Expanded Carrier Sequencing: Would You Rather?

On summer road trips, my kids loves to play a game Would you rather?  For instance, would you rather eat a bowl of spaghetti noodles without sauce or a bowl of spaghetti sauce without noodles?  Would you rather have a unicorn horn or a squirrel tail?

In the spirit of summer road trips and the holiday weekend, I’d like to play a game of Would you rather? that only genetic counselors can appreciate.

This is a trade off we have to make with carrier screening.

Carrier screening programs intended for the general population as supported by the practice guidelines put forth by our professional societies tend to favor Option B. The reason being that more harm than good may result when providing information that is uncertain or ambiguous, especially in the context of reproductive decision making.

These days however, Option A is becoming increasingly common. Although at odds with society recommendations, which generally recommend a more targeted approach, the use of expanded carrier screening (ECS) panels that utilize sequencing are being more commonly accepted into practice with labs often claiming that more prenatal testing is better.

But is more really better?  

In theory, it makes sense to offer screening that provides as much information as possible. However, we know that what makes sense in theory does not necessarily lead to good medical practice. And there are warning tales of screening programs that were initiated with good intention but led to unfortunate, unintended consequences.

Consider the early days of carrier screening for cystic fibrosis (CF) as an example. After years of careful study and deliberation, in 2002 experts from the American College of Medical Genetics together with American College of Obstetricians and Gynecologists published recommendations for use a panel of 25 mutations in the CFTR gene. However this initial panel was revised in 2004  when it became evident that one of the originally defined mutations,  p.I148T (c.443TC) was in fact a benign polymorphism.

On a panel of just 25 mutations, in a well known gene, for a well defined condition, after years of critical expert evaluation, a mutation that  was initially included on a panel as causative of disease was eventually determined not not be, only after being put into practice. It is likely that Option A was a reality for some families in the early days of CF carrier screening.

Now consider that with expanded carrier screening panels that increasingly perform whole exon sequencing, often of >100 genes, one can imagine that many of the mutations being called with carrier screening are not disease causing. I believe that Option A will become much more frequent with greater utilization of carrier screening panels that use sequencing.  

And in addition to the possibility of incorrect variant classification, there is also a concern for increased false positive results as carrier screening expands. A reality with any screening test is that the rarer the condition, the more likely a positive result is a false positive result.


When questions arise regarding interpretation of variants on ECS panels, the labs often respond that they follow the ACMG Standards and Guidelines for Interpretation of Sequence Variants.

But here’s the thing, these guidelines were not developed for carrier screening in a healthy population. To quote the ACMG document: “The following approach to evaluating evidence for a variant is intended for interpretation of variants observed in patients with suspected inherited (primarily Mendelian) disorders in a clinical diagnostic laboratory setting.”


The authors of the ACMG Standards also warn: “Caution must be exercised when using these guidelines to evaluate variants in healthy or asymptomatic individuals or to interpret incidental findings unrelated to the primary indication for testing. In these cases the likelihood of any identified variant being pathogenic may be far less than when performing disease-targeted testing. As such, the required evidence to call a variant pathogenic should be higher, and extra caution should be exercised. In addition, the predicted penetrance of pathogenic variants found in the absence of a phenotype or family history may be far less than predicted based on historical data from patients ascertained as having disease.”


As genetic counselors we are trusted to advise patients of this information, and knowing that such information is used to make life changing reproductive decisions (i.e utilizing prenatal diagnosis, pregnancy termination, undergoing assisted reproductive technologies and preimplantation genetic diagnosis, or deciding not to have biological children) we know how important it is that the information we provide patients is unambiguous, accurate, and evidenced based.

However, we seem to be accepting the move to expanded carrier screening panels using sequencing rather than more targeted genotyping panels with little question about whether this is the right thing to do.

While many have accepted that expanded carrier screening with sequence analysis is the new normal, we should note that despite the marketing spin by the companies that this method of testing is superior, there are still no prospective studies that demonstrate clinical validity and utility of expanded carrier screening panels with sequencing. And guidance from our professional societies recommends a more limited approach to carrier screening.

While labs promote certain conditions included on their carrier screens as “recommended” by the ACMG and ACOG, they fail to acknowledge that those professional societies specifically advise against whole exon sequencing, and instead recommend a more targeted approach that evaluates, and reports on only well characterized mutations.

From the ACMG Position Statement on Prenatal/Preconception Carrier Screening (2013):  “There must be validated clinical association between the mutation(s) detected and the severity of the disorder.”  And more recently, from the ACOG Committee Opinion 691 on Carrier Screening for Genetic Conditions (2017):  “Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening.”

Who should decide which test is best?  The testing laboratories? The professional medical organizations?  Patients?

It seems that for now, that the laboratories are steering this ship. Despite the lack of evidence proving benefit and many cautions against it, several labs have sunsetted genotyping panels and have moved exclusively to sequencing, for what seems to be an ever growing number of rare conditions. It is becoming increasingly difficult for clinicians to follow the guideline recommendations when ordering tests for patients and we seem to be quickly entering a time where Option B is not an option at all.

It should not come as a surprise that the labs are pushing this new expanded testing as there is an incentive for labs to use sequencing over genotyping from a business perspective.

