A large, multi-center clinical
trial led by researchers from Columbia University Medical Center (CUMC) shows
that a new genetic test resulted in significantly more clinically relevant
information than the current standard method of prenatal testing.
The test uses
microarray analysis to conduct a more comprehensive examination of a fetus's
DNA than is possible with the current standard method, karyotyping—a visual
analysis of the fetus's chromosomes. Results were published in the Dec. 6,
2012, issue of The New England Journal of Medicine (NEJM).
The prospective, blinded trial
involved 4,400 patients at 29 centers nationwide; the data took four years to
compile. The study involved women with advanced maternal age and
those whose fetuses were shown in early screening to be at heightened risk for
Down syndrome, to have structural abnormalities (as seen with ultrasound), or
to have indications of other problems. Ronald J. Wapner, MD, professor and vice
chairman for research at the Department of Obstetrics and
Gynecology at CUMC and director of reproductive genetics at
NewYork-Presbyterian/Columbia, was principal investigator. This is the first
and only study to prospectively compare karyotyping with microarray in a
blinded head-to-head trial.
The trial found that microarray
analysis, which compares a fetus's DNA with a normal (control) DNA, performed
as well as karyotyping in identifying common aneuploidies (an abnormal number
of chromosomes—an extra or missing chromosome causes genetic disorders such as
Down syndrome and Edwards
syndrome); it also identified additional abnormalities undetected by
karyotyping.
Among fetuses in which a growth
or structural anomaly had already been detected with ultrasound, microarray
found clinically relevant chromosomal deletions or duplications in one out of
17 cases (6%) that were not observed with karyotyping. In cases sampled for
advanced maternal age or positive screening results, microarray analysis picked
up an abnormality in one out of every 60 pregnancies (1.7%) that had a normal
karyotype.
"Based on our findings, we
believe that microarray will and should replace karyotyping as the standard for
evaluating chromosomal abnormalities in fetuses," said Dr. Wapner.
"These chromosomal micro-deletions and duplications found with microarray
are often associated with significant clinical problems."
As with karyotyping, microarray
requires fetal cells obtained via an invasive procedure such as amniocentesis,
where fetal cells are taken from the amniotic fluid, or chorionic villus
sampling, where cells are taken from the placenta. Parents deciding whether to
take these tests must weigh a number of factors, including their individual
risk of fetal abnormalities, possible procedure-induced miscarriage, and the
consequences of having an affected child. Work is underway to develop a
non-invasive test, the same information seen by microarray, using a blood
sample taken from the mother but is not yet available.
"We hope that in the
future—when microarray can be done non-invasively—every woman who wishes will
be offered microarray, so that she can have as complete information as possible
about her pregnancy," said Dr. Wapner.
Second Paper Published in Same
Issue of NEJM re: Microarray in Stillbirth
In a second paper published in
the same issue of NEJM, about the use of microarray in stillbirth,
results showed that microarray produced a clinical relevant result in 87% of
532 cases, which were analyzed with both karyotyping and microarray. In
contrast, standard methods for analyzing a stillbirth, which include
karyotyping, have been shown in previous research to fail to return information
in 25% of cases.
"Microarray was
significantly more successful at returning clinically relevant information
because, unlike karyotyping, it does not require cultured cells. Viability does
not come into play at all—DNA can be extracted from tissue that is no longer
living," said study senior author, Brynn Levy, MSc(Med), PhD, associate
professor of pathology and cell biology, and co-director of the Division of
Personalized Genomic Medicine at CUMC, and director of the Clinical
Cytogenetics Laboratory at NewYork-Presbyterian/Columbia. "Not being able
to explain why a stillbirth occurred can be very hard for families.
These findings are important
because they give us a significantly more reliable method to provide
information to families and their physicians."
"The primary benefit of
using microarray analysis rather than karyotype analysis is the greater
likelihood of obtaining results," said Uma Reddy, MD, MPH of the Eunice
Kennedy Shriver National Institute of Child Health and Human Development
(NICHD) of the National Institutes of Health, first author of the paper.
"Microarray analysis is
especially useful in stillbirth cases in which the karyotype has failed or
there is a birth defect present. However, microarray analysis is currently more
expensive than karyotyping – and this may be a barrier to some."
The study used data compiled by
NICHD's Stillbirth Collaborative Research Network (SCRN), a population-based
study of stillbirth in five geographic catchment areas.
Clinical Significance of
Chromosomal Abnormalities Growing by Leaps and Bounds
Both microarray and karyotyping
reveal clinically relevant information about conditions that can be
life-threatening for a newborn baby or that can signal a possible health threat
that might be treatable. However, as with all current genetic testing including
karyotyping, the results may reveal findings that have not been described in
the literature or in which the exact implications are known.
"While the vast majority of
abnormalities found with microarray are associated with known conditions, not
all are. But with time, knowledge and understanding of what these abnormalities
mean will continue to grow," said Dr. Wapner. "When we started this
study five years ago, the incidence of findings we did not understand was about
2.5%—now, with more information, that has fallen to 1.5%."
Dr. Wapner is currently leading
phase two of his microarray study. Supported by the NICHD (NIH Grant No.
2U01HD055651-06; Project No. GG006961), he has begun a five-year study to
follow children born to mothers who underwent microarray, to learn the clinical
implications of micro-deletions or duplications that are not yet understood.
"Unfortunately, it is
sometimes difficult to predict the full spectrum of some diseases indicated by
a particular deletion or duplication," said Dr. Wapner. "Genetic
medicine is about obtaining genomic information about an individual and
predicting what affect it will have on that person. But we are all different—so
genetic abnormality in one person may behave differently than in someone else.
For example, an inherited disease could be mild in the mother but severe in her
child. We are studying what these mean clinically, and science continues to
catch up with our ability to obtain the information."
More information: Dr. Wapner's paper is titled, "Chromosomal
Microarray Compared with Karyotyping for Prenatal Diagnosis." An abstract
was presented in Feb. 2012 at the Society for Maternal-Fetal Medicine annual
meeting.
"New prenatal test,
chromosomal microarray, proposed as standard of care." December 5th,
2012. http://medicalxpress.com/news/2012-12-prenatal-chromosomal-microarray-standard.html
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