Oral Concurrent Session 6 – Ultrasound and Genetics

Objective: CFTR full gene sequencing with deletion/duplication analysis is not currently standard of care for cystic fibrosis (CF) prenatal carrier testing.We aim to quantify the extent comprehensive CFTR testing identifies pathogenic, or likely pathogenic (P/LP) variants missed by current limited CFTR variant sets. Study Design:We conducted a retrospective review at a national commercial laboratory (Labcorp) that underwent full CFTR gene sequencing with deletion/duplication analysis for routine prenatal screening, between 3/2023 and 1/2024.Identified P/LP variants were compared to three commonly used CF screening variant sets: ACMG/ACOG-23, the 23 variant ACMG/ACOG recommended guideline; a commercial 32-variant set that includes ACMG/ACOG-23 plus 9 pan-ethnic and high frequency variants; and 2023 ACMG-100, an updated set of 100 variants recommended by ACMG.IRB approval was obtained at collaborating institutions.Results: Among 175,858 individuals tested, 6142 (3.5%) had CFTR P/LP variants.Of these, 98.9% were detected by sequencing and 1.1% by deletion/duplication analysis.Of the 6142 carriers identified, 3376 (55.0%), 3532 (57.5%), and 4044 (65.8%) would have been detected by ACMG/ACOG-23, 32-variant, and ACMG-100 sets, respectively.A total of 340 distinct P/LP CFTR variants were identified.Detection by variant set would have been as follows: 6.8% for ACMG/ACOG-23, 9.4% for 32-variant set, 29.4% for ACMG-100 (Table 1).Thus, 70.6% of P/LP variants would have been missed by the most inclusive CFTR variant set.Notably, 6 of the 10 most frequent P/LP variants (60%) in this cohort were absent from all three variant sets.Conclusion: CFTR full gene sequencing analysis outperforms currently recommended variant set-based approaches, which would have missed one-third to one-half of carriers.This approach captures a broader and more representative variant spectrum, including high-frequency P/LP variants missed by existing variant sets.Our findings support the adoption of comprehensive CFTR testing as the new standard for carrier screening in the U.S. to improve equity and accuracy across diverse populations.