Healthcare October 2012

A new method of genetic testing that can detect more problems in a fetus, but also reveal confusing information about chromosomal anomalies, will soon become more widely available to expectant mothers; a clinical trial has proven its advantages over standard methods of fetal genetic testing.

The development is of particular relevance to Jewish women. The new technology, called “microarray,” is not used to look for the 18 Jewish genetic diseases, like Tay-Sachs. But some hospitals are making it broadly available to women over the age of 35, a time of life when Jewish women are often bearing children.

Microarray can be a mixed blessing. When ultrasound finds a defect, microarray finds additional genetic information that helps explain the defect in 6 percent of cases, according to a federally funded study of more than 4,000 women led by Dr. Ronald Wapner, director of reproductive genetics at Columbia University Medical Center.

But the new test also finds abnormalities in 1.7 percent of all cases, whether ultrasound has found an abnormality or not. And it is sometimes very difficult to know what the anomaly found by microarray means if there are no other indications of a problem.

“You’ve got the really good side, where you pick up this kind of information that’s really helpful, where you can use it for counseling. But then there are situations where you leave people in limbo with unknowns,” said Dr. Adele Schneider, a geneticist with the Victor Center for the Prevention of Jewish Genetic Diseases at Philadelphia’s Einstein Medical Center.

Nonetheless, the new study proved microarray’s superiority over the current method, called karyotyping, which gives a full picture of the fetus’ chromosomes.

The results of the study have already been released at a conference, but they have not been published yet. Once they are, many more women will be offered microarray, said Dr. Lee Shulman, the head of reproductive genetics at Northwestern Memorial Hospital in Chicago and an advisory board member of the Chicago Center for Jewish Genetic Diseases.

Wapner declined to be interviewed until the study is published.

Hospitals that make microarray available to all women over 35 do so when they offer amniocentesis and chorionic villius sampling. Those procedures reveal fetal chromosomal abnormalities such as Down’s Syndrome, which are related to the age of the mother.

In part because of high educational levels and high-status jobs, more than half of Jewish women have not had a child by age 34, compared with only 28 percent of women in the U.S., according to the 2000-2001 National Jewish Population Survey, the most recent such national study. Many Orthodox women, who might start bearing children earlier, continue past age 35.

In the New York area, for example, New York-Presbyterian/Weill Cornell Medical Center has adopted the practice of offering microarray to expectant mothers over the age of 35 at this time, even though the abnormalities microarray screens for are not age-related. Like many new technologies, microarray is being offered first in New York and other major metropolitan areas, where high numbers of Jews live, another factor that predisposes Jewish exposure to microarray.

Microarray doesn’t put the fetal cells under a microscope to examine the chromosomes, as is done in karyotyping. Instead, it finds abnormalities that are too small for karotyping to capture by using a DNA-sensitive chip to detect discrepancies between the sample being studied and a “normal” control sample.

Both microarray and karyotyping require an invasive procedure like amniocentesis or CVS to retrieve material from the womb.

Microarray is extremely helpful for women whose babies have already demonstrated birth defects on an ultrasound screening, said Schneider, who tells a story about a baby whose ultrasound showed only one eye. Karotyping showed normal chromosomes, but microarray showed a missing gene also associated with brain malformations, motor development delays and learning disability. “If we hadn’t had that microarray, we couldn’t have counseled them,” she said. Schneider would not risk identifying the woman by disclosing whether she decided to end the pregnancy.

On the other hand, in women whose babies have not demonstrated a chromosomal abnormality during karotyping, microarray finds genetic anomalies that are sometimes difficult to interpret.
The impact of microarray on this population is much more ambiguous, according to an interview study of 24 such women performed by Barbara Bernhardt, a genetic counselor, professor and ethics fellow at the hospital of the University of Pennsylvania, who worked alongside Wapner’s trial.

Microarray can find such small anomalies – either deletions or duplications of genetic material – that doctors and counselors don’t know what to make of them. The abnormality might not manifest itself in some people, while cause problems, like mental retardation, in others. Or it might be documented in a very small number of people, like 100. Microarray also finds some genetic variants that have no known meaning.

The information provided by microarray still helps some of these women make decisions as to whether to have their babies or end the pregnancies, Bernhardt said.

But many find making such a decision in the absence of more information agonizing, said Estie Rose, a genetic counselor at Montefiore Medical Center and the Yeshiva University Program for Jewish Genetic Health.

“It’s so frustrating when we get results that are neither here nor there,” Rose said. “Sometimes, we’ll get a microdeletion, or a microduplication, and we won’t know what it means until the baby is born, or until it’s even older than that.”

This potential for ambiguity in microarray’s results makes counseling, both before and after the test, all the more important, Rose said. A patient who undergoes the test with an understanding of its complexity will be better prepared emotionally in the event of results that are hard to understand.

Some hospitals only offer microarray to women whose babies have already demonstrated a defect or irregularity for exactly this reason.

Northwestern is one of them, said Shulman, who leads the reproductive genetics department there.

However, the publication of Wapner’s paper in the next few months will most likely change such policies, because microarray does, in the final analysis, uncover important information even in women whose babies seem otherwise typical, Shulman said. Northwestern will try to limit ambiguous findings from microarray by only testing a limited number of genes, ones that have been associated with severe or lethal conditions, Shulman said.

When the paper is published, insurance coverage for microarray, which is spotty, should become more consistent, Rose said.

“We have too much information for which we don’t have clinical information, and with microarray technology, that will expand,” said Shulman. “That is the price we pay for this technology. There is no free lunch.”