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Utility of noninvasive genome-wide screening: a prospective cohort of obstetric patients undergoing diagnostic testing

Genetics in Medicine (2021)Cite this article

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusion

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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Fig. 1: Degree of agreement between genome-wide noninvasive prenatal screening (NIPS) and diagnostic testing.
Fig. 2: Simulated risk modification with genome-wide noninvasive prenatal screening (NIPS).

Data availability

Study data are available from the corresponding author on request.

References

  1. 1.

    Norton, M. E. & Rink, B. D. Changing indications for invasive testing in an era of improved screening. Semin. Perinatol. 40, 56–66, https://doi.org/10.1053/j.semperi.2015.11.008 (2016).

    Article  PubMed  Google Scholar 

  2. 2.

    Rose, N. C. et al. Screening for fetal chromosomal abnormalities: ACOG practice bulletin, number 226. Obstet. Gynecol. 136, e48–e69, https://doi.org/10.1097/AOG.0000000000004084 (2020).

    Article  Google Scholar 

  3. 3.

    Srebniak, M. I. et al. Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: systematic review and meta-analysis. Ultrasound Obstet. Gynecol. 51, 445–452, https://doi.org/10.1002/uog.17533 (2018).

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Wapner, R. J. et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N. Engl. J. Med. 367, 2175–2184, https://doi.org/10.1056/NEJMoa1203382 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Hay, S. B. et al. ACOG and SMFM guidelines for prenatal diagnosis: Is karyotyping really sufficient? Prenat. Diagn. 38, 184–189, https://doi.org/10.1002/pd.5212 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Practice bulletin no. 162: prenatal diagnostic testing for genetic disorders. Obstet. Gynecol. 127, e108–e122, https://doi.org/10.1097/AOG.0000000000001405 (2016).

  7. 7.

    Srebniak, M. I. et al. Social and medical need for whole genome high resolution NIPT. Mol. Genet. Genomic Med. 8, e1062, https://doi.org/10.1002/mgg3.1062 (2020).

  8. 8.

    Helgeson, J. et al. Clinical outcome of subchromosomal events detected by whole-genome noninvasive prenatal testing. Prenat. Diagn. 35, 999–1004, https://doi.org/10.1002/pd.4640 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Snyder, M. W. et al. Copy-number variation and false positive prenatal aneuploidy screening results. N. Engl. J. Med. 372, 1639–1645, https://doi.org/10.1056/NEJMoa1408408 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Schwartz, S. et al. Clinical experience of laboratory follow-up with noninvasive prenatal testing using cell-free DNA and positive microdeletion results in 349 cases. Prenat. Diagn. 38, 210–218, https://doi.org/10.1002/pd.5217 (2018).

  11. 11.

    Hu, H. et al. Noninvasive prenatal testing for chromosome aneuploidies and subchromosomal microdeletions/microduplications in a cohort of 8141 single pregnancies. Hum. Genomics. 13, 14, https://doi.org/10.1186/s40246-019-0198-2 (2019).

  12. 12.

    Ehrich, M. et al. Genome-wide cfDNA screening: clinical laboratory experience with the first 10,000 cases. Genet. Med. 19, 1332–1337, https://doi.org/10.1038/gim.2017.56 (2017).

    Article  PubMed  Google Scholar 

  13. 13.

    Lefkowitz, R. B. et al. Clinical validation of a noninvasive prenatal test for genomewide detection of fetal copy number variants. Am. J. Obstet. Gynecol. 215, 227.e1–227.e16, https://doi.org/10.1016/j.ajog.2016.02.030 (2016).

    Article  Google Scholar 

  14. 14.

    van der Meij, K. R. M. et al. TRIDENT-2: national implementation of genome-wide noninvasive prenatal testing as a first-tier screening test in the Netherlands. Am. J. Hum. Genet. 105, 1091–1101, https://doi.org/10.1016/j.ajhg.2019.10.005 (2019).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Beulen, L., Faas, B. H. W., Feenstra, I., van Vugt, J. M. G. & Bekker, M. N. Clinical utility of noninvasive prenatal testing in pregnancies with ultrasound anomalies. Ultrasound Obstet. Gynecol. 49, 721–728, https://doi.org/10.1002/uog.17228 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Wittman, A. T., Hashmi, S. S., Mendez-Figueroa, H., Nassef, S., Stevens, B. & Singletary, C. N. Patient perception of negative noninvasive prenatal testing results. AJP Rep. 6, e391–e406, https://doi.org/10.1055/s-0036-1594243 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Society for Maternal-Fetal Medicine (SMFM), Dugoff, L., Norton, M. E. & Kuller, J. A. The use of chromosomal microarray for prenatal diagnosis. Am. J. Obstet. Gynecol. 215, B2-9, https://doi.org/10.1016/j.ajog.2016.07.016 (2016).

  18. 18.

    Fiorentino, F. et al. Chromosomal microarray analysis as a first-line test in pregnancies with a priori low risk for the detection of submicroscopic chromosomal abnormalities. Eur. J. Hum. Genet. 21, 725–730, https://doi.org/10.1038/ejhg.2012.253 (2013).

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Wu, X. et al. Chromosomal microarray analysis for pregnancies with or without ultrasound abnormalities in women of advanced maternal age. J. Clin. Lab. Anal. 34, e23117, https://doi.org/10.1002/jcla.23117 (2020).

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Yaron, Y. The implications of noninvasive prenatal testing failures: a review of an under-discussed phenomenon. Prenat. Diagn. 36, 391–396, https://doi.org/10.1002/pd.4804 (2016).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

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.

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Affiliations

  1. Division of Maternal-Fetal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Stephanie Guseh, Louise Wilkins-Haug & Kathryn J. Gray

  2. Division of Maternal-Fetal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Anjali Kaimal, Sarah Carroll, Chelsea Mandigo, Penelope Roberts & Kathleen Steinberg

  3. Division of Maternal-Fetal Medicine, Newton Wellesley Hospital, Harvard Medical School, Boston, MA, USA

    Lisa Dunn-Albanese, Marney Brillinger & Judith Foster

  4. Center for Fetal Medicine and Reproductive Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Sophie Adams, Marie Discenza, Lori Dobson, Samantha Gbur, Hayley Green, Nancy Herrig, Michelle Pacione, Abigail Sassaman & Courtney Studwell

Authors
  1. Stephanie Guseh
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  2. Louise Wilkins-Haug
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  20. Kathryn J. Gray
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Contributions

Conceptualization: S. Guseh, L.D., K.G. Data curation: S. Guseh, K.G. Formal analysis: S. Guseh, K.G. Funding acquisition: S. Guseh, K.G. Investigation: S. Guseh, K.G. Project administration: S. Guseh Resources: S. Guseh, S.A., S.C., M.D., L.D., M.B., J.F., S. Gbur, H.G., N.H., C.M., M.P., P.R., A.S., K.S., C.S. Supervision: S. Guseh, L.W.-H., A.K., L.D.-A., K.G. Writing—original draft: S. Guseh, K.G. Writing—reviewing & editing: S. Guseh, L.W.-H., A.K., L.D., K.G., S.A., S.C., M.D., L.D.-A., M.B., S. Gbur, H.G., N.H., C.M., M.P., K.S., C.S.

Corresponding author

Correspondence to Stephanie Guseh.

Ethics declarations

Ethics declaration

The Mass General Brigham Human Research Committee approved this study. Informed consent was obtained from all participants as required by the IRB.

Competing interests

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.

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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

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