I had only recently become comfortable with 500-ish-gene carrier screening panels when a promotional email landed in my inbox announcing the release of a 1,000-ish-gene version offered by one of my go-to labs. Not having the capacity for an existential deep dive into the question of how much is too much, I deleted the provocative email and continued with my day. But I have been treading water in that existential pond ever since.

The introduction of ethnicity-based carrier screening programs in the late 1970s led to a dramatic reduction in the number of births affected with conditions like Tay-Sachs disease and beta-thalassemia. It represented a major win in the public health realm and provided clear evidence that carrier screening “works!” The 1990s witnessed broader uptake and the next 20 years ushered in an unprecedented era of genomic and sequencing advances. What began as targeted ethnicity-based testing quickly evolved into a pan-ethnic expanded carrier screen, and then a larger expanded carrier screen, and then a larger one still.

The goal of carrier screening is ultimately to identify at-risk carrier couples so the impetus behind these ever-growing panels makes perfect sense. It feels clear that we should screen for cystic fibrosis and PKU and Duchenne muscular dystrophy. But why stop there when we could also help couples at risk of having children with TK2-related mitochondrial DNA depletion syndrome-2 and SUOX-related sulfite oxidase deficiency and all the other rare conditions that even the most bookish genetic counselors have never heard of? If we have the means to identify more at-risk couples, why be satisfied with our measly little 500-ish panel?  

Yet we all know this is not a simple question. Larger panels have the potential to identify more at-risk couples, but the yield eventually plateaus. Once a panel reaches a certain size, adding increasingly rare conditions results in only a small incremental gain in carrier or at-risk couple detection, while substantially increasing the clinical and counseling burden (Wapner & Biggio, 2019; Ben-Shachar 2019). The concern, then, is not simply that bigger panels find more carriers; it is that they may find more information than our current systems are prepared to interpret, contextualize, and support.

Larger panels will generate more uncertainty, more patient anxiety, more costs, and increased strain on an already burdened health care system. More genes do not necessarily translate into more actionable information, especially when panels include conditions with mild phenotypes, reduced penetrance, ambiguous risks in heterozygotes, or unclear reproductive implications.

Beneath the debate over panel size is a deeper ethical question: what are we really trying to accomplish with carrier screening? Although NSGC, ACOG, and ACMG differ in some recommendations, they all emphasize the importance of thoughtful condition selection. The 2017 ACOG committee opinion recommends that each condition on the panel meet several proposed criteria, including “having a detrimental effect on quality of life,” and the NSGC practice guideline on expanded carrier screening (2023) explains that included conditions should “be reasonably expected to affect reproductive planning.” Built into these recommendations is a necessary degree of interpretive flexibility: what one person considers meaningful for reproductive decision-making may not be the same for another. Even with the best tools for assessing disease burden, the question of what constitutes “severe” will always be shaped, at least in part, by subjectivity.  

Part of my reservation about increasing panel size comes from a purely practical place. I am a genetic counselor at a donor gamete bank; I counsel on and talk about carrier screening all the live long day. I confess I am not looking forward to counseling on increasingly obscure conditions for which the severity, carrier frequency, detection rate, or manifesting carrier risk in heterozygotes may be poorly understood.

But my discomfort is not a sufficient argument against larger panels. It is, instead, a sign that we are in the midst of a familiar growing pain in genetics: larger panels stretch the concept of carrier screening as we have traditionally understood it. The technology is moving forward, and our ethical guardrails and counseling practices are being forced to catch up.

Part of me wants to mobilize a group of genetic counselors to reason with the laboratories: “Slow down, please! We’re not ready!” And yet, I know I chose a career in a field defined by constant and rapid change. My discomfort cannot simply become resistance to growth. Perhaps, instead of arguing against larger panels because they do not fit our traditional model of carrier screening, we should acknowledge that the model itself may need to evolve. The goal should not be to force new technology into an old framework, but to create clearer boundaries that allow larger panels to be used responsibly.

After all, there is much to be gained from larger panels: richer variant databases, a better understanding of rare disease genes, more detailed molecular targets for future clinical testing, and clearer insight into how variants behave across ancestries. A carrier screening glow-up will inevitably advance genomic knowledge. Think of the data! The more we learn from population-scale screening, the better equipped we will be to interpret variants across the genome – not only within the framework of tidy Mendelian inheritance, but also within the far more complicated biological layers that shape how genotype becomes phenotype.

It's also worth considering where all of this is headed. At some point, expanded carrier screening may become so expansive that it will resemble whole exome sequencing more than it resembles carrier screening. Eventually, perhaps, all genetic testing will be some version of exome sequencing. And when that happens, we'll find ourselves revisiting many of these same questions, armed with new knowledge, new technology, and a new set of uncertainties. Such is the nature of genetics: the goalposts will keep moving, and the conversations we have today will need to evolve alongside them. We cannot expect to establish standards that will remain appropriate indefinitely. We can only make thoughtful, evidence-based decisions with the tools and knowledge available to us now, knowing that we'll be tasked with reevaluating those decisions as the field continues to evolve.

And there it is. I have stepped out of the existential pond with a renewed sense of purpose. I will not hem and haw over 1,000-ish gene panels. Instead, I will take this as an opportunity to upgrade my standard carrier screening appointment shpiel, subtracting some components and adding new ones. I will prepare patients and providers to expect ambiguous findings. I will emphasize the complexity and fluidity of variant interpretation. I will encourage patients to set an annual calendar reminder to call their performing laboratory and ask whether there have been updates regarding the variants they carry.  And I will refine my trusty “marbles in a jar” metaphor so that it applies not only to multifactorial inheritance, but also to the increasingly blurry boundaries that constitute Mendelian disease.

Does this make me uncomfortable? Absolutely, and rightly so! Discomfort is appropriate when technology begins to outpace the systems we built to manage it. But the more important question is what this discomfort requires of us now. These panels are not a distant hypothetical; they are already here. Our task is neither to resist them, nor to accept them uncritically. It is to help define what responsible expansion should look like. This work will be messy but genetic counselors are uniquely prepared for this moment. We know how to sit with uncertainty, translate complexity, and help patients find clarity, even in the face of “too much information.” 

References

Ben-Shachar R, Svenson A, Goldberg JD, Muzzey D. A data-driven evaluation of the size and content of expanded carrier screening panels. Genet Med. 2019 Sep;21(9):1931-1939. doi: 10.1038/s41436-019-0466-5. Epub 2019 Feb 28. PMID: 30816298; PMCID: PMC6752311.

Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstetrics & Gynecology 129(3):p e41-e55, March 2017. | DOI: 10.1097/AOG.0000000000001952

Gregg, A.R., Aarabi, M., Klugman, S. et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 23, 1793–1806 (2021). https://doi.org/10.1038/s41436-021-01203-z

Sagaser, K. G., Malinowski, J., Westerfield, L., Proffitt, J., Hicks, M. A., Toler, T. L., Blakemore, K. J., Stevens, B. K., & Oakes, L. M. (2023). Expanded carrier screening for reproductive risk assessment: An evidence‐based practice guideline from the National Society of Genetic Counselors. Journal of Genetic Counseling, 32(3), 540–557. https://doi.org/10.1002/jgc4.1676

Wapner RJ, Biggio JR Jr. Commentary: Expanded carrier screening: how much is too much? Genet Med. 2019 Sep;21(9):1927-1930. doi: 10.1038/s41436-019-0514-1. Epub 2019 Apr 11. PMID: 30971834.

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