For decades, cystic fibrosis (CF) carrier screening has been recommended for all pregnant individuals and those planning a pregnancy. A growing body of real-world clinical data is adding nuance to that picture, and understanding its implications is increasingly relevant to pre- and post-test counseling conversations. 

What current guidelines recommend for CF carrier screening 

Following a  joint American College of Medical Genetics (ACMG), American College of Obstetricians and Gynecologists (ACOG), and National Institutes of Health (NIH) initiative, ACMG published laboratory standards in 2001 establishing a standard cystic fibrosis transmembrane conductance regulator (CFTR) variant panel for CF carrier screening..¹ A 2004 revision  established the 23-variant panel referenced in current practice.² In 2023, ACMG released an updated 100-variant set intended to broaden detection across a more diverse U.S. population.³ Full CFTR gene sequencing with deletion/duplication analysis, therefore, remains outside the standard of care for routine carrier screening. However, recent real-world data are shedding light on what that gap means for patients.

 What the data show for CF carrier screening

 Prior work has already challenged the adequacy of the 23-variant panel. In a study of ~100,000 screened patients, sequencing with copy number variation (CNV) analysis detected 58 at-risk couples, 31% of whom would have been missed by the 23-variant panel alone.⁴ Among those identified, 89% of preconception couples took or planned action to reduce the risk of having a pregnancy affected by CF.⁴ 

New data reinforce and extend these findings. A retrospective cohort study of ~176,000 individuals undergoing comprehensive CFTR testing at a single national commercial laboratory identified 6,142 carriers (3.5%). When the minimum variant sets used by current targeted panels were applied to the same cohort, the results revealed detection gaps⁵: 

-   ACMG/ACOG-23: Detected 55.0% of carriers - missing 45.0%

-   Commercial 32-variant set: Detected 57.5% of carriers - missing 42.5%

-   ACMG-100: Detected 65.8% of carriers - missing 34.2%

 Among 340 distinct pathogenic/likely pathogenic (P/LP) variants identified, the ACMG/ACOG-23 panel captured only 6.8% of these variants; even the ACMG-100 panel captured just 29.4%. Six of the 10 most frequently occurring P/LP variants in this cohort were absent from all three sets. 

Targeted panel-based variant approaches also carry an additional technical limitation: CNVs, including exonic deletions and duplications, are absent from the current targeted panel minimum CFTR variant sets. In the same laboratory cohort, 64 P/LP CNVs were identified across individuals, representing approximately 1% of all P/LP variants. These included recurrent deletions (exon 19-20, 12.1%; exon 19-21, 10.6%; exon 2-3, 10.6%) and full-gene deletions.⁶  

Who gets missed with CFTR testing

 The gaps also fall unevenly across populations. This disparity is pronounced in Hispanic populations, where the 23-variant panel has been shown to identify approximately 25% of affected pregnancies.⁴ Analysis comparing the ~176,000 individuals from a national laboratory clinical cohort with data from the Genome Aggregation Database (gnomAD) further illustrates this: real-world variants appeared across a median of seven ancestry groups, compared with four for gnomAD-only variants. This suggests that reference databases alone underrepresent the diversity of patients undergoing testing and may miss clinically relevant variants, including several variants with higher frequencies in African/African American, Latino/Admixed American, and other underrepresented groups that are not included in existing U.S. targeted variant sets.⁷ 

Beyond population-level variant gaps, certain variant classes present additional interpretive complexity that guidelines may not fully capture.  

