New noninvasive test for Down syndrome cuts risks of miscarriages

From The New York Times Oct. 7:

For three decades, scientists have been trying to develop a noninvasive prenatal test for Down syndrome that would replace amniocentesis, which can cause miscarriages.

Now, scientists using powerful genetic techniques are closing in on that goal with tests that require only a blood sample from the pregnant woman.

A biotechnology company in San Diego called Sequenom says it will begin selling such a test next June. Another testing technique, developed at Stanford, is described in a paper published online Monday in The Proceedings of the National Academy of Sciences.

There are reasons to be cautious. The Stanford test has been tried on only 18 blood samples. Sequenom has tried its test on only about 400 samples and has not yet published its results in peer-reviewed journals.

Still, both tests have perfect records so far: no false negatives or false positives. “This is quite simply a major step forward, if it works at all like we expect it might,” Jacob A. Canick, a professor of pathology at Brown, said of the Sequenom test at a recent meeting the company held for its investors.

A former consultant to the company, Dr. Canick will conduct a study of the test’s accuracy in 10,000 women. Results could be available by late 2009. But enthusiastic investors are not waiting for those results. The price of Sequenom’s stock has quadrupled since March.

Down syndrome, the most common chromosomal disorder, occurs when a baby
is born with three copies of Chromosome 21 instead of the usual two. It is marked by mild to moderate mental retardation, unusual facial characteristics and a high risk of heart defects.

The two definitive tests for Down syndrome — amniocentesis and chorionic villus sampling, or C.V.S. — work by retrieving fetal cells so the chromosomes can be counted.

But the tests carry a slight risk of miscarriage, estimated at 1 in 200 to less than 1 in 1,000. Until recently testing was offered mainly to women 35 or older and others most at risk of having a baby with Down syndrome. But the American College of Obstetricians and Gynecologists now says it should be an option for all women.

Sequenom’s test would be used at first to screen women to see who would then undergo amniocentesis or C.V.S., so-called diagnostic tests. But Harry Stylli, chief executive of Sequenom, says that if the test is accurate enough, “it will ultimately replace amnio and C.V.S.”

Such screening is already done using ultrasound and a variety of blood tests, so some experts say that unless a noninvasive test can replace amniocentesis and C.V.S., it will not be that significant.

“The area where need exists is where you would have a noninvasive diagnostic test,” said Dr. Diana W. Bianchi of Tufts Medical Center, president of the International Society for Prenatal Diagnosis. She called Sequenom’s results “preliminary and promising, but not definitive.”

Others say that even an improvement on existing screening would represent a big advance. Those tests can miss 5 to 30 percent of Down syndrome cases. And they have a false positive rate of 5 percent, which means many women undergo amniocentesis or C.V.S. unnecessarily.

For instance, for women approaching 30, the risk of giving birth to a baby with Down syndrome is roughly 1 in 1,000. So if 10,000 women of that age undergo screening, there would be 10 actual cases of Down syndrome. But 500 other women would be recommended for an unnecessary invasive test. And perhaps one of those women would miscarry a healthy baby. A screening test with a much lower false positive rate would reduce unnecessary procedures.

“Doing a procedure on 1 percent is way better than doing it on 5 percent or 10 percent of all people,” said Dr. Stephen A. Brown, an associate professor of obstetrics and gynecology at the University of Vermont.

Some relatives of people with Down syndrome fear that an easier test will lead to more abortions, shrinking the population of people with Down syndrome and eroding societal support. They say people with Down syndrome can lead fulfilling lives and were heartened when the Republican vice-presidential candidate, Gov. Sarah
Palin of Alaska, gave birth this year to a boy she knew would have Down syndrome.

Testing technology “has outpaced society’s understanding of what life with Down syndrome is like,” said Mark Leach, the father of a 4-year-old girl with the condition. Mr. Leach is chairman of the informed-decision-making task force of the group Down Syndrome Affiliates in Action.

Most efforts to develop noninvasive prenatal tests have focused on isolating cells from the fetus in the mother’s blood. But the fetal cells are extremely rare and hard to detect.

More recently, scientists have discovered that there is free-floating fetal DNA in the mother’s bloodstream, probably because fetal cells die and break apart. Tests that analyze this DNA can determine the baby’s sex and whether it has the Rh factor in its blood.

But fetal DNA can be drowned out by the mother’s own DNA. And Down syndrome is caused by an extra chromosome, so it cannot be detected just by looking for a particular gene or mutation. So Dr. Y. M. Dennis Lo, a professor at the Chinese University of Hong Kong who conceived of Sequenom’s test, focused on RNA, DNA’s cousin.

A copy of a gene made of RNA is produced only when that gene is active. So Dr. Lo looked for genes on Chromosome 21 that were active in the fetus but not in the mother. That means that any such RNA found in the mother’s bloodstream comes from the fetus.

The Sequenom test then looks at spots where the version of those genes inherited by the fetus from the father might differ from the version inherited from the mother.

If the baby has the normal two copies of Chromosome 21, the amount of RNA from the mother’s version and the father’s version should be the same. If the baby has an extra copy of the chromosome, one version would be twice as abundant as the other.

One drawback is that for 7 percent of the American population — and 35 percent of Asians — the genes from the mother and father do not differ at the spots examined by the test. In those cases, the test would not produce an answer and the woman would be sent for other types of screening. The fetus does not make enough RNA for the test to work until 12 to 14 weeks’ gestation. Sequenom hopes to reduce that to 10.

The Stanford technique involves determining the sequence of millions of DNA fragments from the mother’s bloodstream. Whether the fragments come from the
mother or the fetus does not matter.

The scientists then determine which chromosome each fragment comes from, using the map developed by the Human Genome Project. If the fetus has an extra copy of Chromosome 21, there will be a higher than expected number of fragments from that chromosome. Unlike the Sequenom test, this technique will work for any woman and any ethnic group. And it will detect extra copies of chromosomes other than 21. It is not clear how early in a pregnancy the test will work.

The Stanford scientists said the sequencing cost $700 per sample, and sequencing costs are falling rapidly.

Stephen R. Quake, a professor of bioengineering who led the work, said Stanford was in talks to license the technology to a company.

Dr. Stylli of Sequenom called the Stanford work “a nice scientific experiment,” but said the test would be too expensive to compete when other costs and profit margins were added.

Sequenom also claims that its patent rights, some acquired just recently as a defensive measure, will block out Stanford and other competitors.

Dr. Stylli said that Sequenom’s test might have a list price of $2,000 but that the real cost insurers would pay would be $600 to $800. That is more than existing screening tests but less than amniocentesis.

Other companies are also working on noninvasive tests. Ikonisys, based in New Haven, hopes to introduce a test by 2009 or 2010 that uses the fetal cell approach. It uses cervical smears, like those for Pap testing, because the concentration of fetal cells is higher there than in the mother’s blood.