Most parents-to-be would never have found out about such missing DNA, because the problem was too small to be detected by standard prenatal genetic tests. But Bratina was a participant in a study of chromosomal microarray analysis, a new kind of test that allows doctors to examine fetal DNA in amniocentesis samples for such tiny genetic variations.
Microarray analysis is part of a sea change in prenatal testing, according Ronald Wapner, a reproductive genetics expert at NewYork-Presbyterian Hospital/Columbia University Medical Center, who led the study. In just the past two to three years, Wapner says, “the genetic testing that’s available for pregnancies has become phenomenally more advanced.”
Researchers have used microarray analysis to link tiny genetic variations in children and adults to problems as diverse as learning disorders, autism and schizophrenia. So using the method to analyze fetal DNA was a natural next step for prospective parents.
New kind of amniocentesis
In a study published in December in the New England Journal of Medicine, Wapner compared microarray analysis to the standard method of amniocentesis analysis, called karyotyping, in 4,406 women who were age 35 or older or had taken a screening test that suggested the possibility of some genetic abnormality in their fetus.
The researchers found that the new technology was as good as karyotyping in finding abnormal numbers of chromosomes (a reason for Down syndrome, for instance).
But it also found DNA abnormalities that karyotyping had missed, including some associated with learning disorders, autism and schizophrenia, as well as three rare disorders, Prader-Willi syndrome,
Jacobsen syndrome and DiGeorge syndrome. Karyotyping missed these problems because it cannot detect variations smaller than about 10 million base pairs of DNA. Base pairs are the chemical building blocks of the human genome, and humans have about 3 billion of them. Microarray analysis, in contrast, can find variations as small as 10,000 base pairs.
Microarray testing is now routinely offered to expectant parents when karyotyping fails to find a genetic cause for problems identified by ultrasound, such as heart or brain defects and other structural problems.
However, microarray testing can be about double the cost of karyotyping, and many insurance plans will not cover it as a standard test, though doctors said that may be changing. But based on his study, Wapner says that it should be offered to all women.
“Why not get as much information as you can?” he asks. Knowing about a problem in advance can help prospective parents weigh their options, including ending a pregnancy and preparing to care for a child with special needs. In addition, he says, such prenatal therapies as in-womb surgery can improve a child’s odds of surviving and thriving in some cases.
Some experts, though, worry that microarray testing might provide too much information, since, as Denise Bratina discovered, it can reveal genetic abnormalities that may not cause a problem or that have not been linked to known problems or disorders.
Parents are rarely prepared for that level of uncertainty, says Barbara Bernhardt, a genetic counselor at the Hospital of the University of Pennsylvania. She surveyed 23 women who took part in Wapner’s study, some of whom were given ambiguous results. Although all participants had been warned that the test results might suggest genetic abnormalities of uncertain consequence, they nonetheless reported being shocked and confused by them anyway.
“People go into testing expecting black and white,” Bernhardt says. “They hear that they could get an uncertain result, but it doesn’t sink in.”
Bernhardt hopes to develop guidelines to help genetic counselors prepare families to understand what they’re getting into before they choose to get such detailed information.
For some women, the worry didn’t stop after they gave birth to a healthy baby.
“Since I had this uncertain microarray result . . . if anything happens to him in the future . . . that will always pop up in my mind,” one woman told Bernhardt. “I’m a lot more vigilant,” the woman said, about watching her child for health issues or developmental delays.
This rings true for Bratina, who says that she is grateful for the follow-up evaluations her daughter receives as part of Wapner’s study and that so far everything is normal. Bratina also says that she is glad to have found out about her daughter’s missing DNA. “If any issues come up in the future, we’ll know why,” she says.
Microarray analysis is not the only major change in prenatal testing. For years, advanced prenatal testing has often meant an invasive procedure — amniocentesis or chorionic villus sampling (CVS) — to get the fetal DNA; these tests come with a small risk of miscarriage. A new test, though, can screen for three disorders caused by an extra chromosome — Down syndrome, trisomy 13 and trisomy 18 — with just a simple blood draw from the mother.
The test, called cell-free fetal DNA testing, works by analyzing fragments of fetal DNA found floating in the mother’s bloodstream. Those fragments aren’t complete enough to easily reveal the small abnormalities that microarray testing can find. The new test is marketed under the names MaterniT21, Harmony and Verifi.
Cell-free fetal DNA testing is considered a screening test, meaning that although studies have found that it can detect Down syndrome about 99 percent of the time, women must still follow up with amnio or CVS to know with 100 percent certainty. But it is more accurate than other noninvasive screening methods, such as ultrasounds and tests of certain hormone and protein levels in the mother’s blood, and it can be done as early as nine weeks into pregnancy.
Those advantages make it useful, according to Mary Norton, the director of perinatal research at Stanford University’s Lucille Packard Children’s Hospital. But she worries that the test may be adopted by doctors and their patients more quickly and widely than the research merits.
At present, the American College of Obstetricians and Gynecologists recommends the test only for women who are 35 or older or have other risk factors such as a family history of one of the disorders, because not enough studies have examined its effectiveness in low-risk women.
Eventually, the advances of noninvasive blood testing and detailed DNA analysis may converge, as researchers are able to draw more information from the fragments of fetal DNA in a mother’s blood sample.
Last year, in fact, University of Washington geneticist Jay Shendure used these fragments to sequence the entire genome of a fetus. The feat cost about $50,000, so it is nowhere near becoming commercially viable, Shendure says.
And, he says, that is probably a good thing. Sequencing fetal DNA from just a blood test would give parents-to-be easy access to their child’s entire genome, vastly more information than even DNA microarray analysis — which looks at only selected sections of the genome — provides.
“I think it’s perfectly fine that it’s not available right now,” he says. “There are a lot of things beyond the cost that we need to sort out before we’d want to see this out there available to the public.”
Winerman is a writer in Alexandria.