Noninvasive prenatal testing: from aneuploidy to single genes
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REVIEW
Noninvasive prenatal testing: from aneuploidy to single genes Stephanie H. Guseh1 Received: 12 April 2019 / Accepted: 4 September 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract Noninvasive prenatal testing has undergone rapid advances in the last few years. Although researchers have long known about circulating pregnancy-based cell-free fragments of DNA in maternal plasma, it was the introduction of massively parallel sequencing that allowed noninvasive prenatal testing to become a widely used clinical test. This review will begin with an in-depth analysis of the use of noninvasive prenatal testing for aneuploidy, including common causes for inaccurate and/or discordant results. It will also review the ongoing expansion of noninvasive prenatal testing to include copy number variants and select single-gene disorders. Finally, integrated throughout the review is a comparison of noninvasive prenatal testing to more traditional screening methods along with some medical and ethical implications of the widespread use of this new technology.
History of noninvasive prenatal testing Over the last number of decades, there has been an increasing desire from both patients and providers to improve the scope and accuracy of noninvasive prenatal diagnosis. With regard to genetic screening, it is important to remember that the series of rapid advances in the last few years actually date back to discoveries made over 100 years ago. In 1893, a German pathologist first documented the anatomic presence of fetal cells in maternal organs of women with eclampsia (Schmorl 1893). As part of a detailed description of the postmortem anatomic and histologic findings, this pathologist noted an abundance of large, multi-nucleated cells in the lungs of eclamptic women, which he speculated most likely originated from the placenta (Lapaire 2007). The next major advance in noninvasive prenatal testing (NIPT) was published in 1969, when intact fetal cells were discovered in maternal blood (Walknowska 1969). By karyotyping lymphocytes from a cohort of pregnant women, a significant number of male cells were noted in the women later found to be carrying male fetuses. This finding led to the theory that chromosomal abnormalities might be detected by karyotypic analysis of whole cells circulating in maternal * Stephanie H. Guseh [email protected] 1
Division of Maternal‑Fetal Medicine, Obstetrics and Gynecology, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis St, Boston, MA, USA
blood (Walknowska 1969). Almost 30 years after this discovery, Y chromosome-specific sequences were amplified from cell-free DNA in much larger quantities than had ever been generated from cell-based studies (Lo 1997). Despite this finding and the growing interest in identifying aneuploid pregnancies, the reliable discrimination of aneuploidy using cell-free DNA did not prove to be technically feasible for at least another decade. The introduction of next-generation sequencing, employing the concept of processing hu
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