Home 5 Clinical Diagnostic Insider 5 What Are the Latest CFTR Carrier Screening Recommendations?

What Are the Latest CFTR Carrier Screening Recommendations?

by | Aug 29, 2023 | Clinical Diagnostic Insider, Diagnostic Testing and Emerging Technologies, Special Focus-dtet

New ACMG recommendations aim to make CFTR carrier detection more equitable among a wider range of ancestries.

Various mutations in the CFTR gene cause cystic fibrosis (CF), which is an inherited disorder affecting the lungs, digestive system, and other organs in the body.1 When someone is a carrier of a CFTR variant, they usually don’t show any signs or symptoms of CF, but are at an increased risk of having a child with the condition.

For this reason, carrier screening for CFTR variants is seen as an important tool that enables people who carry one of these genetic variants to make better-informed decisions when they’re trying to have a baby. Without carrier screening, many people are unaware that they carry an inheritable genetic condition that may affect their child.2

In June of this year, the American College of Medical Genetics and Genomics (ACMG) published new CFTR carrier screening recommendations, increasing the number of CFTR variants recommended for CF carrier screening to 100.3

Previously, ACMG’s CFTR screening recommendations included a list of 23 CFTR variants that were established in 2001 and had remained unchanged since 2004 despite great advances in genetics and molecular diagnostic technologies. The set of 23 variants was based primarily on databases of individuals with CF who were of non-Hispanic White or Ashkenazi Jewish ancestry. This meant it was easier to identify individuals of those ancestries during carrier screening, even though it is well established that CF affects individuals across all ancestries, races, and ethnicities.

“The carrier detection rates for individuals of other backgrounds are significantly lower,” explains Emily Goldberg, MS, CGC, a genetic counselor at JScreen.4 “The goal of the updated recommendations is to increase the rate at which carriers are identified across all individuals within the United States to at least 95 percent.”

The New ACMG Recommendations

In their position statement for the new recommendations, ACMG acknowledged that these changes are necessary to improve equity and minimize bias and disparities in variant detection.

“When it was originally developed, the previous variant list set the standard for CF carrier screening in the country,” lead author Joshua L. Deignan, PhD, FACMG, said in a release. “Now that our databases and technologies have evolved, it was time to raise the bar and set a new minimum standard. This new recommended variant set should help ensure that CFTR variant detection is more equitable among individuals representing a variety of biogeographic ancestries.”5

All variants in the new set are included based on evidence that the variant can cause CF and is in the Genome Aggregation Database (gnomAD).6 Knowing that interpreting CFTR results can be complex and that people would be using this information to make important reproductive decisions, ACMG noted that they took a conservative approach to their new recommendations and only included variants that are well-established or likely to cause CF.

“ACMG used a robust database as the source for CF-causing variants selected for inclusion,” says Gwen Fraley, MS, CGC, a genetic counselor and director of clinical strategy at InformedDNA. “This eliminates some of the uncertainty in reproductive decision-making parents face when variants with less established disease liability are identified.”

The new recommendations only apply to carrier screening, not newborn screening or diagnosis. Aside from quadrupling the list of CFTR variants, all other aspects of the 2020 ACMG technical standards still apply.

Fraley says that ACMG’s official recognition that the minimum 23 variant set for CF carrier screening required updating is a welcome advancement in patient care. “CFTR variant knowledge across all populations and molecular diagnostic technologies have significantly advanced and these new recommendations will improve diagnostic rates in a broader population,” she adds.

Releasing the new recommendations shows that ACMG is committed to improving clinical genetic services available to a diverse population, Goldberg says.

However, it’s important to keep in mind that CF is a complex condition with significant genetic variability—and while the new recommendations include 100 mutations within the CFTR gene, more than 400 pathogenic variants have been identified, Goldberg adds.

“This recommendation is designed to target population-wide screening to identify those at risk for having a child with cystic fibrosis,” Goldberg says. “ACMG argues that it is not appropriate to include variants that are not well established or do not have a clear disease course.”

Implementing the Updated Guidelines

The expanded list of variants is an important step toward reducing disparities in variant detection. Additionally, having a standardized list of mutations will help guide laboratories and ensure consistent testing for patients around the country, Goldberg points out.

There will be some upfront work and costs involved for laboratories, though, as they adapt their carrier screening offerings. To start, they will need to update their platforms to include all the new recommended CFTR variants.

“The American Medical Association (AMA) has assigned a CPT code for the common variants panel as well as full CFTR sequencing and both have an associated PAMA [Protecting Access to Medicare Act] price,” Fraley says. “Laboratories will have the opportunity to work with CMS [Centers for Medicare & Medicaid Services] to increase reimbursement for the new, larger panels due to increased complexity.”

Currently, there are no CF tests available that contain all the newly recommended variants. ACMG noted in the paper that “it may be easier for laboratories to continue testing for the updated minimum variant set if comprehensive testing methods (i.e., NGS [next-generation sequencing]) are used instead of targeted testing methods.”3

Laboratories should also note that although the previous list of variants was often referred to as the “ACMG-23,” the ACMG does not recommend using the term “ACMG-100” when referring to the new variant set.5

The Takeaway

ACMG’s new cystic fibrosis carrier screening recommendations expand the set of CFTR variants from 23 to 100. In doing so, they hope to improve genetic carrier screening for CF and minimize existing biases involved in the process. Experts say the changes are much needed given the advances in technology, genetics, and knowledge of CF since ACMG’s initial list of genetic variants was established more than 20 years ago.

“These new guidelines increase the minimum mutation set by almost five-fold and provide improved carrier detection for patients of non-Ashkenazi and non-Northern European ancestry,” Goldberg says. “This update is an important step in improving carrier detection rates across ethnicities and in increasing awareness of disparities in genetic testing for different populations.”


    1. https://medlineplus.gov/genetics/condition/cystic-fibrosis/

    1. https://www.genome.gov/genetics-glossary/Carrier-Screening

    1. https://www.sciencedirect.com/science/article/pii/S1098360023008808

    1. https://www.jscreen.org/

    1. https://www.acmg.net/PDFLibrary/Updated%20Carrier%20Screening%20Recommendations%20for%20Cystic%20Fibrosis.T.RS.6.9.final.pdf

    1. https://gnomad.broadinstitute.org/

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