Copy-number variant (CNV) assessment is recommended for patients undergoing prenatal diagnostic testing. Noninvasive screening tests have not been extensively validated for CNV detection. The objective of this study was to compare the ability of genome-wide noninvasive prenatal screening (NIPS) to chromosomal microarray to detect clinically significant findings.
We prospectively enrolled 198 subjects at the time of consent for diagnostic prenatal testing. Genome-wide NIPS results were compared with diagnostic testing results to assess NIPS test performance (n = 160, 38 subjects without microarray results excluded). Cohen’s kappa statistic was used to assess test agreement.
Genome-wide NIPS did not detect clinically significant chromosomal abnormalities at the same rate as diagnostic testing, κ = 0.75 (95% confidence interval [CI], 0.62–0.87). When excluding CNVs <7 Mb and findings outside the limits of genome-wide NIPS, test agreement improved, κ = 0.88 (0.79–0.97) driven by agreement for common aneuploidies (κ = 1.0). However, among patients with an abnormal fetal survey, agreement was only fair, κ = 0.38 (0.08–0.67).
While NIPS is an excellent screening test for common aneuploidies, genome-wide NIPS misses clinically significant findings detected on routine diagnostic testing. False positive and false negative cases highlight the importance of pretest counseling regarding NIPS limitations, especially in the setting of fetal anomalies.
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Study data are available from the corresponding author on request.
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We acknowledge our collaborators at Sequenom who ran MaterniT Genome® tests for this study at no cost on a research basis. Sequenom collaborators had the right to review the manuscript prior to publication; however, the authors retained the right to final manuscript preparation and submission. This study was funded by an Expanding the Boundaries grant from the Department of Obstetrics & Gynecology, Brigham and Women’s Hospital.
The Mass General Brigham Human Research Committee approved this study. Informed consent was obtained from all participants as required by the IRB.
L.W.-H. is an editor for the Prenatal Genetics section of UpToDate. S.A. received funding from BillionToOne outside the scope of the submitted work. K.G. receives funding from the NIH and has consulted for Aetion, Illumina, and BillionToOne outside the scope of the submitted work. The other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Guseh, S., Wilkins-Haug, L., Kaimal, A. et al. Utility of noninvasive genome-wide screening: a prospective cohort of obstetric patients undergoing diagnostic testing. Genet Med (2021). https://doi.org/10.1038/s41436-021-01147-4