Sequencing genes rather than using a defined mutation panel allows for labs to boast of a higher detection of carriers, thus provides bragging rights for their marketing materials. One lab highlights on their website that their test identifies “30% more pregnancies affected with cystic fibrosis or spinal muscular atrophy” when compared to the ACMG and ACOG  recommended panel. What is omitted on their website is that for some of the mutations identified, we do not yet have definitive information about disease causation or phenotype. And thus we are asking patients to make reproductive decisions based on uncertain information.

Another compelling reason for the labs to expand to sequencing is that detecting more mutations in the patient begets more testing of their partners. And more testing is the name of the game with laboratories that aim to increase test sales. Understandably that is their goal as it should be, we need labs to sell test in order to stay in business and provide a needed service for patients and providers. That said, lab sales and profits should not be driving best practices for patient care.


While more may seem better in some situations, this notion should be especially scrutinized in the area of reproductive carrier screening. As the professionals that are trusted to interpret these tests results and help patients understand this information in the context of their own lives, we need evidence beyond modeled hypothetical disease risk to demonstrate that these expanded tests will truly benefit pregnancy outcomes. As has been discussed on the DNA Exchange in a prior post by Bob Resta, positive change to do best for our patients in this area will require work from multiple parties. Labs should put the brakes on with regards to marketing new tests and step back while independently funded research assesses the relative harms and benefits of testing. Governments need to fund such research. And clinicians need to critically evaluate the testing that is offered to patients, especially when unproven testing strategies are being introduced and promoted that may create more harm than good.


Filed under Katie Stoll

9 responses to “Expanded Carrier Sequencing: Would You Rather?

  1. Thanks for writing this. I agree that the tendency to do more and more testing is driven by commercial laboratories and marketing— but also by a ?human tendency to want to find out more (or to take a look in the direction of finding out more) when it’s easy to do so. I think part of it is just that NGS takes the cost calculation (and therefore the pause) out of analyzing more genes/variants. DTC testing is an example in that once they price point is low enough, people think “why not?” I’m not sure if over time we’ll become more aware of the why-nots or if we’ll just adjust to a world in which piles of data are the norm and uncertainty about what the piles of data mean are also the norm. Acknowledging uncertainty about the significance of the data and more rigorous standards for variant interpretation would be a big step in the right direction though. In cancer genetics, at least in the earlier days of panel testing, I think labs also had/have a perverse incentive to call a variant either benign or pathogenic since GCs would want to know what a lab’s VUS rate for a panel was. As long as we’re going to keep ordering testing for more and more genes, we should get more and more comfortable with VUSs and telling our patients that we don’t know what the results mean.

  2. The nearly even split on this poll is very interesting. I wonder if the results would look different if the question referred to specific genetic conditions, e.g. a treatable one vs a fatal untreatable one. While I fully understand the concerns over moving towards an NGS-based carrier screening world, we can’t stick our heads in the sand – we need to find ways to utilize the data and counsel our patients as best we can, understanding that it’s not a perfect science yet and being transparent about the level of uncertainty that applies. Patients are often far more resilient than we give them credit for.

  3. Jon Weil

    I have been thinking about two aspects of the counseling issues this situation raises, and I wonder to what extent my ideas resonate with what others are considering or developing in their clinical practice.
    First, data overload, with questions about the reliability and/or utility of specific information, is an issue in many aspects of contemporary life. For the profession, are there ways in which an understanding of the broad occurrence of this situation can help us find new ways to conceptualize the issues as they relate to genomic counseling? In working with individual patients, can we use their experiences in other domains to help them address the clinical situation – a new application of the venerable intervention “Have you or your family had to deal with other situations similar to this? If so, what did you find helpful; what strengths did you bring to it; etc.?”
    Second, when it is a significant aspect of the individual or family’s experience, are there ways to work directly with the sense of being subjected to testing beyond what was desired and/or with having received unwanted or “toxic information” (Bernhardt et al., 2013 Genetics in Medicine 15: 139-145)? At the individual level, this includes empathic acknowledgement of anger and a sense of mistreatment. It could also involve an approach along the lines of, “Every person has multiple variants of unknown significance; in your case one has come to light against your wishes. How can we help reduce its impact or find a way to help you ‘put it in its proper place?’”
    In some situations it may also be helpful to discuss the fact that this is a common problem; the patient or family is not alone is this experience. Reducing the sense of isolation may provide some sense of relief. Beyond that, there is the possibility of approaches such as a support group for people confronting this set of issues or of a mechanism for collectively documenting unwanted testing and its consequences.

  4. Laura Hendon, CGC

    Excellent article! The split is fascinating. This would be a wonderful panel and debate discussion at an upcoming AEC!

  5. Mike

    Hi Katie,

    Thank you for your thoughtful piece. I do wonder how fear of litigation affects these decisions as well; is there a drive to get as much information as possible so as to cover ourselves if something untoward happens? My gut tells me that this happens, and that it may not ultimately be in the best interests of the patient.

  6. Jon Weil

    In my comment I only discussed the possibility of a support group or a mechanism for collectively documenting unwanted or inappropriate testing and its consequences. However, there are also other methods for developing evidence and potential action to create a situation in which unwanted testing with harmful outcomes, or testing based on inappropriate use of professional organization guidelines, can have potential financial, legal and/or publicity consequences. And although much of this lies outside the domain of genetic counseling, it seems to me it as a relevant an aspect of the discussion as are the actions of the for-profit laboratories.

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