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Test Case for Genetic Testing
Population-based screening for cystic fibrosis mutations is coming. Are we ready?
By Julie Buckles

Featured Article.

Soon every pregnant woman in the U.S. will be informed about the gene test for cystic fibrosis. Women may hear about the test from their physician or they may read about it in a brochure. They can choose to be—or not be—screened for mutations in the cystic fibrosis gene that may be passed to offspring. Screening for mutations in healthy individuals with no family history of disease has not been done on this scale before, and no one is sure how it will play out. This much is clear: Cystic fibrosis will be this country's test case for population-based genetic testing.

Several key professional organizations are ready to recommend that pregnant couples be offered CF carrier testing. Once these organizations make CF testing what they call 'standard of care,' physicians will be obligated to tell patients about it or face possible litigation. The American College of Medical Genetics (ACMG) publishes its recommendations this week in Genetics in Medicine. The American College of Obstetricians and Gynecology (ACOG) has delayed announcing recommendations several times but will likely do so later this year. The two organizations, in conjunction with the National Human Genome Research Institute, plan to create a joint document for wide distribution to physicians, patients, clinics, and laboratories.

More than 900 mutations or sequence variations in the CF gene have been identified.

Introducing a genetic test nationwide is uncharted territory and has made the scientific community understandably skittish. There are more than 400 genetic tests on the market, but none targets as large an audience. Only about 900 new cases of CF are diagnosed in the U.S. annually, but it is one of the most common inherited disorders for people of Northern European descent, affecting 30,000 children and adults.

The frequency of CF among Caucasians makes it a prime candidate for population-based testing. But the devil is in the details, says Garry Cutting, a CF expert at the Johns Hopkins University School of Medicine. And there are a lot of details.

Since the gene for cystic fibrosis was isolated in 1989, the medical and scientific communities have wrestled with the particulars of whom to test—and how, when, and where. At least a dozen studies in the literature have analyzed costs and benefits, reviewed educational materials, surveyed physician readiness, and gauged patient interest, all with mixed results.

Virtually everyone agrees that testing the general population does not make sense. Individuals are interested in their carrier status only when they become potential parents. Not everyone agrees that the public is ready to sort through the nuances of CF or that obstetricians are prepared to explain test results. "No one has gone Madison Avenue with this yet because it's very complex," says Michael Kaback, of the Children's Hospital and Health Center at the University of California, San Diego.

Prenatal population screening for CF was first recommended in 1997, when the National Institutes of Health convened the Consensus Development Conference on Cystic Fibrosis. A science court of sorts, the conference recommended that carrier screening for CF mutations be offered to just about anyone who could possibly be eligible: adults with family history of CF, partners of individuals with CF, couples planning a pregnancy, and couples seeking prenatal care.

"Even though our recommendation seems rather straightforward, it was a very big deal to recommend gene testing of this type," says R. Rodney Howell, Chairman of Pediatrics at the University of Miami School of Medicine in Florida and chair of the NIH consensus panel.

Smaller scale carrier screening now exists in pockets of the world. The test for Tay-Sachs disease, a fatal genetic disorder, is offered to Jewish couples of Ashkenazic (Central and Eastern European) descent. In the U.S. and Canada, the incidence of Tay-Sachs in the Jewish population has been reduced by more than 90 percent. "The program works because the affected population is small and well-defined," says Michael Kaback. "Tay-Sachs is uniformly fatal, tragic in every case." Babies born with Tay-Sachs rarely live to age five.

Nothing about CF is straightforward. More than 900 mutations or sequence variations in the CF gene have been identified, and the number continues to grow. The D F508 mutation accounts for approximately 70 percent of cases in Caucasians and is represented in almost all populations. The American College of Medical Genetics Subcommittee on Cystic Fibrosis Screening has published 'a core mutation panel' of common mutations for general population carrier screening. Garry Cutting says less is known about the deleterious effects of the remaining 800 or so and the frequency of disease is very low. In other words, not all mutations cause disease.

Harmful CF mutations cause the body to produce thick, copious mucus, which clogs the lungs and increases the risk for infection. The mucus also obstructs the pancreas and prevents enzymes from reaching the intestines to help break down and digest food. About 90 percent of patients die from lung damage caused by the disease.

Autosomal Recessive Inheritance

The presence of two mutant genes (g) is needed for CF to appear. Each parent carries one defective gene (g) and one normal gene (G). The single normal gene is sufficient for normal function of the mucus glands, and the parents are therefore CF-free. Each child has a 25 percent risk of inheriting two defective genes and getting CF, a 25 percent chance of inheriting two normal genes, and a 50 percent chance of being an unaffected carrier like the parents.

