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Debate Ensues as Prenatal Tests Reach Beyond Down Syndrome

Doctors and genetic counselors question the expanding scope of blood tests during pregnancy.

Genetic counselor Emily Hardisty sat across from three salespeople from the San Diego biotech company Sequenom two weeks ago. The sales team had come to pitch her on a new way to peer more deeply than ever before into the genome of a fetus during pregnancy.

Sequenom says its test, which became available today, promises “more information about your baby’s chromosomes than any prenatal blood test to date.” But Hardisty wasn’t biting. She says her center, at the University of North Carolina, in Chapel Hill, doesn’t plan to order it. It’s not clear how accurate the test is, she says, or even whether it will really benefit parents.

Driven by profit and powerful technology, several biotech companies are expanding popular prenatal screening tests. In addition to looking for Down syndrome, they are starting to check for smaller breaks and errors along a baby’s 23 sets of chromosomes that can also cause severe, if rare, birth defects. In brochures aimed at expectant mothers, Sequenom bills its expanded test as the “only prenatal blood test that analyzes every chromosome of your developing baby.”

In practice, the new test scans across the genome at a high level, looking for missing or added DNA. Like previous tests, it can detect an extra copy of chromosome 21, the cause of Down syndrome. But it will also flag any chunk of missing, duplicated, or misplaced DNA larger than seven million genetic letters—about 1/20th the size of a chromosome.

“This is about detecting any change this big, because it is going to be relevant,” says Dirk van den Boom, chief scientific and strategy officer of Sequenom. He estimates that the expanded test would spot a serious problem in one out of every 1,000 pregnancies.

Sequenom says it is marketing the expanded test, which costs about $3,000, to specialists for now, but it has its eye on every pregnancy. Company executives have told Wall Street analysts that they expect the expanded test to become standard. Most of the cost will be covered by insurance.

The new tests mean that every mother could soon be exposed to esoteric, cutting-edge genetic findings of the kind until now offered only by specialized labs and requiring a biopsy or amniocentesis. Sequenom says its noninvasive test, called MaterniT Genome, is equivalent to a karyotype, or a close inspection of a baby’s chromosomes under a microscope.

Future versions of such tests are expected to comb through the genome with still more precision, companies predict. Daixing Zhou, CEO of the Chinese testing company Berry Genomics, says his company is preparing a prenatal test for launch this fall that would find any “sub-chromosomal” error larger than two million DNA letters.

Such tests would provide parents with unprecedented kinds of information, like risk genes for autism, in addition to hundreds of rare developmental disorders. While that could catch problems in time for an abortion, or to prepare for a disabled child, doctors groups say there’s still too little data backing the use of the tests. In just-released guidelines, the American Congress of Obstetricians and Gynecologists concluded that “routine” screening for smaller chromosome defects “should not be performed.” 

“Bigger is sold as better. The companies are driving this, not patients and not providers,” says Katie Stoll, a genetic counselor in Washington state and a member of the nonprofit Genetic Support Foundation. Companies aren’t bound by the professional guidelines in deciding what test to sell.

Some genetics experts say extracting more information from prenatal DNA is inevitable, and probably a good idea. “I see a grand recognition,” says Ronald Wapner, a Columbia University professor who has worked with companies to help study their prenatal tests. “Why would you not want to see these things? Some people are resistant but it’s because these are brand new thoughts. We need more information, not less.”

Sequenom launched the first accurate blood test for Down syndrome in 2011. That disorder results from having three copies of chromosome 21, instead of the usual two. Since then, a half dozen competing tests have reached the market. Like Sequenom’s, they all use speedy sequencing machines to decode fragments of fetal DNA present in blood drawn from the mother during her first trimester (see “Too Much Information“). By analyzing these fragments, it is possible to determine if the baby has too few chromosomes, or too many.

The convenient screening tests have become a runaway success. Sequenom says it has carried out 450,000 of them. But the better measure of their quick adoption is that is the rate of amniocentesis, or invasive biopsy, has fallen by more than half at many hospitals in just four years.

Companies have been looking for ways to push the noninvasive tests further. Last year, both Sequenom and Natera, another testing firm, began screening for a small number of “microdeletions,” or very specific, smaller pieces of missing DNA that are known to cause rare, but serious, genetic conditions such as DiGeorge syndrome, Prader-Willi disease, and Cri-du-Chat, so named for the high-pitched, cat-like crying of affected infants.

