Expanded Carrier Screening & Frequently Asked Questions

By Valerie Piet

Several leading genetic testing companies have unveiled new offerings in prenatal genetic testing in the form of expanded carrier screenings. ArcherDX has acquired the personalized medicine laboratory Baby Genes, which will allow them to offer newborn and carrier screening tests for the first time. Invitae Genetics unveiled their expanded carrier screening tests last summer but have now coupled the tests with Non-Invasive Prenatal Screening (NIPS). Finally, Myriad Genetics has published new data on their expanded carrier screening in the journal Genetics in Medicine. What, exactly, are expanded carrier screening tests and what do they mean for physicians, genetic counselors, and expectant parents?

What is carrier screening?

Carrier screening is genetic testing done to identify carriers of gene mutations for certain genetic disorders. Carrier screening is especially pertinent before or during pregnancy as screening of one or both partners can indicate a significantly increased risk of having a child with a specific genetic disorder. A carrier, or person with one non-working copy of a gene and one working copy, typically has no symptoms. If both parents are carriers for the same autosomal recessive disorder, there is a 50% chance of their offspring getting one copy of the mutated gene and also being a carrier, a 25% chance of receiving two copies of the mutated gene and developing the disorder, and a 25% chance of inheriting two copies of the working gene and being a non-carrier. These risks are independent for each pregnancy. Typically, pregnant or soon-to-be pregnant women undergo carrier screening and then, if they are found to be a carrier for a particular condition, their partner is then tested for mutations related to that same condition. With regards to timing, carrier screening is best done at a preconception appointment to maximize the available options to prospective parents such as in vitro fertilization or pre-implantation diagnosis. It is also commonly done at an early prenatal appointment. The results for an individual will never change and so typically do not need to be repeated for future pregnancies.

As with any genetic test, there is a risk for inaccuracy in the form of a false positive—a positive result when the individual is not a true carrier for the disorder; or a false negative—a negative result when the individual is in fact a carrier for the disorder.

Carrier screening tests differ from other prenatal screening tests such as those for neural tube defects and chromosomal abnormalities such as Trisomy 21, otherwise known as Down syndrome. New technology in the form of non-invasive prenatal screening (NIPS) is supplanting older screening methods that used a combination of maternal serum and ultrasound imaging.

It is also important to recognize  the difference between screening and diagnostic tests. The purpose of a screening test is to identify those at increased risk, while the purpose of a diagnostic test is to definitively establish the presence or absence of disease.

What are the types of carrier screening?

All women considering pregnancy should be offered carrier screening for Cystic Fibrosis and Spinal Muscular Atrophy under current American College of Obstetricians and Gynecologists (ACOG) guidelines. These genetic conditions are common enough to warrant screening in the general population of potential mothers. So far, carrier screen is largely conducted for relatively common, recessive disorders associated with significant morbidity and reduced life-expectancy.
There are two schools of thought for additional testing: 1) targeted carrier screening and 2) expanded carrier screening.

Targeted carrier screening tests for genetic variants in specific genes based on an individual’s ethnicity and family history. For example, Tay-Sachs disease has a higher carrier rate among individuals of Ashkenazi Jewish, French-Canadian and Cajun descent. If either parent belongs to one of those populations, or has a family history, carrier screening for Tay-Sachs disease is recommended.

Conversely, expanded carrier screening take a very broad approach to testing, testing many different genes associated with a variety of genetic disorders (as many as 200 per panel) with no specificity as to the patient’s reported ethnicity or ancestry. It is worth noting that many of the diseases that are being tested for are very rare.

What are current guidelines for targeted screening?

Professional societies in reproductive medicine currently recommend targeted carrier screening following family history review of the patient and her partner at a preconception or prenatal appointment. The American College of Obstetrics and Gynecology (ACOG) first recommended using family history as a risk assessment tool in 2011. The American College of Medical Genetics and Genomics (ACMG) subsequently issued their initial policy statement in 2013. By 2015, ACOG and ACMG, along with the Perinatal Quality Foundation, the Maternal Society for Maternal-Fetal Medicine, and the National Society for Genetic Counselors issued a joint statement to provide education for clinicians and laboratories regarding the use of expanded genetic carrier screening. The statement discusses the advantages and disadvantages of expanded carrier screening but maintains the prior targeted carrier screening recommendations. Current guidelines, most recently reaffirmed by ACOG in February 2019, continue to recommend targeted carrier screening. If both partners are found to be carriers for the same condition, genetic counseling is recommended, with discussion including options forprenatal diagnosis. Particularly when there is a known family history of a genetic condition, ACOG recommends this testing at a preconception appointment to expand the options available to hopeful parents including testing of an embryo(s) prior to in-vitro fertilization. Professional societies are constantly reviewing best practices and utilization among carrier screening tests.

