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New Molecular DNA Test May Help Detect Down Syndrome

Laino, Charlene

doi: 10.1097/01.NT.0000407909.88810.41
THE NEW TEST detects cell-free fetal DNA in maternal blood indicating trisomy of chromosome 21, the most common cause of Down syndrome

THE NEW TEST detects cell-free fetal DNA in maternal blood indicating trisomy of chromosome 21, the most common cause of Down syndrome

MISCARRIAGE RATES after amniocentesis and chorionic villus sampling were 1

MISCARRIAGE RATES after amniocentesis and chorionic villus sampling were 1

Anew DNA-based blood test detects nearly all cases of Down syndrome with a very low false positive rate, a blinded, nested case-control study of nearly 1,700 high-risk pregnant women shows.

Called MaterniT21 LDT, the test could allow high-risk patients to avoid more invasive amniocentesis or chorionic villus sampling (CVS), which carries a risk of miscarriage, according to the researchers and a neurologist who reviewed the study's findings for Neurology Today.

Sequenom Inc., of San Diego, announced in mid-October that the next-generation gene sequencing test was initially being offered to physicians in 20 US cities. The launch coincided with the Oct. 14 online publication of the company-funded clinical validation study in Genetics in Medicine.

By comparing the results of the new test with those obtained by fetal karyotyping, the researchers found that the molecular test had an accuracy of 98.6 percent, detecting 209 of 212 cases of Down syndrome. Its sensitivity was 99 percent, and its specificity was 99 percent.

There were three false negatives among the 212 Down syndrome cases, and three false positives among 1,471 other pregnancies (0.20 percent), according to first author Glenn E. Palomaki, PhD, associate director of the Division of Medical Screening and Special Testing in the department of pathology and laboratory medicine at Women & Infants Hospital of Brown University Alpert Medical School in Providence, RI. Dr. Palomaki has no financial ties to Sequenom.

In the study, the new test failed to yield a result in 13 women, “meaning that the test is not informative in only eight in 1,000 women,” he said.

The women in the study were considered at high risk for delivering a baby with Down syndrome because of age (38 years or older), family history, or a positive serum and/or sonographic screening test. In the US, there are an estimated 750,000 such high-risk pregnancies each year, according to Sequenom. Gestational age at testing ranged from 8.1 to 21.5 weeks.

Darryl C. De Vivo, MD, Sidney Carter Professor of Neurology and Pediatrics and director emeritus of the Pediatric Neurology Service at Columbia University Medical Center in New York City, said he was impressed by the findings.



“The test's specificity and sensitivity look remarkably accurate. It provides a window into the developing fetus that allows us to assess whether there is any concern about this genetic abnormality,” Dr. De Vivo said.

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Currently, high-risk women are screened with a combination of ultrasound measurement of nuchal translucency in the first trimester and maternal serum screening biomarker tests in the first and second trimesters, Dr. Palomaki said.

“This approach detects 75 percent to 90 percent of cases, at a false-positive rate of 2 percent to 5 percent,” Dr. Palomaki said.

“Women with a suspicious result are offered amniocentesis or CVS, but only one in 16 women will have an affected pregnancy. Fifteen will not,” he said.

Now, physicians can order the new test instead of proceeding right to invasive tests, Dr. Palomaki said. “As a result, most of the pregnancies then referred on for amniocentesis or CVS will be found to have Down syndrome,” he said.

According to a 2009 analysis of 11-year registry data in Sweden reported in Ultrasound in Obstetrics and Gynecology, the miscarriage rates — spontaneous loss and procedure-related loss — after amniocentesis and CVS were 1.4 percent and 1.9 percent,a respectively.

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The new test detects cell-free fetal DNA in maternal blood indicating trisomy of chromosome 21, the most common cause of Down syndrome.

It requires a sample of maternal plasma, which can be obtained as early as 10 weeks into pregnancy. It's typically done toward the end of the first or the beginning of the second trimester, according to Dr. Palomaki.

The test counts small fragments of DNA floating in the mother's blood. Using high-speed gene sequencers, an average of 21 million fragments per patient are sequenced.

Since a fetus with Down syndrome has three copies of chromosome 21, the maternal blood will have more than the expected number of fragments coming from chromosome 21, Dr. Palomaki said.

The entire process, from thawing a plasma sample to getting the report, takes eight to 10 days.

“You can argue that the patient will be anxious during this period. But amniocentesis also involves waiting, most often for a negative result,” he said.



The researchers are now testing whether the approach can be used to screen for trisomy 13 and trisomy 18.

Several other companies, including Verinata Health and Gene Security Network, hope to introduce similar tests in 2012. Tandem Diagnostics are developing tests using somewhat different genetic analysis techniques.

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The test is not appropriate for detecting all chromosomal abnormalities, including some rare forms of Down syndrome not caused by an extra chromosome.

“But it detects the cases we want to know about from a public health impact and the viewpoint of what women want to know,” Dr. Palomaki said.

Dr. De Vivo said that next generation genetic sequencing has implications for screening for far more than Down syndrome. It is going to “revolutionize” maternal, fetal, and newborn testing, he said.

“Molecular genetics is improving with every year. It will eventually replace everything as the technology improves,” he said.

With molecular analysis of blood spots that contain DNA of the newborn, for example, “the number of potential disorders we can screen for in the newborn will increase exponentially,” he said.

While some physicians and patients argue that genetic testing is fraught with potential ethical dilemmas, Dr. De Vivo believes such concerns are overblown.

Testing could reveal a condition that is treatable, he said. In other cases, it gives parents information they need that may help them decide whether to terminate the pregnancy, he said.

“The decision of whether to terminate or not is independent of whether you use the older technique, or a new one,” Dr. De Vivo said.

The test is expected to cost about $1,900. While Sequenom negotiates contract prices with insurers, the company said patients with insurance would have to pay no more than $235 out of pocket. It said it expects reimbursement to be similar to that of amniocentesis or CVS.•

EDITOR'S NOTE: At press time, Neurology Today spoke with a leading expert on Down syndrome who expressed concern about use of this test. Among issues, he noted that the test was based on a single proprietary lab, and the study was conducted with a highly select population at a higher risk for Down syndrome. Neurology Today will continue to monitor developments related to the test and the FDA approval.

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Palomaki GE, Kloza EM, Kanick JA, et al. DNA sequencing of maternal plasma to detect Down syndrome: An international clinical validation study. Genet Med 2011; E-pub 2011 Oct. 14.
    Tabor A, Vestergaard CH, Løkkegaard E. Fetal loss rate after chorionic villus sampling and amniocentesis: An 11-year national registry study. Ultrasound Obstet Gynecol 2009;34(1):19–24.
      ©2011 American Academy of Neurology