Clinical utility of expanded carrier screening: results-guided actionability and outcomes

Purpose Expanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date. Methods Couples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management. Results Three hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis. Conclusion ECS results impacted couples’ reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.

ABSTRACT One in 300 pregnancies is impacted by a recessive or X-linked condition. Universal screening is recommended by guidelines for 2 of these conditions (cystic fibrosis and spinal muscular atrophy), but this misses approximately 70% of carriers of other diseases and fails to detect somewhere between 13% and 94% of pregnancies affected with severe conditions, depending on race/ethnicity. Expanded carrier screening (ECS) addresses this issue, but evidence of its clinical utility has only recently been studied: limited data are available to assess the actions and reproductive outcomes of atrisk couples (ARCs). The studies so far suggest that ECS helps ARCs make decisions that reduce the risk of having an affected offspring, but the researchers sought to confirm and characterize ECS's impact on reproductive decision making in this group.
The researchers developed a survey from an initial cohort of 270,000 individuals who underwent ECS between September 2015 and December 2017; inclusion criteria included females who were found to be carriers of a pathogenic or likely pathogenic variant conferring risk for at least 1 of 176 autosomal recessive or X-linked conditions currently included in ECS, were aged 18 years or older, had consented to being contacted about participating in research, and for those carrying pathogenic or likely pathogenic variants associated with autosomal recessive conditions, had reproductive partners meeting the same eligibility criteria and who were confirmed as being carriers of a pathogenic variant in the same gene. With these criteria, 1701 ARCs were invited to participate; these couples with current or future pregnancies were at combined risk for 78 conditions. Of these, 391 completed the survey for a response rate of 24%.
Among those screened before becoming pregnant, 77% planned to avoid having affected offspring. For those screened during pregnancy, 37% elected prenatal diagnostic testing for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, prenatal diagnosis was pursued in 29% of cases. Among respondents, the decision to decline prenatal diagnosis was most frequently based on the fear of procedure-related miscarriage, as well as their consideration that even in the event of a positive diagnosis they would not pursue termination.
The researchers concluded that the use of ECS prompted pregnancy choices to the point of lowering the amount of births affected with serious genetic diseases. Their finding is consistent across carrier screening studies, and this trend suggests there is value in screening for previously undetected diseases.

EDITORIAL COMMENT
(Since the publication of the Human Genome Project, the availability of genetic tests has increased at a rapid pace. It is now possible to test for thousands of different genetic diseases, although the utility of such testing is not always evident. This is in part due to the complexity of the field and the fact that, with more experience and more nuanced understanding of genetics and the interactions of genes, genetic regulatory mechanisms, and human health and development, it is increasingly evident that a clear and consistent relationship between one specific genetic variant and a predictable phenotype is the exception, rather than the rule. Finding a genomic variant in an individual (or a fetus) is not the same as diagnosing a genetic disease.
For some of these reasons, groups such as the American College of Medical Genetics and the American College of Obstetricians and Gynecologists have generally continued to limit the number of disorders for which population-based screening is recommended. With advances in genetics, costs and availability of some of these tests have reached the point where screening "everyone for everything" is now close to a reality. Several commercial laboratories have taken advantage of developments in genetic testing to offer extensive panels of genetic tests, so that an individual can undergo carrier testing for hundreds of disorders with a single blood test (or cheek swab) often at the same cost as testing for a single disease such as cystic fibrosis. The full American College of Obstetricians and Gynecologists and American College of Medical Genetics recommended panels for prenatal genetic screening can be studied on a single chip at a very modest cost.
But while such testing can be done, should it be? In the field of genetic testing, the metric referred to as "clinical utility" is often used to measure whether a genetic test impacts clinical care. Clinical utility broadly refers to the risks and benefits resulting from test use. The most important considerations in determining clinical utility are (1) whether the test and any subsequent interventions lead to an improved health outcome among people with a positive test result, and (2) what risks occur as a result of testing. It has been noted that "complete measurement of clinical utility requires evaluation of the medical and social outcomes associated with testing, and subsequent interventions for people with both positive and negative test results" (Curr Protoc Hum Genet 2014;81:9.15.1-9.15.8).
In this abstracted article, the authors surveyed patients who had undergone ECS to identify carrier couples, in which both partners were carriers of the same genetic disorder and therefore at risk to have an affected fetus. They asked such ARCs about actions taken in response to their test results and found that 77% of those identified in the preconception period reported that they planned or did pursue actions to avoid having an affected child (eg, preimplantation testing, prenatal diagnosis, use of a gamete donor, or other strategies), whereas 37% of those identified when already pregnant chose to have prenatal diagnosis in that pregnancy. Of note, the response rate to their survey was low (24%), 60% of respondents were not pregnant and the large majority of these individuals were planning to have in vitro fertilization. The authors conclude that ECS impacts couples' reproductive decision making and leads to altered pregnancy management that effectively eliminates the risk of having affected offspring, thus demonstrating clinical utility.
There are a number of important aspects of this study. First, it was published by Counsyl, Inc, a company that provides ECS-there is therefore a strong bias in favor of such testing. Insurance coverage of such testing continues to be fairly limited, and insurers base payment decisions on demonstrated "clinical utility," thus a publication purporting to demonstrate such clinical utility is of great benefit to the company. In addition, they report on both patient intentions as well as actual actions taken, and it is well known that patients often report an intention in advance that they do not actually pursue once faced with a real-life, as opposed to hypothetical, situation. Perhaps most importantly, however, they assume that all actions taken are beneficial, and do not once in the article mention risks that might arise from testing; they only mention the risks of having affected offspring. Discussing the benefits without mentioning the risks is comparable to discussing sensitivity without ever mentioning specificity, it is completely misleading. And finally, they mention a number of times that a benefit of ECS is decreasing the rate of genetic diseases in the population, a perspective that is approaching a eugenics rationale for genetic testing.
Expanded carrier screening is not simply an efficient method to test for more genetic diseases. It is a complex endeavor that identifies carriers of rare diseases for which the precise phenotype, natural history, residual risk with a "noncarrier" partner, and variant interpretation may be unclear or uncertain. In our practice, we have identified a large number of patients in whom ECS results were problematic, most commonly we have seen people in whom interpretation of rare variants found in a prior pregnancy has now been changed, so that their risk of an affected offspring has increased or decreased substantially. There is no mechanism on the part of the laboratories to inform patients or providers of such reinterpretation, so some of the couples reported in this article, who had preimplantation or prenatal diagnosis, undoubtedly did such testing unnecessarily. To accurately and adequately discuss clinical utility requires consideration of this risk and not only the benefit of identifying carriers of genetic variants.
What does this mean for the practicing obstetrical provider? Expanded carrier screening is complicated, and practices offering such testing need to assure a mechanism for accurately interpreting results and patient risks. Carrier couples require counseling by a genetics expert to assure the variant interpretation is accurate. The field of genetics is largely unregulated, and the accuracy of test interpretation is not guaranteed. Before patients embark on preimplantation testing, or prenatal diagnosis, or pregnancy termination, the input of a genetics expert is absolutely required to assure appropriate understanding of the results.-MEN)