Abstract
Cell-free DNA (cfDNA) testing for common fetal trisomies (T21, T18, T13) is highly effective. However, the usefulness of cfDNA testing in detecting other chromosomal abnormalities is unclear. We evaluated the performance of cfDNA testing for genome-wide abnormalities, and analyzed the incremental yield by reporting extra abnormalities. We performed genome-wide cfDNA testing in 15,626 consecutive pregnancies prospectively enrolled in this study. cfDNA testing results were reported and counseling was given depending on the presence of extra chromosomal abnormalities. cfDNA testing identified 190 cases (1.2%) of chromosomal abnormalities including 100 common trisomies and 90 additional abnormalities. By expanding the cfDNA reporting range to genome-wide abnormalities, the false positive rate increased to 0.39% (P<0.001) and positive predictive value (PPV) was reduced to 65.58% (P=0.42). However, the detection yield increased from 0.44% to 0.65% (P=0.014), and cfDNA testing detected 38.61% (39/101) additional abnormalities with no ultrasound and biochemical screening findings. cfDNA testing outperformed biochemical screening by showing 60 times higher true positive rate and fewer false negative results. Genome-wide cfDNA testing significantly increased the diagnostic yield by detecting extra abnormalities, especially those without diagnostic indications. Genome-wide cfDNA testing has fewer false positive and false negative results compared with biochemical screening.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
American College of Obstetricians and Gynecologists. Committee Opinion No. 640: Cell-Free DNA Screening For Fetal Aneuploidy. Obstet Gynecol, 2015, 126: e31–e37.
Baer, R.J., Flessel, M.C., Jelliffe-Pawlowski, L.L., Goldman, S., Hudgins, L., Hull, A.D., Norton, M.E., and Currier, R.J. (2015). Detection rates for aneuploidy by first-trimester and sequential screening. Obstetrics Gynecol 126, 753–759.
Benn, P. (2016). Expanding non-invasive prenatal testing beyond chromosomes 21, 18, 13, X and Y. Clin Genet 90, 477–485.
Bianchi, D.W., Chudova, D., Sehnert, A.J., Bhatt, S., Murray, K., Prosen, T. L., Garber, J.E., Wilkins-Haug, L., Vora, N.L., Warsof, S., et al. (2015). Noninvasive prenatal testing and incidental detection of occult maternal malignancies. JAMA 314, 162–169.
Bianchi, D.W., Parker, R.L., Wentworth, J., Madankumar, R., Saffer, C., Das, A.F., Craig, J.A., Chudova, D.I., Devers, P.L., Jones, K.W., et al. (2014). DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 370, 799–808.
Bianchi, D.W., Platt, L.D., Goldberg, J.D., Abuhamad, A.Z., Sehnert, A.J., Rava, R.P., and Rava, R.P. (2012). Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstetrics Gynecol 119, 890–901.
Chen, S., Lau, T.K., Zhang, C., Xu, C., Xu, Z., Hu, P., Xu, J., Huang, H., Pan, L., Jiang, F., et al. (2013). A method for noninvasive detection of fetal large deletions/duplications by low coverage massively parallel sequencing. Prenat Diagn 33, 584–590.
Curnow, K.J., Wilkins-Haug, L., Ryan, A., Kırkızlar, E., Stosic, M., Hall, M.P., Sigurjonsson, S., Demko, Z., Rabinowitz, M., and Gross, S.J. (2015). Detection of triploid, molar, and vanishing twin pregnancies by a single-nucleotide polymorphism-based noninvasive prenatal test. Am J Obstetrics Gynecol 212, 79.e1–79.e9.
Dan, S., Wang, W., Ren, J., Li, Y., Hu, H., Xu, Z., Lau, T.K., Xie, J., Zhao, W., Huang, H., et al. (2012). Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11 105 pregnancies with mixed risk factors. Prenat Diagn 32, 1225–1232.
Davis, C., Cuckle, H., and Yaron, Y. (2014). Screening for Down syndrome-incidental diagnosis of other aneuploidies. Prenat Diagn 34, 1044–1048.
Gil, M.M., Quezada, M.S., Revello, R., Akolekar, R., and Nicolaides, K.H. (2015). Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 45, 249–266.
