In 1997, it was discovered that during human pregnancy, a fetus would release its DNA into the blood plasma of its pregnant mother. Circulating cell-free fetal DNA in maternal plasma has since then been found to consist of short fragments of DNA present at a surprisingly high fractional concentration and which are cleared rapidly following delivery. The past two decades have seen rapid translation of this discovery into a number of noninvasive prenatal tests. Hence, this technology has found application in the screening of a number of fetal chromosomal aneuploidies, which has seen global adoption. This technology also has applications for the prenatal testing of monogenic disorders. Looking toward the future, the noninvasive prenatal determination of the fetal genome, de novo mutations, and applications for monitoring pregnancy-associated disorders like preeclampsia and preterm birth represent exciting areas of development.
KeywordsHistory, Overview, Fetal chromosomal aneuploidies, Single gene disorders, Genomics
In 1997, Lo et al. demonstrated that during pregnancy, fetal DNA could be seen in the plasma and serum of pregnant women . Subsequent work has demonstrated the gestational variations and rapid clearance of circulating fetal DNA following delivery . Circulating fetal DNA has been found to consist of short fragments of DNA, which have a size distribution shorter than that of circulating maternally derived DNA in maternal plasma .
Diagnostically, we have witnessed a rapid evolution of this young field in the last two decades. This book provides a summary of the important developments during this period. Early work had focused on the detection of DNA sequences that the fetus had inherited from its father, and which were absent in the pregnant mother’s genome, such as the Y chromosome of a male fetus , the RHD gene of a RhD-positive fetus carried by a RhD-negative mother , and a mutation inherited by the fetus from its father, but which is absent in its mother’s genome .
These early applications have been more recently joined by those using newer technologies such as microfluidics digital PCR, droplet digital PCR, and massively parallel sequencing. Hence, noninvasive prenatal testing of single gene disorders has now been extended to elucidation of the paternal and maternal inheritances of the fetus in autosomal recessive disorders and sex-linked disorders .
The area for noninvasive prenatal testing that has received the most attention over the last few years is its use for the detection of fetal chromosomal aneuploidies using massively parallel sequencing . Since the first large-scale clinical trials demonstrating the robustness of this technology in 2011 , this technology has been quickly introduced into clinical practice in dozens of countries around the world. The detection of chromosomal aneuploidies has been rapidly followed by the demonstration that such an approach can also be used to detect subchromosomal aberrations .
Perhaps the ultimate illustration of the diagnostic potential of fetal DNA in maternal plasma is the demonstration that the entire fetal genome could be determined from maternal plasma . These earlier works have recently been followed by the elucidation of a so-called second generation noninvasive fetal genome using newer sequencing and bioinformatics approaches . By means of such methods, fetal de novo mutations could be examined in a genome-wide manner from maternal plasma and the maternal inheritance of the fetus could also be determined with a resolution of approximately two orders of magnitude higher than from previous attempts .
Hence, one can see from the above that developments of the diagnostic applications of fetal DNA in maternal plasma have been most remarkable over the last two decades. However, there is still much to be learnt. For example, the biological characteristics of circulating fetal DNA still remain to be completely elucidated. Emerging areas of investigation include the relationship between circulating DNA and nucleosomal structure , the existence of preferred plasma DNA fragment endpoints , and the tissues of origin of circulating DNA . Finally, a thought-provoking and unresolved problem is whether circulating fetal DNA has any biological or pathogenic functions. Hence, the next two decades will certainly be very exciting.
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