title: Accuracy and clinical value of maternal incidental findings during noninvasive prenatal testing for fetal aneuploidies.
abstract: Genome-wide sequencing of cell-free (cf)DNA of pregnant women aims to detect fetal chromosomal imbalances. Because the largest fraction of cfDNA consists of maternal rather than fetal DNA fragments, maternally derived copy-number variants (CNVs) are also measured. Despite their potential clinical relevance, current analyses do not interpret maternal CNVs. Here, we explore the accuracy and clinical value of maternal CNV analysis.
  
  
  
  Noninvasive prenatal testing was performed by whole-genome shotgun sequencing on plasma samples. Following mapping of the sequencing reads, the landscape of maternal CNVs was charted for 9,882 women using SeqCBS analysis. Recurrent CNVs were validated retrospectively by comparing their incidence with published reports. Nonrecurrent CNVs were prospectively confirmed by array comparative genomic hybridization or fluorescent in situ hybridization analysis on maternal lymphocytes.
  
  
  
  Consistent with population estimates, 10% nonrecurrent and 0.4% susceptibility CNVs for low-penetrant genomic disorders were identified. Five clinically actionable variants were reported to the pregnant women, including haploinsufficiency of RUNX1, a mosaicism for segmental chromosome 13 deletion, an unbalanced translocation, and two interstitial chromosome X deletions.
  
  
  
  Shotgun sequencing of cfDNA not only enables the detection of fetal aneuploidies but also reveals the presence of maternal CNVs. Some of those variants are clinically actionable or could potentially be harmful for the fetus. Interrogating the maternal CNV landscape can improve overall pregnancy management, and we propose reporting those variants if clinically relevant. The identification and reporting of such CNVs pose novel counseling dilemmas that warrant further discussions and development of societal guidelines.Genet Med 19 3, 306-313.
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Nathalie
authors: N
authors: Brison
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Kris
authors: K
authors: Van Den Bogaert
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Luc
authors: L
authors: Dehaspe
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Jessica M E
authors: JM
authors: van den Oever
authors: Centre for Human Genetics, University and University Hospital Antwerp, Antwerp, Belgium.
authors: Katrien
authors: 0000-0002-3249-731X
authors: K
authors: Janssens
authors: Centre for Human Genetics, University and University Hospital Antwerp, Antwerp, Belgium.
authors: Bettina
authors: 0000-0001-9993-7319
authors: B
authors: Blaumeiser
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Hilde
authors: H
authors: Peeters
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Hilde
authors: H
authors: Van Esch
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Griet
authors: G
authors: Van Buggenhout
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Annick
authors: 0000-0003-3545-9981
authors: A
authors: Vogels
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Thomy
authors: 0000-0002-3361-3781
authors: T
authors: de Ravel
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Eric
authors: E
authors: Legius
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Koen
authors: K
authors: Devriendt
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Joris R
authors: JR
authors: Vermeesch
mesh_terms: D000328:Adult; D000782:Aneuploidy; D000073888:Cell-Free Nucleic Acids / Q000032:analysis* / Q000235:genetics; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D004247:DNA / Q000097:blood / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D005333:Fetus; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D033162:Incidental Findings; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D000073888:Cell-Free Nucleic Acids; D004247:DNA