Cystic Fibrosis : Genetic Testing, To Test or Not To Test?

by Food and Drug Administration (FDA)

(Page 2 of 4)

In one study conducted by researchers at the University of Colorado School of Medicine and Children's Hospital in Denver, the trypsinogen test identified 95.2 percent of infants with CF who did not have the earliest sign, a greenish discharge called meconium ileus indicating intestinal blockage. But in the study there were many false positives — of 96 infants who tested high for trypsinogen on two tests, only 31 had CF. So, although the trypsinogen test alone is not perfect, combined with a sweat test and observing symptoms, it can begin to paint a portrait of CF.

Another test detects the level of certain fetal intestinal enzymes in the amniotic fluid (the liquid surrounding the fetus). Amniotic fluid is collected for testing by a procedure called amniocentesis (see "Genetic Screening: Fetal Signposts on a Journey of Discovery" in the December 1990 FDA Consumer). In a fetus with CF, these enzymes are decreased. Again, however, other disorders besides CF can produce this finding, and therefore it is not a specific disease marker. Researchers have turned to the genetic material to develop a definitive CF test.

Enter Genetic Testing

Developing a test to detect the gene that causes CF would provide a definitive diagnosis, because this mutant gene is the only cause of the disorder. The first step was to find out where the gene behind CF lies among the 23 pairs of chromosomes.

By 1985, several research teams had narrowed the search to a part of chromosome 7 (the seventh largest chromosome). Until the CF gene itself was isolated and characterized in 1989, relatives of patients could take an indirect test that uses linkage analysis. Because of the complexity of test interpretation, these tests are primarily performed at academic centers.

A genetic linkage test tracks a known DNA sequence (a genetic marker) that, within a family, always occurs in people with CF, and never in those who do not have the illness. A genetic marker and the gene responsible for the disorder behave like two inseparable friends. If you see one at a party, you know the other is nearby. Genetic linkage testing is based on the observation that genes carried close together on the same chromosome tend to be inherited together.

Ray White at the Howard Hughes Medical Institute at the University of Utah in Salt Lake City and Robert Williamson of St. Mary's Hospital Medical School in London each found a marker, one on either side of the CF gene. Using these two markers, a couple who already had a child with CF could have fetal chromosomes tested in a subsequent pregnancy. If the two markers on the two chromosome 7's in the fetus matched those of the affected child, then it, too, has likely inherited the disease.

A major limitation of linkage tests is that they only work on families known to have CF. Because people can carry CF without having symptoms, a disease-causing gene can be in a family without anyone in recent memory being ill. Finding the CF gene itself, however, may make possible a test useful on anyone, so that carriers could be detected in families where no one has CF.

Like other genetic tests, CF tests can be performed on any type of tissue, because all human cells (except red blood cells) contain two copies of all of the genes, and sperm and egg have one copy of each. The first CF tests used white blood cells. Then Williamson's group in London came up with a pleasanter alternative — a mouthwash! After swishing a saltwater solution in the mouth, the person spits into a bottle. The CF gene can be spotted in cells dislodged from the inside of the cheek.

Taking a cue from London, Genzyme Corp. (Cambridge, Mass.) developed a cheekbrush test for CF, which is investigational. A patient swabs cheek cells onto a brush, and the physician sends the sample to Genzyme. The presence of both normal and mutant CF genes indicates carrier status. If only mutant genes are there, CF is indicated.

To Test or Not To Test?

A carrier test provides information to couples who are not ill but whose children are at high risk of inheriting the condition.

Many experts predict that the day of universal CF screening is approaching, with several companies developing CF tests that simultaneously screen for several CF mutations.

Two factors contribute to the sensitivity of a CF carrier test. The first is the number of mutations that can be detected. The more mutations tested for, the more carriers will be spotted.

Ethnic background is the other important factor, says Marisa Ladoulis, a genetic counselor at Collaborative Diagnostic Services in Waltham, Mass. For example, a 12- mutation test that spots 84 percent of whites with a Northern or Western European background will detect 92 to 95 percent of Ashkenazi Jews, and the 16-mutation test finds 96 to 98 percent of them.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.