title: Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing.
abstract: BACKGROUND
  In the human fetus, sex chromosome aneuploidies (SCAs) are as prevalent as the common autosomal trisomies 21, 18, and 13. Currently, most noninvasive prenatal tests (NIPTs) offer screening only for chromosomes 21, 18, and 13, because the sensitivity and specificity are markedly higher than for the sex chromosomes. Limited studies suggest that the reduced accuracy associated with detecting SCAs is due to confined placental, placental, or true fetal mosaicism. We hypothesized that an altered maternal karyotype may also be an important contributor to discordant SCA NIPT results.
  
  
  METHODS
  We developed a rapid karyotyping method that uses massively parallel sequencing to measure the degree of chromosome mosaicism. The method was validated with DNA models mimicking XXX and XO mosaicism and then applied to maternal white blood cell (WBC) DNA from patients with discordant SCA NIPT results.
  
  
  RESULTS
  Sequencing karyotyping detected chromosome X (ChrX) mosaicism as low as 5%, allowing an accurate assignment of the maternal X karyotype. In a prospective NIPT study, we showed that 16 (8.6%) of 181 positive SCAs were due to an abnormal maternal ChrX karyotype that masked the true contribution of the fetal ChrX DNA fraction.
  
  
  CONCLUSIONS
  The accuracy of NIPT for ChrX and ChrY can be improved substantially by integrating the results of maternal-plasma sequencing with those for maternal-WBC sequencing. The relatively high frequency of maternal mosaicism warrants mandatory WBC testing in both shotgun sequencing- and single-nucleotide polymorphism-based clinical NIPT after the finding of a potential fetal SCA.
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China;
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.forename: Jianguang
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Song
authors.forename: Yi
authors.initials: Y
authors.lastname: Wu
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.forename: Wenjing
authors.initials: W
authors.lastname: Hu
authors.forename: Duan
authors.initials: D
authors.lastname: Ma
authors.forename: David
authors.initials: D
authors.lastname: Cram
authors.forename: Weiwei
authors.initials: W
authors.lastname: Cheng
mesh_terms: D000782:Aneuploidy; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015723:Gene Library; D006801:Humans; D007621:Karyotyping; D008297:Male; D009030:Mosaicism; D011247:Pregnancy; D011296:Prenatal Diagnosis; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D012730:Sex Chromosomes / Q000235:genetics*