform prenatal and carrier screening.

The noninvasive prenatal screening market today is highly competitive and litigious. In the US, four companies have sequencing-based tests on the market that can screen for chromosomal abnormalities such as Down syndrome from a simple blood draw as early as 10 weeks' gestation. These companies — Ariosa Diagnostics, Natera, Sequenom, and Verinata Health (now part of Illumina) — are also all suing each other over intellectual property in an effort to gain a share of what could prove to be a market worth several billion dollars per year if the tests are adopted in the general population. In Europe and Asia, Berry Genomics, BGI, and GATC Biotech subsidiary LifeCodexx offer similar tests, but have so far managed to stay out of the legal fray.

The carrier screening market is not quite as noisy, though there are a handful of US companies and academic institutions that either offer or are currently developing sequencing-based tests to screen for diseases such as cystic fibrosis and Tay Sachs disease — Good Start Genetics is the major player in the sequencing-based carrier screening market with a 23-disease test menu.

Early adopters of such tests say that they are moving toward becoming the standard of care and have the potential to make a big impact on healthcare. Nevertheless, there are still a number of barriers to physician adoption. How the tests should be used, what disorders and genes should be included, how genetic counseling will be managed, and how these tests will affect overall healthcare costs are all issues that will have to be studied and taken into account.

"I do think it will become [the] standard of care," said Anthony Gregg, chief of maternal-fetal medicine in the University of Florida's department of obstetrics and gynecology. "But like anything, when it's first rolled out, it's difficult for practitioners to get their arms around how to do it."

From Gene-By-Gene to Panels

Rather than the single-gene approaches for carrier screening that are used today, with next-gen sequencing, a single panel can assay multiple genes for multiple disorders. Currently, the American Congress of Obstetricians and Gynecologists and the American College of Medical Genetics and Genomics recommend carrier screening for cystic fibrosis to all women planning to become pregnant or who already are pregnant. The ACMG additionally recommends screening for spinal muscle atrophy, and both organizations have a list of disorders that they recommend for screening in the Ashkenazi Jewish population

Current tests evaluate a handful of known mutations on a single gene, Gregg said, but with next-gen sequencing, multiple mutations on multiple genes for a variety of disorders could be screened simultaneously for the same, or even lower, cost.

"Next-gen sequencing is offering a paradigm shift in prenatal and perinatal carrier screening," Gregg said.

Gregg has been offering his patients expanded carrier screening by both sequencing-based methods and array-based methods for a little more than a year now, both to women who are considering becoming pregnant and to women who are already pregnant, up through around 20 weeks' gestation. About 50 percent of women with private insurance opt for an expanded screening test, he said. Medicaid in Florida does not cover the expanded screening test, so fewer women with public insurance choose it, he added.

One Year of NIPT

It's been a little over one year since noninvasive sequencing-based prenatal tests first hit the market, and, in that time, there has been rapid growth. Companies developing these tests have inked distribution deals with firms such as Laboratory Corporation of America, PerkinElmer, and Quest, and insurance providers Aetna, UnitedHealthcare, and WellPoint have said they support coverage for such tests.

"The bottom line is that [these tests] are having a very significant impact on the reduction of invasive procedures," said Diana Bianchi, executive director of the Mother Infant Research Institute at Tufts Medical Center. Invasive procedures like amniocentesis and chorionic villus sampling come with around a 1 percent risk of miscarriage.

Bianchi said that Tufts began offering Sequenom's test when it was first launched in November 2011 and now offers Verinata's and Ariosa's tests as well. In the first year of offering the noninvasive tests, Tufts saw around a 34 percent reduction in invasive procedures, Bianchi said.

Tufts offers the tests to women who have consulted a genetic counselor because of an increased risk for fetal disorders, which could be due to the woman's age or an abnormal test result from either serum screening or an ultrasound, among other reasons. But Tufts also offers the test to low-risk women who request it from a genetic counselor.