Cystic fibrosis occurs when a child inherits two mutated copies of the CF gene, one from each parent. The gene is recessive, so 80 percent of children with CF are born into families with no history of the disease. One in 31 Americans (one in 28 Caucasians)—more than 10 million people—do not exhibit any symptoms of CF but are unsuspecting carriers of the defective gene.

Individuals with CF can live into their forties and fifties. Advanced treatment methods have increased the median life span of CF patients from 18 years in 1976 to 30 years today. The disease can be mild or severe, but particular mutations do not correlate with the type or severity of disease.

Most patients entering an obstetrician's office will have little experience or knowledge of CF, so the delivery of the message becomes critical. Busy physicians will likely rely on brochures to inform patients. For this reason ACOG has spent a lot of time developing educational materials for patients.

The accuracy of the test depends in part on ethnicity, and the number of ethnic-specific mutations that have been identified. Caucasians can expect an 80 to 85 percent accuracy rate. The D F508 mutation accounts for 70 percent of cases. About 15 to 20 mutations account for the additional 10 to 15 percent detection rate. Accuracy is even higher among Ashkenazi Jews, Celtic Bretons, French Canadians from Quebec and some Native Americans. Asian Americans, however, can only expect a 30 percent accuracy rate, African Americans 69 percent, and Hispanics 57 percent. View epidemiological data

Because of the variation in accuracy rates and low incidence of disease in some ethnic groups, David Witt, who oversees one of the largest CF carrier-screening programs in the U.S., does not recommend that everyone be tested. At Kaiser Permanente Medical Care Program, an HMO in San Jose, California, physicians offer a pregnant woman the test if she or her partner is Caucasian. If her test returns positive for CF, they then test the father. If his results return positive then the couple can choose whether to test the fetus.

If the fetus carries the disease, the parents can decide whether to abort or have the child. Data from CF population screening programs and studies in a variety of settings show that approximately 90 percent of parents chose to terminate pregnancy once they discovered the fetus had CF. Witt predicts that the number will be closer to 50 percent if carrier testing is done on a large scale. And he is confident that a program like Kaiser's is ready to 'go national.'

A pilot study at Kaiser in the 1990s screened 5,000 women, and the findings were published in the American Journal of Human Genetics in 1996. Witt, a medical geneticist, says the results showed "we could do CF screening on a large scale, educate patients properly, and that parents did not suffer psychologically." His group has since screened 18,000 women as part of the regular CF carrier-screening program.

Others in the field argue that more time and more studies are needed before implementing a nationwide program. Garry Cutting at Hopkins foresees a "hodge-podge" of testing across the country, done well in some parts and not so well in others. "I am concerned that the test will confuse some people, and this could erode the public's confidence in the potential of genetic testing."

"Not all the wrinkles have been ironed out," says Michael Kaback at UCSD. He would like to see a larger pilot study in a less-controlled environment—and one in which all patients do not have the cost of the procedure covered by insurance. A University of Rochester pilot study offered testing for free (as did Kaiser). When asked how much they would be willing to pay for the test, patients checked $25, the lowest possible answer. The cost of testing ranges from $20 to $300 depending on the lab and the number of mutations they look for. There are at least 60 laboratories in the U.S. that test for anywhere from one to 87 mutations.

For better or worse, everyone in the field expects CF carrier testing to expand significantly. In theory, more than four million women each year will learn about the test. At least half of these women will choose the test, predicts Celeste Chenet-Monte, marketing executive at Genzyme Genetics in Framingham, Massachusetts. In 1995, nearly 60 percent of pregnant women chose the test for Down syndrome a decade after it was introduced. "We expect there will be an even faster uptake of CF testing," says Chenet-Monte. "Women are more educated, accustomed to the tests, and quite frankly we're living in a more litigious society."

See related GNN article
»Recommendations for population-based cystic fibrosis carrier screening

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Grody, W.W. et al. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med 3, 149-154 (March/April 2001).

Witt, D.R. et al. Cystic fibrosis heterozygote screening in 5,161 pregnant women. Am J Hum Genet 58, 823-835 (April 1996).
Kaback, M.M. Population-based genetic screening for reproductive counseling: the Tay-Sachs disease model. Eur J Pediatr 159, S192-S195 (December 2000).

Rowley, P.T. et al. Prenatal screening for cystic fibrosis carriers: An economic evaluation. Am J Hum Genet 63, 1160-1174 (1998).

Demsey, S.A. Carrier screening for cystic fibrosis: A perinatal perspective. J Perinat Neonatal Nurs 2, 14-26 (September 1999).

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