Five Ways Labs Are Addressing Common CFTR Testing Challenges

CFTR testing, which evaluates variants in the CFTR gene associated with cystic fibrosis, has evolved substantially over the past two decades. Early testing strategies focused on a limited number of well-characterized variants, but advances in genetic knowledge and expanded population data have reshaped expectations around coverage, equity, and interpretation.¹

Today, laboratories face a growing set of challenges related to CFTR testing — from variant selection and standards alignment to interpretation and communication of results. In response, CFTR testing strategies are increasingly shaped by professional guidance, technical standards, and a deeper understanding of CFTR biology.

1 Aligning CFTR Testing with Updated ACMG Recommendations

Professional guidelines play a central role in how laboratories approach CFTR testing. For many years, CFTR carrier screening relied on a limited set of pathogenic variants that primarily reflected mutation frequencies in individuals of European ancestry.²

More recent guidance from the American College of Medical Genetics and Genomics (ACMG) has expanded recommended CFTR variant coverage to a minimum of 100 pathogenic variants, reflecting advances in variant knowledge and a focus on more equitable detection across populations.¹  Many laboratories now use these recommendations as a baseline when designing CFTR testing strategies, while remaining adaptable to future updates.

2 Balancing Targeted and Comprehensive Testing Approaches

CFTR testing methods span a range of strategies, from targeted variant panels to more comprehensive sequencing-based approaches. ACMG technical standards acknowledge that both approaches may be appropriate depending on testing context, provided their scope and limitations are clearly defined and communicated.^3,4

Rather than treating coverage as a binary choice, laboratories increasingly emphasize transparency — clearly articulating which variants are included and how results should be interpreted within that framework.

3 Expanding CFTR Variant Coverage to Reflect Population Diversity

Early CFTR variant panels often underrepresented variants more prevalent in non-European populations, limiting detection in diverse cohorts.²  As population-scale data have expanded, CFTR testing strategies have evolved to incorporate a broader range of variants with demonstrated relevance across ancestral groups.¹

This shift reflects a growing recognition that inclusive variant selection is essential for generating meaningful and equitable genetic insights.

4 Clearly Communicating Residual Risk and Test Limitations

Even with expanded CFTR variant coverage, no testing approach can detect all possible pathogenic variants. Professional guidance emphasizes that negative results do not eliminate carrier risk and should be interpreted in the context of test limitations and residual risk.^4,6

Clear documentation and, when appropriate, genetic counseling help ensure that CFTR test results are understood accurately and applied responsibly.

5 Applying Standardized Variant Interpretation Frameworks

Accurate CFTR testing depends not only on which variants are detected, but also on how those variants are classified. Widely adopted ACMG/AMP guidelines define standardized criteria for interpreting sequence variants as pathogenic, likely pathogenic, uncertain significance, likely benign, or benign.⁵

These frameworks support consistency across laboratories and studies, enabling clearer communication and more reliable comparison of CFTR findings.

Looking Ahead

As CFTR testing continues to evolve, laboratories are increasingly navigating these challenges through standards alignment, expanded population awareness, and transparent interpretation practices. Together, these approaches reflect a field that is maturing — one that values intentional design, evidence-based decision-making, and clarity in how CFTR results are generated and communicated.

References
1. Deignan JL, Gregg AR, Grody WW, et al. Updated recommendations for CFTR carrier screening: A position statement of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2023;25(8):100867. doi:10.1016/j.gim.2023.100867  2. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genetics in Medicine. 2004;6(5):387–391. doi:10.1097/01.GIM.0000139506.11694.7C  3. Grody WW, Thompson BH, Gregg AR, et al. ACMG technical standards and guidelines for CFTR mutation testing. Genetics in Medicine. 2001;3(2):149–154. doi:10.1097/00125817-200103000-00010  4. Deignan JL, Astbury C, Cutting GR, et al. CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2020;22(8):1288–1295. doi:10.1038/s41436-020-0830-9  5. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the ACMG and AMP. Genetics in Medicine. 2015;17(5):405–424. doi:10.1038/gim.2015.30  6. American College of Obstetricians and Gynecologists (ACOG). Carrier screening for genetic conditions. Obstetrics & Gynecology. 2017;129(3):e35–e40. doi:10.1097/AOG.0000000000001952