Clinical Trial Is Favorable for a Prenatal Gene Test
A new method of prenatal testing that can detect more genetic problems in a fetus than ever before could be headed toward wider use after encouraging results from a clinical trial, researchers said.
The study, which is expected to be published in a peer-reviewed medical journal soon, found that the new technique, microarray, surpassed standard testing in detecting chromosomal abnormalities that can cause problems like autism or mental retardation.
“The last 8 to 12 months have probably seen the greatest change we’ve had in prenatal screening and diagnostics since the development of amniocentesis,” which became popular in the 1970s, said Dr. Lee Shulman, head of reproductive genetics at Northwestern University’s Feinberg School of Medicine.
The new technique still requires fetal cells to be obtained either by amniocentesis, in which a long needle is stuck into the womb, or by another invasive procedure called chorionic villus sampling, in which tissue is taken from the placenta. But instead of then examining the fetal chromosomes under a microscope, a DNA-sensing chip is used to detect abnormalities too small to be seen.
A big concern, however, is that it is not always possible to tell whether a small abnormality detected by the chip will be harmful to a child, or if so, how severe such a problem will be. That can cause anxiety for expectant parents and make it difficult to decide whether to terminate a pregnancy.
“They are just not prepared for the uncertain information they are getting, often very late in a pregnancy,” said Barbara A. Bernhardt, a genetic counselor at the University of Pennsylvania, who has interviewed women who have had microarray testing.
Proponents say that the benefits of testing outweigh the possible uncertainty. “There definitely are complicated things you run into,” said Dr. Arthur L. Beaudet, chairman of molecular and human genetics at Baylor College of Medicine, which offers microarray testing through its laboratory. “But in order to avoid that, are you willing to give up detection of clear-cut terrible disorders?”
Microarray testing, formally known as array comparative genomic hybridization, is just one of the new techniques sweeping through prenatal diagnosis. Another is the introduction of tests that can determine if an unborn baby has Down syndrome using just a sample of the pregnant woman’s blood.
For some women, such noninvasive testing could be an alternative to amniocentesis or C.V.S., which are invasive procedures that carry a slight risk of inducing a miscarriage.
But with microarrays, invasive testing can now detect far more than just Down syndrome, posing a choice for women of whether the extra information is worth the extra risk.
“Patients are going to be faced with the question ‘Do I want noninvasive testing for Down syndrome or do I want to have an invasive test with more information?’ ” said Dr. Ronald Wapner, director of reproductive genetics at Columbia University Medical Center.
Dr. Wapner was the lead investigator in the clinical trial, sponsored by the National Institutes of Health, in which samples from 4,400 pregnant women were tested using both microarrays and the standard technique, called karyotyping, in which chromosomes are stained and examined under a microscope. While he declined to discuss the results before they were published, they were presented in February at the annual meeting of the Society for Maternal-Fetal Medicine.
Among women who underwent testing because of advanced age, the microarray found worrisome abnormalities in 1.7 percent of cases in which the karyotype was normal. Essentially, the microarray can find about twice as many problem pregnancies, researchers said.
Among women who were tested because an anomaly was found by ultrasound, the microarray found worrisome chromosomal variations in 5.8 percent of cases in which the standard testing found no problems.
A 33-year-old New Jersey woman who participated in the study said the microarray detected a microdeletion on chromosome 17 of her unborn baby that could lead to kidney and uterus problems — but also might not.
“It’s a whole list of it could be but it might not be,” said the woman, whose spoke on condition of anonymity because investigators in the study are not supposed to know her identity. “The largest study on this microdeletion includes nine people. It’s hard, because there’s not much you know about it.”
The woman, who never considered the abnormality serious enough to terminate the pregnancy, said that knowing about the chromosomal aberration had made her more alert to any budding health problems of her daughter, who is now almost 2 years old.
“If there is a kidney issue, we’d be on top of it rather than chasing it,” said the woman, who is a nurse. “But it sure does create a lot of unneeded anxiety.”
Microarrays are chips on which tiny strands of DNA from various locations throughout the human genome are arranged in an orderly grid, to act as probes.
The DNA from the fetal sample is labeled with a colored fluorescent dye, and DNA from a normal control is labeled with a different color dye.
When the DNA from the two samples is put onto the chip, fragments will bind to the probes with a corresponding sequence of bases. How much binding occurs is measured by scanners that detect the light emanating from each spot.
If much less fetal DNA binds to a probe than control DNA, the fetus is missing DNA at the corresponding location in the genome. If there is much more fetal DNA than control DNA, the fetus has duplicated DNA.
Microarray tests are offered by various laboratories, including Signature Genomic Laboratories and LabCorp, and by academic centers like the Baylor College of Medicine, and Emory.
The tests can cost $1,500 to $3,000 in addition to the cost for the amniocentesis or C.V.S. procedure. Karyotyping can cost $250 to $1,500. Insurance does not always pay for microarray testing since it is not considered the standard of care for prenatal testing.
Microarrays are already the standard diagnostic procedure after children are born with mental disabilities. But until now, there has been reluctance to use the technique prenatally, because errors or unclear results might lead to stress and unnecessary abortions.
“If you make a mistake in postnatal care, you still have a child,” said Lisa G. Shaffer, chief scientific officer for molecular diagnostics at PerkinElmer, which owns Signature Genomic Laboratories. “If you make a mistake in prenatal care, it could lead to a family making a wrong decision.”
Whether microarray testing will become a standard is still unclear. The American College of Obstetricians and Gynecologists does not endorse it, except as an extra testing option when abnormalities are found on an ultrasound. Cost and insurance issues could also suppress use.
There is also the question of demand. Dr. Stephen A. Brown, associate professor of obstetrics and gynecology at the University of Vermont, said that while some women want to know everything possible, he had seen little demand in general for microarray testing.
“There’s a lot of sentiment that technology doesn’t answer all questions, and they’ve sort of had enough of it,” he said.
The window of opportunity for microarray testing might also be limited. Researchers recently demonstrated that it was possible to determine the entire genome sequence of a fetus using DNA samples from the mother and father, or even from the mother alone. In several years, some doctors say, noninvasive tests using DNA sequencing will be able to do everything the microarrays can do now.
Our Thoughts & Responses
At Ravgen, we offer noninvasive testing through a blood collection which does not ask for an amnio or CVS and does not put the baby at risk. Contact us today with questions or for more information about prenatal genetic testing.