title: Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management.
abstract: Noninvasive prenatal testing by massive parallel sequencing of maternal plasma DNA has rapidly been adopted as a mainstream method for detection of fetal trisomy 21, 18 and 13. Despite the relative high accuracy of current NIPT testing, a substantial number of false-positive and false-negative test results remain. Here, we present an analysis pipeline, which addresses some of the technical as well as the biologically derived causes of error. Most importantly, it differentiates high z-scores due to fetal trisomies from those due to local maternal CNVs causing false positives. This pipeline was retrospectively validated for trisomy 18 and 21 detection on 296 samples demonstrating a sensitivity and specificity of 100%, and applied prospectively to 1350 pregnant women in the clinical diagnostic setting with a result reported in 99.9% of cases. In addition, values indicative for trisomy were observed two times for chromosome 7 and once each for chromosomes 15 and 16, and once for a segmental trisomy 18. Two of the trisomies were confirmed to be mosaic, one of which contained a uniparental disomy cell line. As placental trisomies pose a risk for low-grade fetal mosaicism as well as uniparental disomy, genome-wide noninvasive aneuploidy detection is improving prenatal management.
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Baran
authors.initials: B
authors.lastname: Bayindir
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dehaspe
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brison
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Brady
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Simon
authors.initials: S
authors.lastname: Ardui
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Molka
authors.initials: M
authors.lastname: Kammoun
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, AB Utrecht, The Netherlands.
authors.forename: Lars
authors.initials: L
authors.lastname: Van der Veken
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, AB Utrecht, The Netherlands.
authors.forename: Klaske
authors.initials: K
authors.lastname: Lichtenbelt
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Van den Bogaert
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Van Houdt
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Peeters
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Thomy
authors.initials: T
authors.lastname: de Ravel
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
mesh_terms: D000782:Aneuploidy; D002869:Chromosome Aberrations; D025063:Chromosome Disorders / Q000235:genetics*; D002877:Chromosomes, Human / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics; D005260:Female; D005333:Fetus / Q000473:pathology; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D010920:Placenta / Q000473:pathology; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D012189:Retrospective Studies; D014314:Trisomy / Q000235:genetics; D000073842:Trisomy 18 Syndrome