San Diego, CA. Scientists have have taken the next step toward practical use of fetal DNA sequencing to detect missing or extra chromosomes, replacing the surrogate biochemical markers used today in clinical practice.

In a study published in the American Journal of Obstetrics & Gynecology (AJOG), researchers from the Sequenom Center for Molecular Medicine confirmed that DNA sequencing of maternal blood plasma could accurately detect trisomy 21 (47,XX,+21), or Down syndrome. The new development is expected to influence further research on detecting missing, extra, and/or malformed chromosomes.

"In this study we have taken the next step in evaluating the practical use of fetal DNA sequencing and have shown that it has the potential to be highly accurate in a clinical setting," commented senior author Dirk van den Boom, PhD.

Women over 35 are at increased risk of giving birth to babies with trisomy 21

Approximately 4.5% of all pregnant women were of advanced maternal age in 1980. That figure increased to 14% by 2007.

Because the plasma of pregnant women contains circulating cell-free (ccf) fetal (ccff) DNA the DNA sequencing method is able to identify the extra chromosome 21 material present in a fetus with trisomy 21.

Using samples from 449 high-risk pregnant women, the DNA sequencing method correctly identified 39 trisomy 21 samples and 409 normal samples, and misclassified 1 normal sample as trisomy 21.

The overall classification showed 100% sensitivity and 99.7% specificity.Independent of gestational age assessments, the new approach allows for direct fetal assessment using massively parallel shotgun sequencing to detect missing or extra chromosomes, rather than surrogate biochemical markers that are used today in clinical practice.

"We have implemented technical improvements that will increase sample throughput and reduce costs. Following completion of an ongoing clinical validation study the above improvements will greatly facilitate introduction into clinical practice," says van den Boom.

The data show that, in the future, a noninvasive prenatal trisomy 21 test from ccff DNA might be used in concert with other clinical assessments, such as ultrasound, and become an option to better identify those women who would, or would not, benefit from confirmatory invasive diagnostic tests.

There has been continuing improvement in various non-invasive aneuploidy detection technologies over the past two decades. Lee P. Shulman MD, is a prenatal testing expert at The Feinberg School of Medicine of Northwestern University, Chicago."

Many more steps and studies will be needed in order to arrive at the goal that most of us who provide and study prenatal screening and diagnosis have long sought after: a facile, economical, and more accurate approach to prenatal screening and, eventually, an effective noninvasive alternative to invasive prenatal testing."

Roberto Romero is Chief of the Perinatology Research Branch of the National Institute of Child Health & Human Development (NICHD), NIH and Professor of Molecular Obstetrics and Genetics at Wayne State University. "... progress is being made towards the realization of prenatal diagnosis of fetal disorders based upon maternal blood analysis and the use of high throughput technologies. While this study shows feasibility for the detection of trisomy 21, further studies are required to establish utility in clinical practice."

"A new frontier is the diagnosis, not only of trisomy 21 and other genetic disorders of the human fetus, but also the assessment of the functional state of the unborn baby by analysis of circulating fetal and/or placental RNA in the maternal circulation." Dr. Romero is an Associate Editor of the American Journal of Obstetrics & Gynecology (AJOG).

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