title: Maternal X chromosome copy number variations are associated with discordant fetal sex chromosome aneuploidies detected by noninvasive prenatal testing.
abstract: BACKGROUND
  The sensitivity and specificity of noninvasive prenatal testing (NIPT) for detection of sex chromosome aneuploidies (SCAs) compared to common autosomal trisomies are significantly lower. We speculated that in addition to altered maternal X chromosome karyotype, maternal X chromosome copy number variations (CNVs) may also contribute to discordant NIPT SCA results.
  
  
  METHODS
  Clinical NIPT was performed for pregnant women at a single hospital. Copy number variation sequencing (CNV-Seq) was used to identify and quantitate the copy number of maternal X chromosome CNVs for each positive SCA pregnancy.
  
  
  RESULTS
  Two out of 25 SCA positive NIPT samples had slightly abnormal ChrX/ChrY z-scores and were referred for invasive test confirmation. However, fetal karyotypes were found to be normal. CNV-Seq analysis of the maternal white blood cell DNA archived from the original two NIPT blood samples identified small CNVs spanning the STS gene, which is associated with X-linked ichthyosis. Correcting for the altered plasma levels of X chromosome DNA caused by the two CNVs and, taking into consideration the phenotypic consequences for X-linked disease, both fetuses were diagnosed as normal.
  
  
  CONCLUSIONS
  Maternal DNA sequencing is recommended for all positive NIPT SCA results to avoid unnecessary referral for invasive testing and also to evaluate the risk to the fetus of X-linked disease.
authors.affiliation: The Obstetrics and Gynecology Department of Beijing Hospital, No. 1, Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China. Electronic address: w-sw999@sohu.com.
authors.forename: Shaowei
authors.initials: S
authors.lastname: Wang
authors.affiliation: The Obstetrics and Gynecology Department of Beijing Hospital, No. 1, Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Huang
authors.affiliation: The Obstetrics and Gynecology Department of Beijing Hospital, No. 1, Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Ma
authors.affiliation: The Obstetrics and Gynecology Department of Beijing Hospital, No. 1, Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liang
authors.affiliation: The Obstetrics and Gynecology Department of Beijing Hospital, No. 1, Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China.
authors.forename: Junrong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Berry Genomics Co., Ltd, Building 9, No 6 Court Jingshun East Road, Chaoyang District, Beijing 100015, China.
authors.forename: Jianguang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Berry Genomics Co., Ltd, Building 9, No 6 Court Jingshun East Road, Chaoyang District, Beijing 100015, China. Electronic address: david.cram@berrygenomics.com.
authors.forename: David S
authors.initials: DS
authors.lastname: Cram
mesh_terms: D000782:Aneuploidy; D041321:Chromosomes, Human, X / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D011247:Pregnancy; D011296:Prenatal Diagnosis; D025064:Sex Chromosome Disorders / Q000235:genetics*
keywords: Copy number variation; Noninvasive prenatal diagnosis; Sequencing; Sex chromosome aneuploidy; X-linked disease