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Single-cell-based non-invasive screening for fetal pathogenic microimbalances using maternal blood: comparison with
T Stampalija1,2, C Forcato3, F R Grati3
1Unit of Fetal Medicine and Prenatal Diagnosis, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
Objective:
Pathogenic or likely pathogenic copy-number variants (p/lpCNVs) are a significant cause of perinatal morbidity and mortality. Current prenatal screening based on cell-free DNA (cfDNA) fails to detect the majority of microimbalances (microdeletions/microduplications), leaving a significant residual risk of undetected chromosomal abnormalities. This study evaluated the clinical performance of a novel single-cell-sequencing-based non-invasive prenatal testing (scsbNIPT) method utilizing circulating extravillous trophoblasts (cEVTs) for the detection of fetal p/lpCNVs, particularly microimbalances < 8 Mb.
Methods:
This was a prospective, blinded, observational multicenter cohort study of 1390 high-risk pregnant women undergoing prenatal invasive diagnostic testing between November 2021 and December 2023. A 20-mL maternal blood sample was collected from each subject between 11 + 0 and 22 + 6 weeks' gestation prior to invasive sampling. cEVTs were isolated and subjected to whole-genome sequencing, using a proprietary workflow. scsbNIPT results were compared with standard invasive prenatal diagnostic results obtained by karyotyping and/or chromosomal microarray analysis.
Results:
scsbNIPT showed a sensitivity of 92.9% (95% CI, 76.5-99.1%) and a specificity of 98.2% (95% CI, 97.0-99.0%) for the detection of genome-wide microimbalances measuring ≥ 300 kb to < 8 Mb. The sensitivity for p/lpCNVs ≥ 300 kb in pregnancies screened at 11 + 0 to 14 + 6 weeks was 100% (95% CI, 83.9-100%). For trisomy 21, the sensitivity of scsbNIPT was 98.0% (95% CI, 92.9-99.8%) and the specificity was 99.7% (95% CI, 99.0-99.9%).
Conclusions:
This study demonstrates the scientific validity and clinical utility of scsbNIPT for the non-invasive detection of genome-wide fetal p/lpCNVs, particularly microimbalances, with high sensitivity and a resolution comparable to that of chromosomal microarray analysis. scsbNIPT may offer more complete screening for genome-wide p/lpCNVs, markedly lowering the residual risk early in pregnancy compared with existing cfDNA-based methods. © 2026 Menarini Silicon Biosystems. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Insights
A new single-cell sequencing non-invasive prenatal test (scsbNIPT) accurately detects fetal copy-number variants, including microimbalances, offering improved screening over current cfDNA methods.
Area of Science:
- Genetics
- Prenatal Diagnostics
- Genomic Medicine
Background:
- Pathogenic copy-number variants (p/lpCNVs) cause significant perinatal issues.
- Current cell-free DNA (cfDNA) screening misses most microimbalances, leaving a residual risk.
- A novel method is needed for comprehensive prenatal detection of fetal chromosomal abnormalities.
Purpose of the Study:
- To evaluate the clinical performance of single-cell sequencing-based non-invasive prenatal testing (scsbNIPT).
- To assess scsbNIPT's ability to detect fetal p/lpCNVs, especially microimbalances (<8 Mb).
- To compare scsbNIPT with standard invasive diagnostic methods.
Main Methods:
- Prospective, blinded, observational multicenter cohort study of 1390 high-risk pregnancies.
- Maternal blood samples collected (11-22 weeks gestation) for circulating extravillous trophoblast (cEVT) isolation.
- Whole-genome sequencing of cEVTs followed by comparison with karyotyping/chromosomal microarray analysis.
Main Results:
- scsbNIPT demonstrated 92.9% sensitivity and 98.2% specificity for microimbalances (≥300 kb to <8 Mb).
- Sensitivity for p/lpCNVs ≥300 kb was 100% when screened between 11-14 weeks.
- High sensitivity (98.0%) and specificity (99.7%) were observed for trisomy 21 detection.
Conclusions:
- scsbNIPT is scientifically valid and clinically useful for detecting fetal p/lpCNVs, including microimbalances.
- The test offers high sensitivity and resolution comparable to chromosomal microarray analysis.
- scsbNIPT provides more complete screening, significantly reducing residual risk early in pregnancy.
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