NEW YORK (GenomeWeb) – Expanded carrier screening tests that make use of next-generation sequencing technology to assess carrier status for a whole host of genetic conditions are increasingly being used despite the fact that guidance on who should use the tests as well as data on clinical utility and downstream impacts on healthcare and health costs are lacking.
A number of genetics and reproductive medicine organizations are now beginning to address these questions. Last week, the American College of Medical Genetics and Genomics, the American College of Obstetricians and Gynecologists, the Maternal Society for Maternal-Fetal Medicine, the National Society for Genetic Counselors, and the Perinatal Quality Foundation issued a joint statement on expanded carrier screening tests that was published in Obstetrics and Gynecology.
While the statement does not endorse the use of such test and falls short of making specific recommendations for who should use them and when, it is a first move to bring the issue to light and educate clinicians and laboratories on the use of expanded carrier screening tests.
"It's really to say, what, in the interim, we think is appropriate," Nancy Rose, the director of reproductive genetics at Intermountain Healthcare in Salt Lake City and chair of the ACOG's committee on genetics, told GenomeWeb.
Expanded carrier screening tests are "penetrating clinical medicine more … and the general desire is for the professional organizations to be certain that the obstetric care providers and people in a position to benefit from these tests understand the implementation process as well as some of the pitfalls," Anthony Gregg, an ACMG board member and a professor of obstetrics and gynecology at the University of Florida, told GenomeWeb.
A number of companies now offer such carrier screening tests. Good Start Genetics offers a next-generation sequencing-based test that assesses carrier status in up to 23 disorders, including all those that are recommended in guidelines set by ACOG, ACMG, as well as societies supporting the Ashkenazi Jewish population.
Natera's Horizon test screens for 38 disorders, and Gene by Gene is developing an array-based carrier screen. Counsyl offers both array-based and NGS-based carrier screening tests that can detect 400 and 10,000 mutations, respectively.
With the advent of these multiplexed tests, screening for multiple diseases is now cheaper than testing for just the individual disorders that are recommended by the professional organizations one at a time, Gregg said. But, "what's missing are adequate studies to guide professional organizations in terms of their ability to make a firm statement that expanded carrier screening should or shouldn't be offered to all patients," he said.
Rose agreed. "This kind of screening has been available for a while, but there hasn't been much guidance about how to use these kinds of tests."
The joint statement is aimed at obstetric care providers, laboratories performing such tests, and policy makers alike.
For obstetric care providers, the goal is to help them "understand the nuts and bolts, the risks and benefits of expanded carrier screening," Gregg said. In addition, it "addresses what should be included on the panels and the interpretation of molecular findings," and it also points to the need for future studies on the longer-term health impacts and healthcare costs of expanded carrier screening.
According to the statement, conditions screened for should affect cognitive disability; require surgery or medical intervention; affect quality of life; and/or be a condition for which a diagnosis may result in an intervention to improve outcome, better delivery management, or education of the disorder in order to better prepare for caring for the child.
In addition, it includes caveats for conditions that can either be childhood or adult-onset variants with high allele frequencies and low penetrance, and conditions that have a more appropriate test other than molecular testing. It may be preferable to exclude such conditions from expanded carrier screening panels, the authors wrote.
The organizations also advise healthcare providers to consider the specific test — whether it is based on genotyping or next-generation sequencing and what types of genes and variants are included in the test. "The genes and variants should have a well-understood relationship with a phenotype," the authors wrote.
If carrier frequency and risk estimation are both known, laboratory reports should also provide a residual risk estimate. Variants of unknown significance should not be reported, the authors said, although they wrote that providers should consider the benefits and risks of screening only known pathogenic variants. Variants that are found to be pathogenic or likely pathogenic according to ACMG definitions should be reported.
Gregg said that one main point of discussion among the group was about diseases with highly variable phenotypes, including some in which supposedly pathogenic mutations do not always result in any symptoms in the patient. Several such diseases are already included in some commercially available carrier screening panels, Gregg said.
One thing that needs to be studied, he added, is the utility in screening for such disorders. "Does screening for these types of variable expressivity, low-penetrance mutations create unnecessary anxiety and additional downstream testing costs?" he said.
Rose agreed that it is important to make sure that the diseases included in such panels were appropriate ones to screen for.
"I think there's a balance between screening for diseases that are well known where we know the phenotype, and diseases that are extremely rare and we don't have any idea what the phenotype is," Rose said.
"We need to take a careful look at what goes on a screening panel so that we're not looking for something that we're not sure that finding it matters," she added. "We want to find things that make a difference for the family, as opposed to screening just because we can."
The panels can also uncover information that may have unanticipated healthcare consequences, Gregg said. While screening for diseases whose phenotype is highly variable or low-penetrance disorders have the potential to have negative consequences, in some cases testing may lead to future benefits.
Gregg cited screening for Factor V Leiden, a blood clotting disorder that is typically only tested for in patients with past or family history, but has been included on some of the commercial carrier screening panels. If a woman who wouldn't normally have been screened for Factor V Leiden tests positive for it on a carrier screen panel, that will have downstream effects, Gregg said. For instance, she wouldn't be prescribed estrogen-containing contraceptives, because that increases the risk of developing a blood clot. If that woman at some point later requires surgery, knowing she's a carrier will change her management. "That one screening test could uncover risks that might have future healthcare benefits," Gregg said.
Another question that will have to be addressed in the future is how these tests should be paid for, Gregg said. While it makes sense for third-party payors to pay for the expanded carrier screening tests, since they are less expensive than screening for individual diseases, who should pay for additional downstream testing that may happen as a result of the screen is still a big question, Gregg said. "That is where additional studies on the value of such tests will come in handy," he said.
As more data is collected on individuals receiving such tests and their healthcare outcomes, "we'll learn what rare, serious conditions we're able to avert, and also we'll learn how much anxiety was brought to the table and what the added expense was to families," he said.
Gregg said that although there isn't a timeline for the issuance of specific recommendations by any of the individual professional organizations with regards to who should be screened, what disorders should be screened for, and who should pay, he anticipated that such recommendations would happen in a stepwise fashion.