Grati, F.R., Barlocco, A., Grimi, B., Milani, S., Frascoli, G., Meco, D., Maria, A., Liuti, R., Trotta, A., and Chinetti, S. (2010). Chromosome abnormalities investigated by non-invasive prenatal testing account for approximately 50% of fetal unbalances associated with relevant clinical phenotypes. Am J Med Genet A 152, 1434–1442.
Gregg, A.R., Skotko, B.G., Benkendorf, J.L., Monaghan, K.G., Bajaj, K., Best, R.G., Klugman, S., and Watson, M.S. (2016). Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genet Med 18, 1056–1065.
Helgeson, J., Wardrop, J., Boomer, T., Almasri, E., Paxton, W.B., Saldivar, J.S., Dharajiya, N., Monroe, T.J., Farkas, D.H., Grosu, D.S., et al. (2015). Clinical outcome of subchromosomal events detected by wholegenome noninvasive prenatal testing. Prenat Diagn 35, 999–1004.
Jiang, F., Ren, J., Chen, F., Zhou, Y., Xie, J., Dan, S., Su, Y., Xie, J., Yin, B., Su, W., et al. (2012). Noninvasive Fetal Trisomy (NIFTY) test: an advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies. BMC Med Genomics 5, 57.
Lau, T.K., Cheung, S.W., Lo, P.S.S., Pursley, A.N., Chan, M.K., Jiang, F., Zhang, H., Wang, W., Jong, L.F.J., Yuen, O.K.C., et al. (2014). Noninvasive prenatal testing for fetal chromosomal abnormalities by lowcoverage whole-genome sequencing of maternal plasma DNA: review of 1982 consecutive cases in a single center. Ultrasound Obstet Gynecol 43, 254–264.
Lau, T.K., Jiang, F.M., Stevenson, R.J., Lo, T.K., Chan, L.W., Chan, M.K., Lo, P.S.S., Wang, W., Zhang, H.Y., Chen, F., et al. (2013). Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service. Prenat Diagn 33, 602–608.
Lefkowitz, R.B., Tynan, J.A., Liu, T., Wu, Y., Mazloom, A.R., Almasri, E., Hogg, G., Angkachatchai, V., Zhao, C., Grosu, D.S., et al. (2016). Clinical validation of a noninvasive prenatal test for genomewide detection of fetal copy number variants. Am J Obstetrics Gynecol 215, 227. e1–227.e16.
Liu, H., Gao, Y., Hu, Z., Lin, L., Yin, X., Wang, J., Chen, D., Chen, F., Jiang, H., Ren, J., et al. (2016). Performance evaluation of NIPT in detection of chromosomal copy number variants using low-coverage whole-genome sequencing of plasma DNA. PLoS ONE 11, e0159233.
Lo, K.K., Karampetsou, E., Boustred, C., McKay, F., Mason, S., Hill, M., Plagnol, V., and Chitty, L.S. (2016). Limited clinical utility of noninvasive prenatal testing for subchromosomal abnormalities. Am J Hum Genet 98, 34–44.
Mazloom, A.R., Džakula, Ž., Oeth, P., Wang, H., Jensen, T., Tynan, J., McCullough, R., Saldivar, J.S., Ehrich, M., van den Boom, D., et al. (2013). Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn 33, 591–597.
Morris, J.K., Alberman, E., Scott, C., and Jacobs, P. (2008). Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet 16, 163–170.
Nicolaides, K.H., Syngelaki, A., Gil, M., Atanasova, V., and Markova, D. (2013). Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat Diagn 33, 575–579.
Norton, M.E., Baer, R.J., Wapner, R.J., Kuppermann, M., Jelliffe-Pawlowski, L.L., and Currier, R.J. (2016). Cell-free DNA vs sequential screening for the detection of fetal chromosomal abnormalities. Am J Obstetrics Gynecol 214, 727.e1–727.e6.
Norton, M.E., Jacobsson, B., Swamy, G.K., Laurent, L.C., Ranzini, A.C., Brar, H., Tomlinson, M.W., Pereira, L., Spitz, J.L., Hollemon, D., et al. (2015). Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med 372, 1589–1597.
Pescia, G., Guex, N., Iseli, C., Brennan, L., Osteras, M., Xenarios, I., Farinelli, L., and Conrad, B. (2017). Cell-free DNA testing of an extended range of chromosomal anomalies: clinical experience with 6,388 consecutive cases. Genet Med 19, 169–175.
