title: Cell-free DNA testing of an extended range of chromosomal anomalies: clinical experience with 6,388 consecutive cases.
abstract: Cell-free DNA (cfDNA) testing for fetal aneuploidies was broadly implemented for common trisomies and sex-chromosome anomalies (SCAs). However, such an approach identifies only 75 to 85% of clinically relevant aneuploidies.
  
  
  
  We present a consecutive series of 6,388 cases, thus uncovering a broader array of aneuploidies, including the rare autosomal trisomies (RATs) and the maternally inherited deletion and duplication copy-number variations (CNVs), with complete and stratified follow-up by amniocentesis. Combined measurements of z-scores and the fetal fraction, in conjunction with fetal cfDNA enrichment, were used to stratify the likelihood of true and false results.
  
  
  
  We obtained an incremental diagnostic yield of 50%; RATs and CNVs were found to be significant causes of fetal pathology. Scrutinizing z-scores and the fetal fraction made it possible to distinguish the sources of false-negative results; predict the likelihood of false-positive results for major trisomies and SCAs; classify maternal mosaic SCAs and CNVs, preventing false-positive results; and robustly identify maternally inherited CNVs and detect recurrent genomic disorders as a standardized function of the fetal fraction.
  
  
  
  With the clinical pertinence of this broader detection scheme confirmed, we offer recommendations for its implementation.Genet Med 19 2, 169-175.
authors.affiliation: Aurigen, Lausanne, Switzerland.
authors.forename: Graziano
authors.identifier: 0000-0002-9930-2636
authors.initials: G
authors.lastname: Pescia
authors.affiliation: SIB, Swiss Institute of Bioinformatics, Quartier Sorge-Bâtiment Génopode, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guex
authors.affiliation: SIB, Swiss Institute of Bioinformatics, Quartier Sorge-Bâtiment Génopode, Lausanne, Switzerland.
authors.forename: Christian
authors.identifier: 0000-0002-2296-2863
authors.initials: C
authors.lastname: Iseli
authors.affiliation: Genesupport, Lausanne, Switzerland.
authors.forename: Liam
authors.initials: L
authors.lastname: Brennan
authors.affiliation: Fasteris, Geneva, Switzerland.
authors.forename: Magne
authors.identifier: 0000-0002-3773-4855
authors.initials: M
authors.lastname: Osteras
authors.affiliation: SIB, Swiss Institute of Bioinformatics, Quartier Sorge-Bâtiment Génopode, Lausanne, Switzerland.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.affiliation: Fasteris, Geneva, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Farinelli
authors.affiliation: Genesupport, Lausanne, Switzerland.
authors.forename: Bernard
authors.identifier: 0000-0002-3662-9041
authors.initials: B
authors.lastname: Conrad
mesh_terms: D000782:Aneuploidy; D000073888:Cell-Free Nucleic Acids / Q000235:genetics*; D002869:Chromosome Aberrations; D025063:Chromosome Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D006801:Humans; D007621:Karyotyping; D011247:Pregnancy; D012729:Sex Chromosome Aberrations; D014314:Trisomy / Q000235:genetics* / Q000503:physiopathology
chemical_list: D000073888:Cell-Free Nucleic Acids