Extracting Information About the Fetal Chromosomal Status from Maternal Blood Samples
Abstract & Commentary
By John C. Hobbins, MD, Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.
Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver
Dr. Hobbins reports no financial relationship to this field of study.
Synopsis: Use of free fetal DNA to diagnose fetal chromosomal abnormalities has been hindered by the inability to distinguish fetal DNA from maternal DNA. The researchers here aim to establish whether single nucleotide polymorphisms (SNPs) can be used to distinguish fetal DNA from maternal DNA—and to determine the number of fetal chromosomes—in maternal blood samples.
Source: Dhallan R, et al. A noninvasive test for prenatal diagnosis based on fetal DNA present in maternal blood: a preliminary study. Lancet. 2007;369:474-481.
Has there been any progress in extracting information about the fetal chromosomes status from maternal blood samples?
For the last 15 years, investigators have been attempting to isolate fetal cells from the maternal circulation to screen for aneuploidy. Since the techniques to accomplish this feat have been cumbersome, expensive, and not consistently reliable, there has been a strong movement to work with fetal DNA in the maternal circulation as an alternative, because this fetal material has a short half-life in this environment (and, therefore, does not represent the last pregnancy's fetal information), and it does not require prohibitively expensive cell sorting equipment.
In a recent article in The Lancet, a technique has been described which puts into play single nucleotide polymorphisms (SNPs). The concept is that one can identify fetal DNA by noting paternal signals at various SNP sites. Then, by comparing the amount of these signals with the amount of separate SNP signals which are specific to the mother, one can indirectly quantify the amount of fetal DNA in the sample (by assuming that fetal DNA contains one half maternal DNA). Step 2 involved looking specifically at chromosomes 21 and 13 in the maternal blood sample. In normal fetuses, one copy of chromosome 21 comes from the mother and one from the father. In trisomy 21, the fetus has two copies from his/her mother and one copy from the father. Therefore, with this technique in normal pregnancies one would expect 1 paternal signal for every 3 maternal signals, resulting in a ratio of the amount of paternal signal to combined (maternal and fetal) SNP signals of about 0.33. In trisomy 21 pregnancies, the addition of an extra maternal chromosome would result in a ratio that would be closer to 0.25. The authors used chromosome 13 as a control (to make sure that the normal ratio was maintained for this chromosome in the same maternal sample).
The investigative group analyzed 57 maternal and paternal bloods from normal pregnancies and 3 sets of samples from pregnancies complicated by fetal Down syndrome. As expected, the amount of free fetal DNA in the samples varied appreciably, but averaged 34%, with generally smaller yields in the first trimester. Regarding the trisomy cases, the technique identified 2 out of 3 cases. Therefore, this translated into 1 false-negative and 1 false-positive, giving a sensitivity and positive predictive value of 66 percent, and a negative predictive value of 98.2%.
Commentary
The total numbers of Down syndrome fetuses in this study were very small, and spiking the deck with more cases of trisomy 21 might show different results, therefore negating the enthusiasm that is being generated by this report. Hopefully, this will not be the case, as it seems to have taken so long for anything new and exciting to occur in this field after the initial hype generated by the early reports of the ability to isolate fetal red blood cells and DNA in the maternal circulation.
It is cautioned that this is simply another form of non-invasive screening that could either replace, or be used in conjunction with, other prenatal diagnostic methods such as first and second trimester biochemistry, nuchal translucency screening, and the genetic sonogram. Nevertheless, the possibility of finally separating out specific fetal information from simple maternal and paternal blood sample sets is very exciting.
References
- Dhallan R, et al. Lancet. 2007;369:474-481.
- Bianchi DW, et al. Proc Natl Acad Sci USA. 1990;87:3279-3283.
- Lo YM, et al. Lancet. 1997;350:485-487.
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