Shaowei Wang1, Shuai Huang2, Linlin Ma2, Lin Liang2, Junrong Zhang2, Jianguang Zhang3, David S Cram4. 1. The Obstetrics and Gynecology Department of Beijing Hospital, No. 1, Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China. Electronic address: w-sw999@sohu.com. 2. The Obstetrics and Gynecology Department of Beijing Hospital, No. 1, Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China. 3. Berry Genomics Co., Ltd, Building 9, No 6 Court Jingshun East Road, Chaoyang District, Beijing 100015, China. 4. Berry Genomics Co., Ltd, Building 9, No 6 Court Jingshun East Road, Chaoyang District, Beijing 100015, China. Electronic address: david.cram@berrygenomics.com.
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.
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: Matthew R Grace; Emily Hardisty; Sarah K Dotters-Katz; Neeta L Vora; Jeffrey A Kuller Journal: Obstet Gynecol Surv Date: 2016-08 Impact factor: 2.347
Authors: Line Dahl Jeppesen; Tina Duelund Hjortshøj; Johnny Hindkjær; Lotte Hatt; Olav Bjørn Petersen; Ripudaman Singh; Palle Schelde; Lotte Andreasen; Rikke Christensen; Dorte L Lildballe; Ida Vogel Journal: Front Genet Date: 2022-03-11 Impact factor: 4.599