Poly-T/TG variants and clinical complexity

 Current guidelines address CFTR poly-T/TG-repeat variants in specific reflex contexts for carrier screening.^3,8 Genotypes with these variants carry variable clinical significance, and their interpretation can be complex. A national laboratory cohort study linking CFTR test results to longitudinal medical claims across more than 125,000 individuals found that congenital bilateral absence of the vas deferens (CBAVD) enrichment was highest for individuals with a pathogenic CFTR variant and TG13T5 (without R117H; OR=288), compared to classic biallelic CF genotypes (OR=33), underscoring TG13T5's contribution to male infertility independent of pulmonary disease.⁹ 

For these variants, genotype-phenotype prediction can be challenging; however, real-world clinical data are helping to characterize the clinical outcomes associated with specific poly-T/TG variant combinations. A recently published educational resource provides descriptive phenotype likelihoods across R117H and poly-T/TG genotype combinations, offering genetic counselors a structured framework for discussing variable expressivity and penetrance with patients and families.¹⁰  

Looking forward: CF carrier screening and genetic counseling

 Taken together, these data suggest that each of the targeted panel CFTR variant sets left a substantial proportion of carriers undetected, with gaps that fall unevenly across populations. As of 2026, neither ACMG nor ACOG recommends full CFTR gene sequencing in carrier screening. Comprehensive sequencing with CNV analysis is not without its own limitations, but it can be less constrained by the assumptions built into targeted panel design. For patients from underrepresented population groups or those carrying structural variants, that distinction is especially meaningful. As guidelines continue to evolve, genetic counselors are well-positioned to understand what emerging evidence means, both for residual risk and for the interpretation of complex variant results, and to reflect those nuances in conversations with their patients. 

Labcorp's comprehensive CFTR carrier screening integrates full-gene sequencing with deletion/duplication analysis in a single test order. Genetic counseling support resources are also available. To learn more, visit our resources page. 

References

1. Grody WW, Cutting GR, Klinger KW, et al. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med. 2001;3(2):149-154. doi:10.1097/00125817-200103000-00010
2. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. 2004;6(5):387-391. doi:10.1097/01.GIM.0000139506.11694.7C
3. 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). Genet Med. 2023;25(8):100867. doi:10.1016/j.gim.2023.100867
4. Beauchamp KA, Johansen Taber KA, Grauman PV, et al. Sequencing as a first-line methodology for cystic fibrosis carrier screening. Genet Med. 2019;21(11):2569-2576. doi:10.1038/s41436-019-0525-y
5. Makhamreh MM, Soster E, Teicher J, et al. Rethinking CF carrier screening: comprehensive CFTR testing vs. limited variant sets. Pregnancy. 2026;2(suppl 1):Abstract 64. doi:10.1002/pmf2.70157
6. Makhamreh MM, Soster E, Teicher J, et al. The role of deletion and duplication analysis in cystic fibrosis carrier screening. Genet Med Open. 2026;4(suppl 1):104249. doi:10.1016/j.gimo.2026.104249
7. Makhamreh MM, Soster E, Teicher J, et al. Gaps in CFTR carrier screening: population diversity and variant representation. Genet Med Open. 2026;4(suppl 1):104250. doi:10.1016/j.gimo.2026.104250
8. Deignan JL, Astbury C, Cutting GR, et al. CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(8):1288-1295. doi:10.1038/s41436-020-0822-5
9. Vaccari EM, Garcia J, Neitzel D, Pineda-Alvarez DE. Pre-test clinical enrichment refines interpretation of CFTR TG-T with or without R117H haplotypes. Genet Med Open. 2026;4(suppl 1):103633. doi:10.1016/j.gimo.2026.103633
10. Raraigh KS, Balcom JR, Langfelder-Schwind E. Developing a primer for communicating about penetrance, expressivity, and genotype-phenotype correlation of R117H and the poly-T tract in CFTR. J Genet Couns. 2025;34(6):e70151. doi:10.1002/jgc4.70151 

 Disclosure: AI was used as a writing aid in the preparation of this article. Final content reflects the author’s own analysis, expertise, and editorial decisions.

Erica Vaccari, MS, CGC

is a clinical program manager supporting women’s health, population genetics, and hereditary cancer research at Labcorp. She holds a Bachelor of Science in biochemistry from Lehigh University and a Master of Science in genetic counseling from Boston University School of Medicine. She has held both clinical and industry roles in genetic counseling since 2013.