title: Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA.
abstract: OBJECTIVE
  The objective of this study was to validate the clinical performance of massively parallel genomic sequencing of cell-free deoxyribonucleic acid contained in specimens from pregnant women at high risk for fetal aneuploidy to test fetuses for trisomies 21, 18, and 13; fetal sex; and the common sex chromosome aneuploidies (45, X; 47, XXX; 47, XXY; 47, XYY).
  
  
  METHODS
  This was a prospective multicenter observational study of pregnant women at high risk for fetal aneuploidy who had made the decision to pursue invasive testing for prenatal diagnosis. Massively parallel single-read multiplexed sequencing of cell-free deoxyribonucleic acid was performed in maternal blood for aneuploidy detection. Data analysis was completed using sequence reads unique to the chromosomes of interest.
  
  
  RESULTS
  A total of 3430 patients were analyzed for demographic characteristics and medical history. There were 137 fetuses with trisomy 21, 39 with trisomy 18, and 16 with trisomy 13 for a prevalence rate of the common autosomal trisomies of 5.8%. There were no false-negative results for trisomy 21, 3 for trisomy 18, and 2 for trisomy 13; all 3 false-positive results were for trisomy 21. The positive predictive values for trisomies 18 and 13 were 100% and 97.9% for trisomy 21. A total of 8.6% of the pregnancies were 21 weeks or beyond; there were no aneuploid fetuses in this group. All 15 of the common sex chromosome aneuploidies in this population were identified, although there were 11 false-positive results for 45,X. Taken together, the positive predictive value for the sex chromosome aneuploidies was 48.4% and the negative predictive value was 100%.
  
  
  CONCLUSIONS
  Our prospective study demonstrates that noninvasive prenatal analysis of cell-free deoxyribonucleic acid from maternal plasma is an accurate advanced screening test with extremely high sensitivity and specificity for trisomy 21 (>99%) but with less sensitivity for trisomies 18 and 13. Despite high sensitivity, there was modest positive predictive value for the small number of common sex chromosome aneuploidies because of their very low prevalence rate.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Presbyterian/St Luke's Medical Center, Obstetrix Medical Group of Colorado, Denver, CO. Electronic address: richard_porreco@pediatrix.com.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Porreco
authors.affiliation: University of California, Irvine, Orange, CA, and Pediatrix/Obstetrix Medical Group, Inc, Sunrise, FL/Perigen Inc, Princeton, NJ.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Garite
authors.affiliation: Pediatrix/Obstetrix Medical Group, Inc, Sunrise, FL.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Maurel
authors.affiliation: Pediatrix/Obstetrix Medical Group, Inc, Sunrise, FL.
authors.forename: Barbara
authors.initials: B
authors.lastname: Marusiak
authors.affiliation: Sequemon, Inc, San Diego, CA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Ehrich
authors.affiliation: Sequemon, Inc, San Diego, CA.
authors.forename: Dirk
authors.initials: D
authors.lastname: van den Boom
authors.affiliation: Sequemon, Inc, San Diego, CA.
authors.forename: Cosmin
authors.initials: C
authors.lastname: Deciu
authors.affiliation: Sequemon, Inc, San Diego, CA.
authors.forename: Allan
authors.initials: A
authors.lastname: Bombard
mesh_terms: D000328:Adult; D025063:Chromosome Disorders / Q000175:diagnosis; D002882:Chromosomes, Human, Pair 13; D002887:Chromosomes, Human, Pair 18; D041321:Chromosomes, Human, X; D041322:Chromosomes, Human, Y; D004314:Down Syndrome / Q000175:diagnosis; D005260:Female; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D062145:Maternal Serum Screening Tests; D011237:Predictive Value of Tests; D011247:Pregnancy; D011446:Prospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods*; D012729:Sex Chromosome Aberrations; D025064:Sex Chromosome Disorders / Q000175:diagnosis*; D014314:Trisomy / Q000175:diagnosis*; D000073839:Trisomy 13 Syndrome; D000073842:Trisomy 18 Syndrome
keywords: cell-free deoxyribonucleic acid; massively parallel genomic sequencing; noninvasive prenatal screening