Peters, D., Chu, T., Yatsenko, S.A., Hendrix, N., Hogge, W.A., Surti, U., Bunce, K., Dunkel, M., Shaw, P., and Rajkovic, A. (2011). Noninvasive prenatal diagnosis of a fetal microdeletion syndrome. N Engl J Med 365, 1847–1848.
Petersen, O.B., Vogel, I., Ekelund, C., Hyett, J., Tabor, A., Tabor, A., and Tabor, A. (2014). Potential diagnostic consequences of applying noninvasive prenatal testing: population-based study from a country with existing first-trimester screening. Ultrasound Obstet Gynecol 43, 265–271.
Rose, N.C., Benn, P., and Milunsky, A. (2016). Current controversies in prenatal diagnosis 1: should NIPT routinely include microdeletions/microduplications? Prenat Diagn 36, 10–14.
Shani, H., Goldwaser, T., Keating, J., and Klugman, S. (2016). Chromosomal abnormalities not currently detected by cell-free fetal DNA: a retrospective analysis at a single center. Am J Obstetrics Gynecol 214, 729.e1–729.e11.
Society for Maternal-Fetal Medicine Publications Committee, (2015). SMFM Statement: clarification of recommendations regarding cell-free DNA aneuploidy screening. Am J Obstet Gynecol 213, 753–754.
Srebniak, M.I., Diderich, K.E., Joosten, M., Govaerts, L.C., Knijnenburg, J., de Vries, F.A., Boter, M., Lont, D., Knapen, M.F., de Wit, M.C., et al. (2016). Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs. Eur J Hum Genet 24, 645–651.
Srinivasan, A., Bianchi, D.W., Huang, H., Sehnert, A.J., and Rava, R.P. (2013). Noninvasive detection of fetal subchromosome abnormalities via deep sequencing of maternal plasma. Am J Hum Genet 92, 167–176.
Wapner, R.J., Babiarz, J.E., Levy, B., Stosic, M., Zimmermann, B., Sigurjonsson, S., Wayham, N., Ryan, A., Banjevic, M., Lacroute, P., et al. (2015). Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstetrics Gynecol 212, 332. e1–332.e9.
Wapner, R.J., Martin, C.L., Levy, B., Ballif, B.C., Eng, C.M., Zachary, J. M., Savage, M., Platt, L.D., Saltzman, D., Grobman, W.A., et al. (2012). Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 367, 2175–2184.
Yao, H., Jiang, F., Hu, H., Gao, Y., Zhu, Z., Zhang, H., Wang, Y., Guo, Y., Liu, L., Yuan, Y., et al. (2014). Detection of fetal sex chromosome aneuploidy by massively parallel sequencing of maternal plasma DNA: initial experience in a Chinese hospital. Ultrasound Obstet Gynecol 44, 17–24.
Yin, A., Peng, C., Zhao, X., Caughey, B.A., Yang, J., Liu, J., Huang, W., Liu, C., Luo, D., Liu, H., et al. (2015). Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA. Proc Natl Acad Sci USA 112, 14670–14675.
Zhang, H., Gao, Y., Jiang, F., Fu, M., Yuan, Y., Guo, Y., Zhu, Z., Lin, M., Liu, Q., Tian, Z., et al. (2015). Non-invasive prenatal testing for trisomies 1, 18 and 13: clinical experience from 146 958 pregnancies. Ultrasound Obstet Gynecol 45, 530–538.
Acknowledgements
The authors would like to thank all the pregnant women who participated in this work and their family. Thank also goes to all laboratory personnel and medical staffs who could not be listed as authors. The authors also would like to thank Dr. Dev Sooranna, Imperial College London, and Prof. Lars Bolund, Aarhus University for editing the manuscript. This work was supported by the National Natural Science Foundation of China (81501264), Shenzhen Birth Defect Screening Project Lab (JZF No. [2016] 750), Shenzhen Municipal Government of China (JCYJ20150403101146312, JCYJ20170412153136375) and Guangzhou Science and Technology Program (201604020078).
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Yao, H., Gao, Y., Zhao, J. et al. Genome-wide detection of additional fetal chromosomal abnormalities by cell-free DNA testing of 15,626 consecutive pregnant women. Sci. China Life Sci. 62, 215–224 (2019). https://doi.org/10.1007/s11427-017-9344-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-017-9344-7