title: Fetal sex chromosome testing by maternal plasma DNA sequencing: clinical laboratory experience and biology.
abstract: OBJECTIVE
  To describe the clinical experience with noninvasive prenatal testing for fetal sex chromosomes using sequencing of maternal plasma cell-free DNA in a commercial laboratory.
  
  
  METHODS
  A noninvasive prenatal testing laboratory data set was examined for samples in which fetal sex chromosomes were reported. Available clinical outcomes were reviewed.
  
  
  RESULTS
  Of 18,161 samples with sex chromosome results, no sex chromosome aneuploidy was detected in 98.9% and the fetal sex was reported as XY (9,236) or XX (8,721). In 4 of 32 cases in which the fetal sex was reportedly discordant between noninvasive prenatal testing and karyotype or ultrasonogram, a potential biological reason for the discordance exists, including two cases of documented co-twin demise, one case of a maternal kidney transplant from a male donor, and one case of fetal ambiguous genitalia. In the remaining 204 samples (1.1%), one of four sex chromosome aneuploidies (monosomy X, XXX, XXY, or XYY) was detected. The frequency of false positive results for sex chromosome aneuploidies is a minimum of 0.26% and a maximum of 1.05%. All but one of the discordant sex chromosome aneuploidy results involved the X chromosome. In two putative false-positive XXX cases, maternal XXX was confirmed by karyotype. For the false-positive cases, mean maternal age was significantly higher in monosomy X (P<.001) and lower in XXX (P=.008).
  
  
  CONCLUSIONS
  Noninvasive prenatal testing results for sex chromosome aneuploidy can be confounded by maternal or fetal biological phenomena. When a discordant noninvasive prenatal testing result is encountered, resolution requires additional maternal history, detailed fetal ultrasonography, and determination of fetal and possibly maternal karyotypes.
authors.affiliation: Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts; and Illumina, formerly Verinata Health, Inc, Redwood City, California.
authors.forename: Diana W
authors.initials: DW
authors.lastname: Bianchi
authors.forename: Saba
authors.initials: S
authors.lastname: Parsa
authors.forename: Sucheta
authors.initials: S
authors.lastname: Bhatt
authors.forename: Meredith
authors.initials: M
authors.lastname: Halks-Miller
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kurtzman
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Sehnert
authors.forename: Amy
authors.initials: A
authors.lastname: Swanson
mesh_terms: D005260:Female; D006801:Humans; D062145:Maternal Serum Screening Tests / Q000706:statistics & numerical data*; D011247:Pregnancy; D017422:Sequence Analysis, DNA; D012729:Sex Chromosome Aberrations; D012730:Sex Chromosomes; D012732:Sex Determination Analysis