Assessment of Placental Chromosomal Mosaicism during Prenatal Cell-Free DNA Screening Refines Positive Predictive Values for Fetal Trisomy

Background Confined placental mosaicism can cause false-positive prenatal cell-free DNA (cfDNA) screening results, thereby reducing the positive predictive value (PPV) of the test. We sought to investigate how PPVs for the common fetal trisomies can be refined based on the presence or absence of chromosomal mosaicism in cfDNA sequencing data. Methods The study cohort included singleton pregnancies tested between March 2019 and December 2021. Outcome data were requested for high-risk results. Mosaic ratio (MR) generated by VeriSeq NIPT Solution v2 was used to classify high-risk cfDNA results as mosaic trisomy (MR < 0.7) or non-mosaic trisomy (MR ≥ 0.7) and the PPVs calculated. Results The cohort consisted of 821 high-risk results from 76 329 tests (1.08%). Prior to applying MR, PPVs for T21, T18 and T13 were 93.3% [95% CI 90.2–95.5], 81% [95% CI 73.1–87.0], and 55.3% [95% CI 44.7–65.4], respectively. After applying MR, PPVs for non-mosaic trisomy results were significantly higher (P < 0.001) than the PPVs for mosaic trisomy results; T21: 99.3% and 50%, T18: 97.6% and 22.7%, T13: 93.9% and 0%, respectively. Conclusions Mosaic ratio can be used to calculate more specific PPVs for the common trisomies. There is currently limited guidance on the application of VeriSeq v2 MR. Our approach provides a framework for laboratories to consider using MRs to refine PPV estimates for the common trisomies. High-risk cfDNA screening results are distressing for tested individuals. A refined PPV incorporating the presence or absence of mosaicism provides patients with more accurate information on the likely outcome of the diagnostic testing result, helping guide genetic counseling, choice of prenatal procedure, and overall pregnancy management.