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| photo courtesy:Wikimedia commons |
Noninvasive
prenatal testing (NIPT) used for antenatal detection of fetal aneuploidy is
expanding worldwide. NIPT is the most recent addition to the growing armament of
methods available for diagnosing chromosomal malformations. The test detects
the fetal circulating DNA in maternal blood.
In USA, cell-free
DNA analysis became clinically available in 2011 and the American College of
Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine recommended
it as a screening option for women at increased risk of fetal aneuploidy. Its
use has since been expanded as a screening tool in general obstetric
population.[1]
Fetal
circulating cell free DNA is derived mostly from placenta and is present in maternal
blood for testing as early as 10 weeks of gestation. Different laboratories
have validated different techniques and mainly rely on next-generation
sequencing technologies and advanced bioinformatic analyses.[2]
Cell free
DNA is commonly used to screen for only the common trisomies and, if requested,
sex chromosome composition. The sensitivity and specificity as well as the
negative predictive value of the method is >99% for trisomy 21 (Down
syndrome), with slightly lower performance for trisomy 13 and 18.[3]
However,
this test is sometimes limited by low fetal cell fraction in the collected
sample. The other two most commonly used test are both invasive. (amniocentesis
and chorionic villus sampling).
A recent
paper published by Jain et al in Science translational medicine describes a
method for still earlier detection of trophoblastic cells, carrying fetal DNA
by Papanicolaou smear. It is possible to analyze fetal DNA as early as 5 weeks
without any of the invasive tests.[4]
Incidence of
fetal aneuploidies are on the rise because of more and more women delaying
pregnancies till late thirties or early forties.
The new
technique was shown to be effective in correctly picking up cell free DNA from
cells collected from maternal endocervical canal in 20 consecutive samples.
Chandni V.
Jain, PhD, a research associate in the laboratory of Sascha Drewlo, PhD, and D.
Randall Armant, PhD, and colleagues at Wayne State University School of
Medicine, Detroit, Michigan, devised a "nuclear isolation protocol"
to exclude most maternal DNA from ECC samples.[5]
The
investigator quoted “a straightforward alternative that uses a Pap smear to
capture intact fetal trophoblast cells in numbers sufficient for
next-generation sequencing as early as 5 weeks of gestation."
The average
fetal cell free DNA fraction was 92.2% ± 6.5%, way more than 4% to 10% obtained
from maternal blood at 10 weeks for Noninvasive prenatal testing (NIPT).
This test
has got tremendous commercial potential as it utilizes existing technology in a
novel way.
The
limitation at present are small sample size (20) and placental mosaicism.
James Byrne,
MD, maternal-fetal medicine specialist and chair of the Department of
Obstetrics and Gynecology at the Santa Clara Valley Medical Center and
affiliated clinical professor, Stanford University School of Medicine,
California opined that the technique is simple, safe and will be accepted
widely by patients and physician once it is endorsed by national organization
like American Congress of Obstetricians and Gynecologists and Society for
Maternal and Fetal Medicine.
Larger
studies with large sample size are awaited before it can be used for screening
of all pregnant women, who are at average risk. It’s also very suitable for
genetic testing, which targets high-risk groups, such as women
over age 35 or with a family history of a detectable genetic or chromosomal
condition.
A perfect
example of new use of old technology.
[1] http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Genetics/Cell-free-DNA-Screening-for-Fetal-Aneuploidy
[2] Zimmermann
B, Hill M, Gemelos G, Demko Z, Banjevic M, Baner J, et al. Noninvasive prenatal
aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted
sequencing of polymorphic loci. Prenat Diagn 2012;32:1233–41
[3] http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156088
[4] http://stm.sciencemag.org/content/8/363/363re4
[5] Prenatal
Genetic Screening Through Pap Smear?.
Medscape. Nov 02, 2016.
