Circulating Fetal DNA: Its Origin and Diagnostic Potential—A Review

Abstract

Objective In contrast to the traditional teaching that the placenta forms an impermeable barrier, multiple studies show that both intact fetal cells and cell-free nucleic acids circulate freely in maternal blood. Complications of pregnancy, such as pre-eclampsia, or fetal cytogenetic abnormalities, such as trisomy 21, increase transfusion of both intact fetal cells and cell-free fetal nucleic acids into the maternal circulation. The objective of our research is to show that abnormal feto-maternal trafficking of nucleic acids is associated with fetal and placental pathology, and that these observations may lead to novel non-invasive diagnostic and screening tests. Methods Real-time quantitative PCR amplification of DYS1 is used to measure the levels of male fetal DNA in case-control sets of serum or plasma taken from pregnant women. In our laboratory, we use DYS1, a Y-chromosome specific gene, as a uniquely fetal DNA marker for the development of gestation-specific normal values and theoretical models. Results Women carrying fetuses with trisomies 21 or 13 (but not 18) have increased levels of fetal DNA in their fresh or archived serum and/or plasma samples. Women destined to develop pre-eclampsia have a characteristic bi-phasic elevation of cell-free fetal DNA that precedes clinical symptoms. Data obtained from a variety of clinical scenarios suggest that the placenta is the predominant source of the circulating fetal nucleic acids, although apoptotic haematopoietic cells may contribute to the pool as well. Conclusions Fetal cell-free DNA is elevated in a number of conditions associated with placental pathology. Widespread clinical implementation of fetal DNA as a screening tool awaits discovery of a reliable gender-independent marker, which may be DNA polymorphisms, epigenetic markers, or mRNA. Fetal cell-free nucleic acids have potential for non-invasive monitoring of placental pathology.