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Genome-Wide Fetal Aneuploidy Detection by Maternal Plasma DNA Sequencing

Bianchi, Diana W. MD; Platt, Lawrence D. MD; Goldberg, James D. MD; Abuhamad, Alfred Z. MD; Sehnert, Amy J. MD; Rava, Richard P. PhD

doi: 10.1097/AOG.0b013e31824fb482
Original Research
Journal Club

OBJECTIVE: To prospectively determine the diagnostic accuracy of massively parallel sequencing to detect whole chromosome fetal aneuploidy from maternal plasma.

METHODS: Blood samples were collected in a prospective, blinded study from 2,882 women undergoing prenatal diagnostic procedures at 60 U.S. sites. An independent biostatistician selected all singleton pregnancies with any abnormal karyotype and a balanced number of randomly selected pregnancies with euploid karyotypes. Chromosome classifications were made for each sample by massively parallel sequencing and compared with fetal karyotype.

RESULTS: Within an analysis cohort of 532 samples, the following were classified correctly: 89 of 89 trisomy 21 cases (sensitivity 100%, 95% [confidence interval] CI 95.9–100), 35 of 36 trisomy 18 cases (sensitivity 97.2%, 95% CI 85.5–99.9), 11 of 14 trisomy 13 cases (sensitivity 78.6%, 95% CI 49.2–99.9), 232 of 233 females (sensitivity 99.6%, 95% CI 97.6 to more than 99.9), 184 of 184 males (sensitivity 100%, 95% CI 98.0–100), and 15 of 16 monosomy X cases (sensitivity 93.8%, 95% CI 69.8–99.8). There were no false-positive results for autosomal aneuploidies (100% specificity, 95% CI more than 98.5 to 100). In addition, fetuses with mosaicism for trisomy 21 (3/3), trisomy 18 (1/1), and monosomy X (2/7), three cases of translocation trisomy, two cases of other autosomal trisomies (20 and 16), and other sex chromosome aneuploidies (XXX, XXY, and XYY) were classified correctly.

CONCLUSION: This prospective study demonstrates the efficacy of massively parallel sequencing of maternal plasma DNA to detect fetal aneuploidy for multiple chromosomes across the genome. The high sensitivity and specificity for the detection of trisomies 21, 18, 13, and monosomy X suggest that massively parallel sequencing can be incorporated into existing aneuploidy screening algorithms to reduce unnecessary invasive procedures.



This prospective study demonstrates that massively parallel sequencing of maternal plasma DNA is effective for detecting fetal aneuploidy for multiple chromosomes across the genome.

From the Mother Infant Research Institute, Tufts Medical Center and Tufts University School of Medicine, Boston Massachusetts; the Center for Fetal Medicine and Women's Ultrasound and the David Geffen School of Medicine, the University of California, Los Angeles, Los Angeles, California; the Prenatal Diagnosis Center, San Francisco Perinatal Associates, San Francisco, California; the Eastern Virginia Medical School, Norfolk, Virginia; and Verinata Health, Inc., Redwood City, California.

See related editorial on page 883.

* For a list of study sites that participated in the MELISSA study, see the Appendix online at

Funded by Verinata Health, Inc., Redwood City, California.

The authors thank the pregnant women who enrolled in this study and the center staff at the participating sites, without whom this research could not be conducted; the expertise and contributions of Dr. Philip Cotter for performing karyotype classifications; Andrea Rowe, Senior Biostatistician at Quintiles; April Ruby and Kelly Oliver for their lead roles in clinical operations and overseeing site and data management; all members of the Verinata Health laboratory staff for processing, sequencing, and data processing of the samples; and the clinical research and clinical research organization teams for site recruitment, coordination, and monitoring.

Presented at the Society for Maternal-Fetal Medicine 32nd annual meeting, February 6–11, 2012, Dallas, Texas.

Corresponding author: Richard P. Rava, 800 Saginaw Drive, Redwood City, CA 94063; e-mail:

Financial Disclosure Drs. Bianchi, Platt, and Abuhamad received honoraria for their roles on the Verinata Health, Inc. Clinical Advisory Board and hold equity in the company. Dr. Goldberg received honoraria for his role on the Verinata Health Clinical Advisory Board. Dr. Sehnert is an employee of Verinata Health, Inc. Dr. Rava is the President and Co-Scientific Founder of Verinata Health.

© 2012 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.