Bianchi said that Tufts decided there was "no physical harm in offering the test to low-risk women" and that if these women inquired about it and wanted to pay for it, "we wouldn't obstruct them."

In all cases, though, Tufts requires both pre- and post-test genetic counseling.

All three test offerings are available to patients, and the test that is ultimately given depends on a number of factors. In most cases, the choice is driven by the patient's insurance, Bianchi said. For instance, Tufts sees a significant number of women with public insurance, and most of those will receive Ariosa's test since it does not bill patients out of pocket, she said. But also, the specific genetic counselor may recommend one over another based on personal preference.

Somewhat surprisingly, the reduction of invasive procedures has primarily been for women in their second trimester, rather than the first, Bianchi said, even though the NIPT tests can all be performed as early as at 10 weeks' gestation.

Bianchi attributed this to the way in which women are using the tests. She suspects that women in the first trimester who are receiving an invasive test have already "seen something on a first trimester ultrasound that is serious enough that they don't want an interim step, and want to go straight to a diagnosis," she said.

But women in the second trimester are likely coming in for the invasive test because of an abnormal serum screen or nuchal translucency test. With those tests, there is "nothing definite that says the fetus is abnormal. So, most [of those] women opt to go for the noninvasive test first," she said. If that test comes back negative, then the physician does not recommend an amniocentesis.

Mary Norton, an obstetrics and gynecology professor at Stanford University, has seen a slightly different uptake among patients there. Stanford offers Ariosa's test to women with high-risk pregnancies either due to age or because of an abnormal screening result.

Around 25 percent of women who are at risk due to age opt for the test, while between 40 percent and 50 percent of women at increased risk due to an abnormal screen choose it.

However, she said that these numbers were likely lower than in other states because of a California-run program that pays for women's screening tests and any necessary follow-up tests including amniocentesis and genetic counseling.

"There's a lot of incentive for patients to go that route," since in most cases it is not guaranteed that the insurance company will pay for the noninvasive test, she said. Patients are "unsure whether they'll have to pay, and it can be a hefty bill," Norton said.

Nevertheless, noninvasive tests are changing prenatal screening in another way, Norton said, by increasing the total number of women who have follow-up tests after an abnormal screen.

Around a year ago, about half of all patients with an abnormal screening test would decline an amniocentesis, said Norton. But now, even though the rate of amniocentesis procedures has dropped only slightly, more women are choosing to have a follow-up procedure of some kind. "Instead of declining follow-up altogether, women are choosing noninvasive testing," Norton said.

Norton speculated that the women who were previously declining follow-up tests but are now choosing the noninvasive test are women who do not plan to terminate their pregnancy, but still want a definitive result about whether their child will have Down syndrome or another chromosomal aneuploidy. Women who choose to have an amniocentesis are likely those who would strongly consider an abortion if the test were positive, she said.

Going forward, Norton said that the introduction of noninvasive prenatal testing for all women could impact the types of screening tests that are provided to pregnant women. For instance, she said that nuchal translucency testing will likely remain because it can detect things like birth defects, but she predicted that the serum markers may eventually "go by the wayside."

Proper Use and Education

Even though Norton, Bianchi, and Gregg are early adopters of these tests, they all have concerns about how they are implemented into clinical practice, and said that ensuring that physicians are properly educated about the tests, how to use them, and their capabilities will be critical.

"I worry that noninvasive prenatal testing may be offered by Ob/Gyns that may not understand the nuances," said Norton, adding that "patients [may] terminate without confirmation."

Additionally, some groups are offering noninvasive tests and serum screening at the same time, "which doesn't make a lot of sense," she said.

"It demonstrates the confusion of a complex testing menu," she added. In California, there's a requirement that the healthcare provider offer the state-sponsored program, which comes with serum screening, a nuchal translucency test, and ultrasound, she said. The patient can decline the tests, but there has to be documentation that the tests are offered, she said.