All these syndromes are characterized by physical and intellectual disabilities, but doctors complain the tests have downsides that are rarely mentioned, including a high chance that a positive result will be a false alarm. Neeta Vora, a professor of maternal fetal medicine at the University of North Carolina and director of its maternal blood screening laboratory, says that’s because these syndromes are very rare, affecting as few as one in 50,000 births. Depending on the error rate of the test, this means that “false positives” can outnumber true positive results. “It’s very hard to counsel patients,” Vora says.

Testing company Natera, for instance, estimated in a paper published this March that as few as one in 20 positive results for DiGeorge syndrome would really have the disease. Zach Demko, a scientist at the company, says the false positive rate is lower with an updated version of its test. Natera, which has been selling about 20,000 tests a month, raised $180 million in an IPO in July.

Vora says a danger of false positives is that some patients, and some doctors, assume the screening tests are foolproof. They don’t realize that a positive result has to be confirmed with an invasive test, like amniocentesis. That can cause unnecessary anxiety, and has led to cases where women have ended pregnancies that were, in fact, healthy.  

Wapner, who coauthored the Natera paper, also faults companies for launching tests before outside experts have had a chance to weigh in. But Wapner doesn’t think false positives themselves are a problem. He notes that before the noninvasive blood tests, nearly every expectant mother over 35 was sent for amniocentesis, even though the odds of finding Down syndrome was one in 270. “Now we have people saying one in 20 is too high for microdeletions,” he says. “It’s ridiculous.”

Widening the scope of noninvasive tests could increase demand for them. Some medical organizations don’t yet recommend the expensive tests for younger women, reasoning that the chance of Down syndrome is very low. But the microdeletion syndromes, though not common, affect all ages equally. That creates an argument to test younger women, too. “They don’t seem to be age-related, so we think they are appropriate for all the pregnancies,” says Zhou, the CEO of Berry Genomics.

Sequenom’s genome test breaks new ground because, unlike prior tests, which have sought out information about specific medically important microdeletions, it scans all chromosomes and reports any DNA alteration it finds, whether or not they are known to cause disease. In fact, Van den Boom was not able to name a single specific birth defect or disease the new feature of the test is designed to catch.

But Van den Boom says in practice all the alterations it finds will be serious, since the company will only report alterations greater than seven million DNA letters, about two to three times as large as the microdeletions the tests currently look for. Other experts say DNA errors of that size might lead to death in utero or conditions so rare they don’t have a name.

Sequenom’s uncertainty about what it is actually testing for points to another significant concern: if doctors don’t know what the DNA errors mean, how can they counsel patients? Even some well-studied forms of chromosome damage aren’t certain to cause serious health problems. Vora’s clinic at the University of North Carolina says it counseled an expecting mother whose blood came back positive for the microdeletion that causes Angelman’s syndrome. It turned out that the mother was the one with the genetic error, yet she wasn’t greatly affected. “There are people walking around with some of these microdeletions that don’t even know they have them,” says Hardisty.

Van den Boom says Sequenom is also worried about finding DNA errors whose meaning isn’t certain and which could expose patients and doctors to information they may not know how to handle, such as risk factors for autism. He says Sequenom has discussed the danger that information would be “misused” to terminate pregnancy or that doctors would “not even know what they are testing for.” That is one reason it set the cutoff at seven million bases, he says. “We want to make sure there is clinical relevance.”

Sequenom’s new test will cost about $300 more than the $2,700 test it has been offering for several years. Van den Boom says he believes it is likely that noninvasive tests will eventually be used to report much smaller errors, as well to diagnose common inherited disease genes and metabolic disorders in utero, rather than at birth. For its part, Natera told investors during its IPO that it also sees few limits to the technology. It said it thinks it has “the ability to generate close to the full genome of an individual, roughly nine weeks after the individual is conceived.”

To Wapner, that means today’s debate over whether to look more closely at chromosomes is just a dress rehearsal for the day that the genome of a fetus will be known, letter for letter (see “10 Breakthrough Technologies 2013: Prenatal Sequencing”). “We will unquestionably be able to sequence a fetus noninvasively,” he says. “Whether we should do it is another matter.”

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