Genome-wide detection of additional fetal chromosomal abnormalities by cell-free DNA testing of 15,626 consecutive pregnant women
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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.
Keywordscell-free DNA genome-wide chromosomal abnormalities sensitivity specificity PPV
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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.  750), Shenzhen Municipal Government of China (JCYJ20150403101146312, JCYJ20170412153136375) and Guangzhou Science and Technology Program (201604020078).
- American College of Obstetricians and Gynecologists. Committee Opinion No. 640: Cell-Free DNA Screening For Fetal Aneuploidy. Obstet Gynecol, 2015, 126: e31–e37.Google Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.Google Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar