Reproductive carrier screening is a form of genetic testing typically performed on asymptomatic individuals to determine if that person has a mutation associated with a genetic disorder that could be passed on to their offspring. Most, though not all, conditions tested are for autosomal recessive, X-linked, or common conditions seen in certain ethnic groups. Reproductive carrier screening for a wide variety of genetic conditions (“pan-ethnic”) is also called expanded carrier screening (ECS). As the scope of conditions that can be tested broadens, it becomes essential that genetic counselors (GCs) and professionals trained in reproductive genetics are available to assist patients in making the most informed decisions for themselves and their families.

Below, we outline the current landscape of reproductive carrier screening tests, as well as the benefits, limitations, and testing complexities.

Current Landscape

There are currently three major categories of reproductive testing: 

1. Expanded Carrier Screens (often including hundreds of genes)
2. Ashkenazi Jewish Carrier Screens (targeted to conditions much more prevalent in this population)
3. Individual genes or small panels recommended by professional organizations

Multiple professional organizations have published recommendations for when and how carrier screening should be offered and what disease genes should be targeted. An American College of Obstetrics and Gynecology  (ACOG) opinion states that diseases included in carrier screening should meet the following criteria¹:

• The carrier frequency should be less than one in 100; 
• There should be a well-defined phenotype that negatively impacts one’s quality of life, causing cognitive or physical impairment, requiring medical or surgical intervention; 
• The onset should be early in life¹.

ACOG recommends that carrier screening for Cystic Fibrosis (CF) and Spinal Muscular Atrophy (SMA) should be discussed with all pregnant women regardless of ethnicity^1a.

Although some type of carrier screening has been the standard of care for decades, the type of testing offered has changed significantly in recent years. Carrier screening test requests were categorized by gene content into ECS, Ashkenazi Jewish screening, or smaller carrier screening tests in line with professional guideline recommendations.² We noted that the proportion of smaller, society-guided carrier screening tests (CF, SMA) makes up the largest request type (~ 90%). The proportion of ECS test requests currently stands at ~9% of all reproductive carrier screening requests. Ashkenazi Jewish ethnicity-based screening is ordered less frequently at ~1%. An important caveat to this data is that it represents the tests requested for prior authorization and may differ from the final tests performed.

Benefits of Expanded Carrier Screening

In many ways, ECS is more informative than smaller screening panels/tests; one can obtain more genetic information, and therefore have a broader understanding of potential risks. This can be particularly important as it is difficult and problematic to assign people to a specific ethnic group.  Recent studies have confirmed that expanded carrier screening detects approximately twice the number of carriers as ethnicity-based screening³ maximizing the opportunity for individuals to make reproductive decisions. Larger panels of rare conditions may also benefit those from consanguineous relationships as they’re more likely carriers for the same or even multiple conditions than couples who are from non-consanguineous unions.

In the absence of family history, it can be especially difficult to predict which rare condition any couple is most at risk for. Lastly, although many conditions are rare individually, about 35% of individuals who have pursued ECS were shown to be a carrier for at least one condition. This finding suggests that being a carrier for a rare condition is common. Therefore, screening only for common conditions will fail to identify most carriers in the general population⁵. The use of a pan-ethnic panel can benefit minority populations and those who have not been as well-studied as others, thereby increasing the number of people who benefit from carrier screening and potentially addressing a health disparity. 

Limitations of Expanded Carrier Screening

Researchers have estimated that only one in 175 pregnancies will be affected with a recessive condition⁶. Although ECSs look at a large number of genes, the conditions associated with each gene are individually rare. 

First, it is unlikely that both reproductive partners will be carriers for the same condition, but the necessity of follow-up testing can increase anxiety during pregnancy⁴. Second, there is often limited information about the natural history of a rare disease, and there is limited information about the spectrum of mutations. Rare conditions often have variable presentations, severity, and ages of onset, meaning that one mutation in a gene known to cause a condition does not always confer the same outcome as for someone else with a different mutation in the same gene. Finally, calculating the residual risk of a reproductive partner as a carrier for the same rare condition is challenging, not to mention that identifying a mutation(s) does not always translate into the ability to predict prognosis in one’s offspring. 

Benefits Versus Risks

In summary, there are benefits and limitations to broad ECS panels. While the information obtained through an ECS or a smaller panel can be informative and lead to more informed decision-making, it is most valuable when performed in tandem with education and the support of a genetics specialist. The complexities surrounding the decision to pursue carrier screening, when to have the test done, which test to select, and how to interpret the results highlight the importance of having a healthcare provider trained in genetics. Genetic counselors (GCs) are those professionals. A GC appointment provides the subject matter expert, time, and support to discuss all options so that each patient can make the most informed decisions for themselves and their families. 

InformedDNA leverages the expertise of the largest, most experienced, full-time staff of lab-independent, board-certified genetics specialists in the U.S. to help ensure that health plans, health systems, hospitals, pharmaceutical companies, clinicians, and patients all have access to the highest quality genetics services.

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References:

1. “Carrier Screening in the Age of Genomic Medicine,” Committee Opinion, No. 690, March 2017
   1a. “Carrier Screening for Genetic Conditions,” No. 691, Committee Opinion, March 2017
2. “Expanded Carrier Screening in Reproductive MedicinePoints to Consider,”  Edwards, J. G., Feldman, G., Goldberg, J., Gregg, A. R., Norton, M. E., Rose, N. C., Schneider, A., Stoll, K., Wapner, R., & Watson, M. S, March 2015
3. “An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.”,  Lazarin, G. A., Haque, I. S., Nazareth, S., Iori, K., Patterson, A. S., Jacobson, J. L., Marshall, J. R., Seltzer, W. K., Patrizio, P., Evans, E. A., & Srinivasan, B. S., March 2012
4. “Prenatal screening for cystic fibrosis: psychological effects on carriers and their partners,” Mennie ME, Compton ME, Gilfillan A, Liston WA, Pullen I, Whyte DA, Brock DJ,  J Med Genet. July 1993
5. ” A universal carrier test for the long tail of Mendelian disease,”  Reproductive biomedicine online, Srinivasan, B. S., Evans, E. A., Flannick, J., Patterson, A. S., Chang, C. C., Pham, T., Young, S., Kaushal, A., Lee, J., Jacobson, J. L., & Patrizio, P., October 2010.
6. “Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach,” Genetics in medicine : official journal of the American College of Medical Genetics, 22, Westemeyer, M., Saucier, J., Wallace, J., Prins, S. A., Shetty, A., Malhotra, M., Demko, Z. P., Eng, C. M., Weckstein, L., Boostanfar, R., Rabinowitz, M., Benn, P., Keen-Kim, D., & Billings, P. , May 2020