What about Expanded Carrier Screening (ECS)?

Conversely, Expanded Carrier Screening (ECS) allows testing of all individuals, without regarding to reported ethnicity or ancestry, for a myriad of diseases. Sometimes referred to as ‘pan-ethnic’ or ‘universal’ screening, these tests take advantage of faster and cheaper genetic technologies to test a much larger number of genes for variants that may be pathogenic, or disease-related mutations. An expectant mother might be interested in pursuing expanded screening, for example, if she has gaps in her knowledge of her family history or if her ethnic makeup is unknown. As we are learning through the soaring popularity of at-home DNA ancestry kits like 23andMe, a lot of families are finding discrepancies in their genetic family histories. The move to universal screening can serve to increase equity and reduce medical stigma around ethnic groups.

Is it possible to have peace of mind in pregnancy?

Expanded carrier screening (ECS) can be appealing to a mother who shows no increased disease risk based on ethnic or family history but is looking for ‘peace of mind’ through genetic testing. It’s true that the majority of affected children are born to couples with no previous known family history. There may be as many as 1300 recessively inherited disorders with differing ranges of severity. Cumulatively, these disorders affect approximately 30 in every 10,000 children. This means that out of 100 couples, 1-2 are at risk of having a child affected by a recessive genetic condition.

However, true peace of mind is hard to find because there are risks inherent in any pregnancy. All ECS panels screen for a subset of recessively inherited disorders, with little consistency between panels from different companies. Having a negative ECS screen can give some peace of mind that potential parents are avoiding many common disorders, but it is not possible to screen for all recessively inherited disorders. Furthermore, negative ECS testing has no bearing on the risk for aneuploidy and does not modify the background risk of birth defects, which is about 3% for babies born in the United States.

Is detecting more carriers better?

Genetic testing companies are certainly trying to make the case that expanded testing is more effective at screening mothers-to-be, not just in the general population but also in populations with increased frequencies of genetic diseases. A study by the testing company Counsyl (now Myriad Women’s Health) published in the Journal of the American Medical Association in 2016 found that ECS identified more hypothetical fetuses with a disorder than recommended targeted screening. For instance, among Middle Eastern couples at increased risk for being carriers of hemoglobinopathies or beta-thalassemia, researchers found that 91 percent of affected fetuses would not have been identified using a guideline-based targeted panel but would have been detected under an expanded panel. Other, sometimes company-funded, studies over the past few years seem to confirm these results.

ECS panel testing companies may gloss over some of the emotional and values-based components of carrier screening. The estimated 1000+ recessively inherited genetic disorders range in severity of health impact. Many included conditions on commercially available ECS panels do not cause significant health impairment, have highly variable clinical courses, and/or are found at a low frequency in most or all populations. Both prospective parents are not usually screened at the same time, and identification of carrier status in the first parent screened can cause significant anxiety, the need for genetic counseling, additional testing, logistical difficulty for healthcare providers, and increased financial burden. Inclusion of each additional condition is therefore a trade-off between those negative consequences and the benefit of identifying an at-risk couple who is informed with actionable information for their pregnancy management.

Is expanded carrier screening accurate if you have a family history?

If one or both prospective parents have a family history of a common, inherited genetic condition and the couple has decided to undergo carrier screening, it may be tempting for the couple to undergo an ECS panel that includes that condition. They could be looking for more ‘bang for their buck’ in a carrier screening panel. Unfortunately, these genetic disorders are much more complex.

There are at least 1,700 mutations that have been identified for cystic fibrosis. Of those, the current recommendations by the College of Medical Genetics and Genomics issued in 2004, indicate testing at least 23 of the most common mutations. Enhanced mutation panels are now commercially available that include more mutations and increase the efficacy especially in non-Caucasian populations. Some cystic fibrosis screening panels include variants that are not disease causing on their own but would be relevant to couples with significant family history. In this case, genetic counseling would help determine whether a combination of mutations could possibly be disease causing.

Similarly, ACOG guidelines indicate specifically that ECS is not the best approach to screening in the presence of a family history of Tay-Sachs Disease.

What is next?

Genetics in medicine is a rapidly growing field. Similarly, the technology that lets us evaluate more genes and genetic disorders easier and cheaper is evolving equally fast. There are numerous parties who have a stake in how the field develops including healthcare providers and their professional societies, genetic counselors, commercial genetic testing laboratories, and patients with their families and potential offspring. With any new technology, attention must be paid to ethics, utilization, transparency, validity, and cost. Whether expanded carrier screening supplants targeted screening remains to be seen.

With so many testing options related to pregnancy, preconceptual genetic counseling can be valuable to patients to help them make informed decisions that are consistent with their own goals and values. 

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