Cell‐free fetal DNA coming in all sizes and shapes

Abstract

Cell-free fetal DNA analysis has an established role in prenatal assessments. It serves as a source of fetal genetic material that is accessible non-invasively from maternal blood. Through the years, evidence has accumulated to show that cell-free fetal DNA molecules are derived from placental tissues, are mainly of short DNA fragments and have rapid post-delivery clearance profiles. But questions regarding how they come to being short molecules from placental cells and in which physical forms do they exist remained largely unanswered until recently. We now know that the distributions of ending sites of cell-free DNA molecules are non-random across the genome and bear correlations with the chromatin structures of cells from which they have originated. Such an insight offers ways to deduce the tissue-of-origin of these molecules. Besides, the physical nature and sequence characteristics of the ends of each cell-free DNA molecule provide tell-tale signs of how the DNA fragmentation processes are orchestrated by nuclease enzymes. These realizations offered opportunities to develop methods for enriching cell-free fetal DNA to facilitate non-invasive prenatal diagnostics. Here we aimed to collate what is known about the biological and physical characteristics of cell-free fetal DNA into one article and explain the implications of these observations. Key points What's already known about this topic?� Cell-free fetal DNA originates from placental tissues and circulates in maternal plasma as a minor population in the form of short fragments which disappears from maternal circulation rapidly after delivery. What does this study add?� Cell-free DNA studies at the per molecule per nucleotide level documented the detailed genomic distributions, fragment end characteristics and physical forms of cell-free DNA unveiling the fine feature differences between maternal and fetal DNA as well as their intricate relationships with the chromatin structure of the cells-of-origin. These studies have substantially bridged the knowledge gaps in the biology of cell-free fetal DNA and may provide insights on how to enhance prenatal tests based on their analyses.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

A dPCR-NIPT assay for detections of trisomies 21, 18 and 13 in a single-tube reaction-could it replace serum biochemical tests as a primary maternal plasma screening tool?

“…Unfortunately, we did not get the placental tissue to verify whether CMP occurred to this case. The other might be related to the microheterogeneities of the cfDNA target sequences presented in these samples, a phenomenon associates with the apoptosis processes of both maternal and fetal cells, which leads to the concentration of the cfDNA fragments unequally presented in the maternal plasma [ 53 ]. Nevertheless, this sample had to be unfavorably counted as a T18 false negative and a T21 false positive, separately, for the dPCR-NIPT assay’s T18 and T21 evaluations.…”

Future Prospects for Epigenetics in Autism Spectrum Disorder

“…Furthermore, the development of methods for assessing ASD biomarkers prenatally through the assessment of cell-free fetal DNA (cffDNA) would provide a window of opportunity for in utero interventions. CffDNA is derived from the placenta, representing circulating fetal genetic material deposited in the maternal bloodstream throughout gestation [ 90 , 91 ]. This potential value is highlighted in a preprint by Laufer et al describing how longitudinal cffDNA DMRs in a macaque model of maternal obesity was associated with behavioral measure and brain methylation patterns of offspring [ 92 ].…”

Expanded knowledge of cell-free DNA biology: potential to broaden the clinical utility

“…contributions [38,39] . CffDNA is rapidly removed from maternal circulation after delivery and the estimated half-life of cffDNA clearance is about 1 h [40] .…”