Noninvasive Prenatal Diagnostics: Recent Developments Using Circulating Fetal Nucleated Cells

Abstract

Purpose of ReviewThe purpose of this review is to highlight recent research advances in noninvasive prenatal diagnostic methods.Recent Findings Recent studies developing noninvasive prenatal diagnostic (NIPD) methods have been focused on either fetal nucleated red blood cells (fNRBCs) or circulating trophoblasts (cTBs). Enriched cTBs were successfully utilized for whole genome profiling and short tandem repeat (STR) identification to confirm feto-maternal relationship. However, further analysis of isolated fNRBCs remains confined to examining fetal cytogenetics. Summary Invasive prenatal diagnostic procedures, amniocentesis, and chorionic villus sampling, are the gold standard for the diagnosis of fetal chromosomal abnormalities and genetic disorders. Meanwhile, noninvasive techniques of analyzing circulating cell-free fetal DNA (cffDNA) have been limited to screening tools and are highly fragmented and confounded by maternal DNA. By detecting circulating fetal nucleated cells (CFNCs) we are able to noninvasively confirm fetal chromosomal abnormalities, truly realizing the concept of "noninvasive prenatal diagnostics". The primary technical challenge is the enrichment of the low abundance of CFNCs in maternal peripheral blood. For any cell-based NIPD method, both fetal whole genome profiling and confirmation of the feto-parental relationship are essential. This has been successfully performed using enriched and isolated cTBs, making cTB a better candidate for NIPD. cTB enumeration also correlates with abnormal fetal or placental development. On the other hand, downstream analysis of fNRBCs remains limited to examining fetal sex and aneuploidies. Furthermore, trophoblast-based NIPD via an endocervical sample is also promising because of reduced dilution from hematologic cells. KeywordsNoninvasive prenatal diagnostic . Circulating fetal nucleated red blood cell . Circulating trophoblast . Whole genome amplification . Array comparative genomic hybridization . Short tandem repeat Pin-Jung Chen and Pai-Chi Teng contributed equally to this work. This article is part of the Topical Collection on High-risk Gestation and Prenatal Medicine

Stimuli-Responsive Microfluidic Interface Enables Highly Efficient Capture and Release of Circulating Fetal Cells for Non-Invasive Prenatal Testing

“…As fetal cells traveling as passengers for fetal–maternal information exchange, CFCs can provide essential diagnostic tools, previously obtained by invasive procedures such as amniocentesis and chorionic villus sampling . CFC-based noninvasive prenatal testing (NIPT) would potentially eliminate the need for invasive approaches, and truly realize the concept of noninvasive prenatal diagnosis . However, fetal cells are both fragile and rare in abundance compared to ca.…”

“…6 CFC-based noninvasive prenatal testing (NIPT) would potentially eliminate the need for invasive approaches, and truly realize the concept of noninvasive prenatal diagnosis. 7 However, fetal cells are both fragile and rare in abundance compared to ca. 10 6 white blood cells (WBCs) and ca.…”

HUNTER-Chip: Bioinspired Hierarchically Aptamer Structure-Based Circulating Fetal Cell Isolation for Non-Invasive Prenatal Testing

“…Circulating fetal cells (CFCs) possess intact fetal genome and have been proven to be an ideal target for non-invasive prenatal testing (NIPT) . Unlike the traditional invasive methods with narrow sampling window, such as amniocentesis and chorionic villus sampling, , CFCs can be directly obtained from maternal circulation starting from early weeks to the trimester, which are ideal targets in the analysis of genetic disorders and open a new avenue for NIPT. , To realize CFC-based NIPT, two successional processes including isolation and genetic analysis are both necessary and important. At first, extraordinary rarity (as few as several CFCs among 10 9 blood cells) makes their isolation challenging.…”

Emerging Microfluidic Technologies for the Detection of Circulating Tumor Cells and Fetal Nucleated Red Blood Cells

“…It is a great hope that CTCs can serve as an important source of tumor tissue to help with noninvasive cancer diagnosis, in particular for cases for which traditional tissue biopsy is challenging or not available. Similar to CTCs, rare fetal nucleated cells such as circulating trophoblasts (cTBs) and fetal nucleated red blood cells (fNRBCs) in maternal peripheral blood have recently been widely concerned by researchers in pursuit of noninvasive prenatal diagnosis (NIPD). − As an alternative to cell-free fetal DNA (cffDNA)-based noninvasive prenatal testing, fetal cell-based NIPD shows great promise in obstetric clinics, in view of the intrinsic obstacles of cffDNA being fragmented within masses of maternal DNA and particularly originating from the placenta. , Among these fetal cells, the presence of fNRBCs in maternal blood circulation has been fully verified since half the past century, and their existence could be detected at early gestational ages around seven weeks, which is beneficial to an early prenatal diagnosis. − One key point for fNRBCs regarded as an optimum target for NIPD is that these cells are directly derived from the fetus and contain the whole fetal genome information that can be used for fetal disease-associated gene detection, considering that circulating trophoblasts are documented to be the same as cffDNA for being derived from the placenta …”