The American College of Medical Genetics and Genomics (ACMG) recently updated its guidelines on preconception and prenatal carrier screening. In this blog post, we explore these updates and hear from Dr. Marra Francis, Head of Medical Affairs for Women’s Health at Sema4, on what they mean for patients and providers.
Carrier screening is a type of genetic testing that can help individuals understand their risk of passing on a genetic condition to their child. The test analyzes a patient’s DNA to see if they are a carrier of a genetic variant (or change) that could cause an inherited disease in their children. You can learn more about carrier screening here. Medical societies, such as the American College of Obstetricians and Gynecologists (ACOG), recommend that carrier screening be offered to all women who are pregnant or planning for pregnancy. Similarly, ACMG’s position statement, first published in 2013, linked the utility of carrier screening to reproductive decision-making.
ACMG’s 2021 practice resource replaces their 2013 statement and uses more recent evidence to answer emerging questions clinicians and patients should consider during carrier screening. The updated guidance covers optimal panel size, the conditions that should be included, the use of pan-ethnic versus ethnicity-specific panels, the importance of pre- and post-test genetic counseling, and the need for a consistent and equitable approach to offering carrier screening to patients.
A tiered approach to carrier screening
One of the most significant updates to ACMG’s guidelines is the development of a four-tiered approach to carrier screening, based on carrier frequency, to standardize the design of and communication about panel offerings.
In the new system, Tier 1 aligns with historical carrier screening approaches, which include screening of cystic fibrosis (CF), spinal muscular atrophy (SMA), and risk-based screening. Tier 2 includes autosomal recessive conditions with a carrier frequency of at least 1/100, including the Tier 1 conditions. The more extensive Tier 3 consists of the conditions from Tier 2, conditions with a carrier frequency of at least 1/200, and X-linked diseases. Finally, Tier 4 is inclusive of the previous tiers, plus it includes less common diseases. Due to differences in carrier frequency estimates, the conditions included in Tier 4 will vary by lab. ACMG recommends that carrier screening laboratory reports include the tier and a list of the genes screened.
ACMG recommends offering Tier 3 screening to all pregnant patients and those planning a pregnancy. Tier 3 covers 113 genes (97 autosomal recessive and 16 X-linked) and provides equitable screening of all racial and ethnic groups. The United States has extensive population intermixing, and, as such, a central tenet of the new guidelines is that carrier screening should be pan-ethnic and inclusive of diverse populations.
ACMG advises consideration of Tier 4 screening when indicated by family or medical history, in cases of consanguinity (including second cousins), or upon patient request. However, ACMG does not recommend routine offering of Tier 4, suggesting that the addition of conditions with a carrier frequency less than 1/200 would not significantly increase the number of at-risk pregnancies identified. Importantly, ACMG recommends against offering only Tier 1 and 2 conditions, as these panels do not provide equitable screening across all populations.
Towards more equitable care
“The ACMG’s recommendation to move away from population-specific panels and offer population-neutral panels is important, as self-reported ancestry is often inaccurate,” says Dr. Marra Francis, Head of Medical Affairs for Women’s Health at Sema4 and a board-certified ObGyn. “Studies have shown that, on average, one in five individuals incorrectly self-identify their ethnicity1. Additionally, 43 years have now passed since the birth of the first “test-tube baby,” and we potentially have many reproductive-aged individuals unknowingly conceived with a sperm donor, making their true ethnicity a mystery. The rate of misattributed parentage, commonly referred to as non-paternity, is estimated to be between 1% to 10% of all births2.”
Dr. Francis believes that ethnicity-specific testing based on self-reported ancestry can miss carriers and potentially lead to affected pregnancies. “Pan-ethnic carrier panels are therefore the safest testing option,” she advises. In addition, due to recent advances in genomic testing, providers can also receive personalized residual risk estimates based on genetically determined ancestry, a market-leading feature of the Sema4 ElementsTM Expanded Carrier Screen.
Counseling is key
The new ACMG statement offers providers guidelines for pre-test counseling. In addition to informing patients of the risks, benefits, and consequences of carrier screening, providers will want to be comfortable discussing that preconception screening is recommended over screening during pregnancy to reduce stress and allow for dialogue regarding reproductive options such as preimplantation genetic testing (PGT). When screening is offered during pregnancy, ACMG supports concurrent partner testing to reduce the overall time for results to support earlier decision-making.
ACMG also recommends providers inform patients of carrier screening limitations, including its inability to detect de novo (new) mutations that may arise in offspring and that not all genetic conditions are addressed by carrier screening. Finally, ACMG indicates that residual risks (the chance an individual is a carrier even though they received a negative result) should also be addressed. Patients need to understand that while a negative screening result reduces the risk of having an affected child, it does not eliminate this risk.
While ACMG supports discussing residual risks with patients, it does not recommend including residual risk estimates in lab reports. ACMG’s reasoning is that generating precise residual risk calculations relies on carefully defined carrier frequencies and detection rates, as well as patients’ self-reported ethnicity. The Sema4 Elements Expanded Carrier Screen was purposefully designed to provide highly accurate residual risk scores. Sema4 incorporates extensively reviewed carrier frequencies across many populations, precise analytical and clinical detection rates, and proprietary technology to identify patient molecular ancestry for reporting precise, personalized residual risks.
Updated guidelines for an evolving field
In summary, the new ACMG guidelines provide an educational resource to help medical geneticists and other clinicians offer a consistent and equitable approach to carrier screening. Offering a comprehensive Tier 3 panel to all patients is a first step towards empowering diverse populations to benefit from advanced genomic technologies. As such, ACMG strongly recommends that all payers provide Tier 3 and, where clinically appropriate, Tier 4 coverage to ensure equitable healthcare across all populations and socioeconomic groups.
1: Hollenbach JA, et al. (2015) Race, Ethnicity and Ancestry in Unrelated Transplant Matching for the National Marrow Donor Program: A Comparison of Multiple Forms of Self-Identification with Genetics. PLoS One, 10(8):e0135960
2: Prero MY, et al. (2019) Disclosure of Misattributed Paternity. Pediatrics, 143(6):e20183899.
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Sema4 Elements Expanded Carrier Screen provides personalized residual risk assessments by applying proprietary technology to identify a patient’s molecular ancestry on a genome-wide level. Learn more about the screen here and the recently announced Sema4 Elements portfolio of data science-driven products and services to support reproductive and generational health here. Please contact us below if you would like additional information about our reproductive and generational health solutions.