With existing methods, we are already able to obtain genetic material or DNA from an unborn baby. However, current methods are invasive and involve inserting long needles into the uterus. This can lead to miscarriage in as many as 1 in 200 pregnancies. The magic of this new technology then resides in the word noninvasive.
What made the development of noninvasive prenatal genome testing possible was the discovery that hidden in the mother’s plasma—the colorless, fluid part of blood—resides free-floating DNA from the baby. In the mother’s plasma, as much as 30% of the free-floating DNA found comes from the baby.
A few years ago, research labs successfully quantified free-floating DNA from a mother’s plasma. They realized they could use this to figure out if a baby had large chunks of extra or missing genetic information compared to the mother. With this, they could determine if the baby had a genetic condition such as Down syndrome, which is caused by having an extra copy of chromosome 21. Sequenom, a company based in California, has used this research to develop the MaterniT21 test to detect Down Syndrome in unborn babies. The MaterniT21 test is performed on the mother’s blood sample and is effective as early as 10 weeks into pregnancy.
But what has challenged researchers so far is really differentiating the baby’s DNA from the mother’s so they could read or sequence the unborn baby’s genome. Sequencing would enable noninvasive, prenatal detection of the small-scale mutations that cause most genetic disorders.
Researchers at the University of Washington solved this problem earlier this year by comparing the mother and father’s DNA to the mixture of mother-baby DNA found in the mother’s plasma. Because human genomes are over 99% identical, they only needed to compare the unique differences or mutations found in these 3 versions of the genetic code. They first catalogued all the mutations found in the sequenced DNA from the mother’s blood and the father’s saliva. They then sequenced the DNA in the mother’s plasma and catalogued every detectable mutation. Counting the frequencies of the different mutations in the maternal plasma allowed the researchers to establish which mutations the mother transmitted to the baby, which mutations the father transmitted to baby, and which mutations arose newly in the baby (de novo mutations).
Researchers from Stanford recently streamlined the procedure to make it faster and cheaper. Instead of meticulously reading the mother’s blood and the mother’s plasma genome for every single mutation, the Stanford team screened both sets of genomes for a million mutations that appear often according to population data. As in the Washington study, counting the frequency of the one million marker mutations in the mother’s plasma uncovered the fetal genome.
The Stanford researchers went another step further in simplifying the process by removing the father from the equation. Though this would prevent them from accurately determining which mutations the baby inherited from the father and which arose newly in the baby, they could still sequence the fetal genome.
However, these impressive discoveries are not quite perfect yet. For instance, with the Stanford method, it is not possible to accurately detect de novo mutations, which underlie a substantial fraction of dominant genetic disorders and are thus important to identify for comprehensive prenatal genetic diagnostics. Washington’s sequencing process, though more detailed, also cannot accurately determine de novo mutations. This is because it is difficult to separate de novo mutations from the small errors that are made by the machines that sequence DNA.
So, even though Noninvasive Prenatal Genome Sequencing is new and exciting, the technology is not yet ready for the clinic. Moreover, we cannot yet accurately interpret and make clinical meaning of the wealth of data that sequencing offers.
- Fan, H. C., Gu, W., Wang, J., Blumenfeld, Y. J., El-Sayed, Y. Y., & Quake, S. R. (2012). Non-invasive prenatal measurement of the fetal genome. Nature. Jul 19;487(7407):320-4.
- Kitzman, J. O., Snyder, M. W., Ventura, M., Lewis, A. P., Qiu, R., Simmons, L. E., Gammill, H. S., et al. (2012). Noninvasive whole-genome sequencing of a human fetus. Sci Transl Med. Jun 6;4(137):137ra76.
- Odibo, A. O., Gray, D. L., Dicke, J. M., Stamilio, D. M., Macones, G. A., & Crane, J. P. (2008). Revisiting the fetal loss rate after second-trimester genetic amniocentesis: a single center’s 16-year experience. Obstet Gynecol. Mar;111(3):589-95.