If a patient also requests a noninvasive test, there's no downside to the provider in offering all the tests, she said.

Gregg also said that physician education is currently a concern and a barrier to more widespread adoption of expanded carrier screening tests, particularly with regards to genetic counseling. Primary providers can likely offer pre-test counseling, he said, because "you don't have to know all about the 80 to 120 different diseases. But, once these results start to come in, and you don't know anything at all about familial Mediterranean fever or non-syndromic deafness, for example, when your patient comes back and asks, 'What does this mean?', then that patient needs [a] referral."

Physicians must also understand what the test does and does not measure, he said. For instance, for a given disease on a carrier screening panel, a negative result does not necessarily mean the patient is not a carrier. Some of the existing panels don't include every gene related to the disease or every known mutation, he said.

"Even though you get a negative result on the test, maybe it tested only two out of the 20 mutations in the gene," he added.

Physicians will have to be able to counsel their patients about these cases and give them an accurate estimate of residual risk.

Gregg is able to provide the necessary genetic counseling to his own patients himself because he is board certified in genetics and has one genetic counselor on staff.

Currently, he said that he is working on building a standardized process by which the test is provided and counseling is given. Initially, the process will be designed for patients from consanguineous relationships because those are "uniquely fitted for this kind of carrier screening," since the fetus is at an increased risk, he said. The process could then be broadened out to a wider population.

Moving forward, Gregg said that guidelines from professional organizations like ACOG and ACMG will be important for determining how the tests enter the clinic more broadly and for what conditions they screen.

For instance, he'd like to see companies be required to give detailed information about the genes and disorders that are included on the tests, and why they've included the specific genes or mutations, and what is missing from the test and why.

Currently, "companies could put anything they want on the panel," he said. "We need to have criteria by which certain conditions are put on the panel. And not only conditions, but the genes that cause the conditions and the mutations that are associated with those genes that cause the conditions."

Similar questions will also need to be asked for noninvasive prenatal tests. One issue that has already come up is that sometimes the test will indicate an abnormality, but the abnormality will not be in the fetus itself.

"There's the possibility of detecting abnormalities in the mother or a demised twin," Bianchi noted. There's already one published example of this happening, she said, citing a recent Prenatal Diagnosis study in which a noninvasive test for a chromosomal abnormality came up positive for the fetus, but it turned out that the mother had an extra X chromosome. The disorder displays variable phenotypes, and the mother did not know she had this disorder and only showed very mild symptoms.

The concern with such findings is that "women are not always getting sophisticated pre-test counseling," she said. "They need to be aware that the test can find genetic abnormalities in the woman herself, not only the fetus."

These findings, while rare, will only increase as the tests become available to not just women with high-risk pregnancies, but to all women.

Economic Impact

Another important, and still largely under-studied, aspect of these tests is how they will affect the cost of healthcare. Sequencing-based prenatal tests that screen for fetal aneuploidies currently run between $795 and $2,900.

In a study sponsored by Verinata and published in the Journal of Managed Care Medicine last year, researchers found that introducing the company's Verifi test as a follow-up test to initial screening would result in a modest 1 percent reduction in healthcare costs.

Ariosa has also said that in its economic analyses, introducing its test among a high-risk population would result in savings if the test was priced at less than $1,000. Ariosa's test costs $795.

However, studies are also needed on the economic consequence of introducing the tests in an average-risk population. This could potentially result in increased costs because of the potential need for increased follow-up testing.

Gregg said that the same holds true for carrier screening. While the price of an expanded screening test is clearly more efficient than testing one gene at a time, there is the potential for that "inexpensive test to lead to more costly healthcare" in the form of increased follow-up testing to confirm results and genetic counseling, he added.

Despite these barriers, sequencing is already having an impact on prenatal testing and carrier screening, and as the cost of sequencing goes down, companies will only continue to expand the number of disorders for which they can screen.