Response to Stoll and Resta

Journal name:
Genetics in Medicine

To the Editor: We thank Stoll and Resta1 for their feedback on our data in their letter titled “Considering the Cost of Expanded Carrier Screening Panels,” and welcome discussion on the merits of expanded carrier screening. We understand this is the beginning, not the end, of genomic applications in reproductive care and fully expect that enhancements will continually increase the test’s efficacy. As we consider the correct path to a test’s maximal clinical utility, an analogy to prenatal screening for Down syndrome seems applicable.

Down syndrome screening began with crude risk estimates based on maternal age. Introduction of the α-fetoprotein biochemical assay improved sensitivity, but it was still poorly reliable by current standards. False reassurances occurred, as did difficulties regarding counseling and results interpretations. Nonetheless, these tests were implemented. They represented an improvement over contemporary approaches but did not signal the end of related research. Today, the options for prenatal aneuploidy screening are more promising than ever and yet still merit further refinement. Similarly, expanded carrier screening represents a vast improvement over an ethnicity-based approach for a small number of diseases, and routine implementation can serve to further development.

We are first obliged to address specifics from the correspondents’ letter. They make a factually incorrect assertion: in the disease list of the original study, the detection rate is actually 80% or greater in at least one ethnicity for more than half (n = 55) of the diseases and is more than 50% for almost all (n = 84). Panethnic screening by targeted genotyping results in a given ethnicity experiencing a lower detection rate for a subset of diseases. We believe this approach is acceptable for the ease of having a single protocol, in contrast with the ethnic stratification approach, because of the substantial limitations we described in the original paper and that were acknowledged by Stoll and Resta.

The authors call for more investigation into clinical outcomes, counseling resources, and ultimately, clinical guidelines issued by the relevant professional organizations. We eagerly await these guidelines and will continue to furnish data to support the field’s development. Reasonably, organizations such as the American College of Medical Genetics and Genomics aim to make evidence-based recommendations. Therefore, data creation through testing implementation is a necessary first step. Individual use of the test prompts guidelines, not vice versa. Noninvasive aneuploidy testing of cell-free fetal DNA is a most recent example of this ordering.

Stoll and Resta express concern about costs associated with follow-up testing, including gene sequencing, and posit that these should be included in the total cost of a carrier screening program. Using cystic fibrosis as an established standard, panethnic carrier screening was implemented despite reduced ethnic-specific detection rates and expensive sequencing.

They also suggest that the diseases tested are too rare by noting that most have a prevalence of <1 in 5,000 individuals. Mendelian diseases, by their very nature, are uncommon. A 1 in 5,000 prevalence strikes us as an unreasonable threshold because few monogenic diseases exceed it. In fact, many diseases already endorsed for screening by the American College of Medical Genetics and Genomics occur with a lower frequency, including spinal muscular atrophy.

“Rare” must be examined in light of the ability to analyze genes in a multiplex fashion. In fact, ~1 in 400 US births is affected by a disease in our original study. According to the criteria for general population screening established by the World Health Organization in 1968, “a disease need not have a high degree of prevalence to be considered an important problem.”2 Individually rare diseases, when viewed collectively, are acknowledged to occur with common frequency and confer significant public health and patient burden.3

Finally, psychosocial implications of carrier screening have been exhaustively studied. A recent meta-analysis of long- and short-term effects concluded that (i) anxiety was overridden by knowledge of reproductive options and may be allayed by counseling services, and (ii) guilt was significantly associated with individuals who discovered carrier status after they had an affected child (i.e., “survivor guilt”).4 On the basis of this, one may conclude that the benefits of testing more often outweigh the risks, and that the effects of not testing carry potentially greater psychosocial risks. Many similar conclusions have been drawn on persons who have undergone genomic analysis.

As genomic technologies continue to advance, we look forward to their many positive contributions to the health of our populations while pursuing the answers to ensuing difficulties. While this undoubtedly long process unfolds, we consider the bioethical principles that guide medical care. The suggestion of an “ethical dilemma” by the authors may strike a dissuasive chord. Yet a fundamental ethical principle Stoll and Resta do not address is respect for a patient’s autonomy. Current carrier screening models hinge critically on personal, not provider, values regarding reproductive autonomy. Given that screening remains voluntary, we argue for allowing individuals the self-determination of their reproductive options, with the benefits and limitations that accompany them. Patients, by and large, are able to weigh and decide on complex information, as they do every day in all parts of medicine. A more significant ethical problem, then, is to not provide patients the opportunity to learn and act on information that can be easily gained with today’s technological resources.


All authors are employees of Counsyl.


  1. Stoll K, Resta R. Considering the cost of expanded carrier screening panels. Genet Med 2013;15:318319.
  2. Wilson JM, Jungner YG. Principles and Practice of Screening for Disease. World Health Organization: Geneva, 1968.
  3. Dietz HC. New therapeutic approaches to mendelian disorders. N Engl J Med 2010;363:852863.
  4. Lewis C, Skirton H, Jones R. Can we make assumptions about the psychosocial impact of living as a carrier, based on studies assessing the effects of carrier testing? J Genet Couns 2011;20:8097.

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  1. Counsyl, South San Francisco, California, USA

    • Gabriel A. Lazarin,
    • Imran S. Haque,
    • Shivani Nazareth &
    • Eric A. Evans

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