Expanded Prenatal cfDNA Screening Detects Aneuploidies, Microdeletions and Monogenic Variants in a Single Test
This prospective multicentre study evaluated a comprehensive cfDNA screening test combining aneuploidy, microdeletion and single-gene variant detection using coordinative allele-aware target enrichment sequencing in 1,090 high-risk pregnancies. The test achieved 98.5% sensitivity and 99.3% specificity, with the addition of monogenic conditions increasing detection yield by 60.7% over chromosomal aberrations alone. Among fetuses with ultrasound anomalies, 37.8% of detected variants were single-gene pathogenic mutations that would have been missed by standard NIPT.
The original study
Prospective prenatal cell-free DNA screening for genetic conditions of heterogenous etiologies.
- Authors
- Zhang J, Wu Y, Chen S, Luo Q, Xi H, Li J, et al.
- Journal
- Nature medicine
- Type
- Observational Study, Multicenter Study, Journal Article, Research Support, Non-U.S. Gov't
- PMID
- 38253798
Original abstract
Prenatal cell-free DNA (cfDNA) screening uses extracellular fetal DNA circulating in the peripheral blood of pregnant women to detect prevalent fetal chromosomal anomalies. However, numerous severe conditions with underlying single-gene defects are not included in current prenatal cfDNA screening. In this prospective, multicenter and observational study, pregnant women at elevated risk for fetal genetic conditions were enrolled for a cfDNA screening test based on coordinative allele-aware target enrichment sequencing. This test encompasses the following three of the most frequent pathogenic genetic variations: aneuploidies, microdeletions and monogenic variants. The cfDNA screening results were compared to invasive prenatal or postnatal diagnostic test results for 1,090 qualified participants. The comprehensive cfDNA screening detected a genetic alteration in 135 pregnancies with 98.5% sensitivity and 99.3% specificity relative to standard diagnostics. Of 876 fetuses with suspected structural anomalies on ultrasound examination, comprehensive cfDNA screening identified 55 (56.1%) aneuploidies, 6 (6.1%) microdeletions and 37 (37.8%) single-gene pathogenic variants. The inclusion of targeted monogenic conditions alongside chromosomal aberrations led to a 60.7% increase (from 61 to 98) in the detection rate. Overall, these data provide preliminary evidence that a comprehensive cfDNA screening test can accurately identify fetal pathogenic variants at both the chromosome and single-gene levels in high-risk pregnancies through a noninvasive approach, which has the potential to improve prenatal evaluation of fetal risks for severe genetic conditions arising from heterogenous molecular etiologies. ClinicalTrials.gov registration: ChiCTR2100045739 .