Expanded Carrier Screening: A Rational Approach to Screening for Rare Diseases

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Advances in genetic technology have resulted in the development of multiplex panels that can test for hundreds of genetic diseases simultaneously. Such panels can screen expectant couples or those planning a pregnancy for many more conditions than recommended by current guidelines, regardless of ethnicity. Despite limited information on the clinical utility of such expanded carrier screening, these panels are increasingly being used as an alternative to traditional carrier screening. Recent guidelines from the American College of Obstetricians and Gynecologists (the College) indicate that expanded carrier screening is an acceptable option in pregnancy.1 But what are all these extra conditions that are being sought, and is it truly helpful to screen for them?
Data suggest that expanded carrier screening increases the detection of carrier couples, and it would seem obvious that this would be better than single-gene screening for a few disorders. However, several concerns have been raised regarding such screening.2 Traditional ethnicity-based carrier screening focuses on conditions that significantly affect quality of life due to cognitive disabilities, physical disabilities, a requirement for lifelong medical therapies, or a combination of these factors, and have a fetal, neonatal, or early childhood onset and well-defined phenotype. The disorders included in the College guidelines have been evaluated by a group of stakeholders and consider prevalence and severity, the accuracy of the screening test, and other accepted metrics. In contrast, expanded panels are developed by commercial laboratories, and it is not always clear how the 200+ conditions on some panels were selected. Some conditions may have significant variation in severity or age of onset. For those that are rare, the relationship between a given genetic variant and the predicted phenotype or outcome for the child may not be clear. Even with cystic fibrosis, a common, familiar, and well-characterized disorder, only after screening had been offered for many years was it recognized that some variants initially thought to cause severe, classical cystic fibrosis were in fact quite benign.3 With rare conditions, even if such variability exists, it may never be recognized because there will always be too few data and cases. In addition, the precise carrier frequency as well as the proportion of condition-causing variants that can be detected also may be unknown; therefore, the residual risk is uncertain if one parent is found to be a carrier. Panels also often include conditions that are relatively common but for which population carrier screening is not recommended by current guidelines owing to the mild phenotype, as with hemochromatosis or Factor V Leiden.
In this issue of Obstetrics & Gynecology (see page 279), Stevens et al provide a comprehensive review of the conditions included on expanded panels that are currently commercially available in the United States.4 Using criteria described by the College and the American College of Medical Genetics and Genomics regarding prevalence, test sensitivity, disease phenotype, and other characteristics, they evaluated included conditions to identify those that should, or should not, be included on screening panels. They conclude that, overall, only 27% of conditions on commercial panels meet criteria for inclusion whereas 73% do not. The most common reason conditions did not meet their criteria was a low carrier prevalence (less than 1/100), or a detection rate of less than 70%. As the authors note, “in their current state, commercially available expanded carrier screening panels are putting patients at risk for undue anxiety, and time and money are being spent on follow-up testing for remarkably rare or mild conditions with low screening performance.”4
The commercial laboratories point out that health care providers have the option to customize the panels to meet their patients' needs.
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