For years, I’ve been presenting at conferences on prenatal testing for Down syndrome, explaining how the new tests are based on cell free fetal DNA or “cffDNA.” Turns out I was wrong. Here’s why.
This past week I gave a poster presentation at the Annual Clinical Meeting for the American College of Medical Genetics (ACMG). There is where I learned I was mistaken about the basis for newest form of prenatal testing.
Poster presentations are where you stand in front of a poster and present on the information it displays. (I’ll have more on my particular poster later). One of the first conference attendees to walk up to talk about my poster was a medical geneticist that, we figured out, was stationed with me when I was in the United States Air Force. In talking about the newest form of prenatal testing, non-invasive prenatal testing (“NIPT”), he off-handedly mentioned, “well everyone knows cffDNA is really placental DNA.” Well, this everyone did not.
NIPT has received a lot of media attention, due in no small part to the private laboratories promoting their various versions of it. Currently, in the United States, there are four laboratories that provide NIPT: Sequenom, Ariosa, Verinata, and Natera. Figure 1 displays these laboratories’ respective NIPT tests in clockwise order, respectively. In the professional medical committee opinions and materials from the testing laboratories, where reference is made, often it is to “cell free fetal DNA.” So, I suppose I should be forgiven for not understanding that the DNA was not, in fact, fetal DNA.
Instead, it is placental DNA. Now, here’s where we time travel back to high school. Some of us may remember cellular biology: the nucleus, mitochondira, etc. When a conceived cell implants into the mother, the cell has divided into further cells that perform certain functions. There are the cells that go on to become the fetus; there are those cells that go on to form the placenta (these cells come from the group of cells called “cytotrophoblasts”); and, there is even other genetic material which performs the function of anchoring the fetal and placental cells to the cell wall of the mother (called “syncytiotrophoblast”). Figure 2 is a rendering of these various forms of cells.
It turns out, that almost all of the cffDNA found in the maternal blood stream actually comes from the DNA of the cells that form the placenta or perform the anchoring function, not the cells that form the fetus. Therefore, it’s not entirely accurate to use “cell free fetal DNA” when discussing MaterniT21, Harmony, Verifi, or Panorama-style non-invasive prenatal testing.
As a fellow conference attendee explained, this is a distinction without much difference; while it is not cffDNA, in his opinion, it was not that big of a deal to refer to it as cffDNA. And, perhaps it’s not. But, I would guess that expectant mothers would think differently on the accuracy of a test if it were explained to them that the test did not actually test fetal DNA, but instead was “cell free placental DNA.” And, based on one of the last presentations I attended, they would have reason for that different perspective on the test’s accuracy.
The last session’s speakers presented cases involving various genetic issues arising in the prenatal stage, including false positives and false negatives they had experienced with NIPT. It is for this reason—that there are false positives and false negatives—that NIPT was revised from NIPD, non-invasive prenatal diagnosis (and will soon undergo another name change).
In one of the presentations, the presenter explained how a patient had received a positive NIPT result that ultimately was found to derive from what’s called “placental mosaicism.” “Mosaicism” occurs in the case of triploidy where there is a triplicate of a chromosome in some, but not all, of the cells. In placental mosaicism, the placenta can have cells with triplicates of chromosomes while the fetus does not have any triplicate chromosomes in its cells. Indeed, the diagnostic test that can be performed in the first trimester, chorionic villus sampling (“CVS”), tests placental cells, and has returned results of Down syndrome even when the fetus does not have Down syndrome, because the particular placental cells tested had a triplicate of the 21st Chromosome.
The presenter on the false positive based on placental mosaicism concluded by saying that because NIPT tests placental DNA, the most it can ever become is as accurate as a CVS. While CVS is considered a diagnostic test, CVS results still have the risk, however slight, of returning results from a mosaic placental cell that is not represented in the fetus itself.
Placental versus fetal DNA may be a distinction without much of a difference when it comes down to the accuracy of the results. In the vast majority of cases, the results will be accurate for the fetus even when the test is of placental DNA. But, this is more than just a semantical difference—or, even if that is all it is—then there is a significant semantical reason why “fetal DNA” was chosen over the more accurate “placental DNA.”
Mothers will expect prenatal tests to be of fetal DNA, not placental DNA. If “placental DNA” were used, perhaps expectant mothers and general society would further appreciate how the newest wave of prenatal testing is, in most cases, not actually testing DNA from the fetus, but from the placenta. Using precise language would further make clear that NIPT results are, at best, highly accurate screening tests, but not certain enough to make any decision without first receiving a diagnostic test result.
Update: For more lessons learned about NIPT (including why it’s NIPS) click here.
Update: The National Society of Genetic Counselors has issued a fact sheet on NIPT, which is linked to and covered at this post.
Update: The largest known clinical study of NIPS discusses the testing of placental DNA.