Last updated: October 01, 2012
National Institutes of Health Workshop Statement on Population Screening
for the Cystic Fibrosis Gene
(published in The New England Journal of Medicine. 1990:323:1)
CYSTIC FIBROSIS is an autosomal recessive genetic disorder clinically characterized by chronic lung disease and pancreatic insufficiency. Median survival is 25 years, with an increasing number of patients surviving into their 30's. This disease affects about one in 2,500 persons of European ancestry. It is less frequent among black and Hispanic Americans and is rare in Asians. One in 25 persons of European ancestry is a carrier, having one normal and one abnormal cystic fibrosis gene.
The cloning of the cystic fibrosis gene and identification of the most common mutation in the gene were major advances in medical genetics. These breakthroughs provide a basis for understanding the pathophysiology of the disease and offer the hope that improved therapy can be developed. In addition, there are immediate implications for the identification of carriers of a mutant cystic fibrosis gene.
Currently, DNA analysis can identify a single mutation in the cystic fibrosis gene that is present in 70 to 75 percent of carriers of European ancestry. Many additional mutations producing cystic fibrosis, currently about 20, have been identified. The identification of multiple individually rare mutations rather than a small number of common mutations will make carrier testing more difficult. The inability to detect all carriers creates complexities for the use of carrier testing at this time.
A major question is whether population-based screening for cystic fibrosis carriers could or should be implemented at present. Population-based screening implies offering a program of carrier testing, with appropriate informed consent and genetic counseling, to potentially millions of healthy people. The purpose of such screening would be to allow people to make more informed reproductive decisions with regard to the risk of cystic fibrosis in their offspring.
Unlike testing in the general population, testing for carriers in families in which the disease has occurred is nearly 100 percent informative. This is because carrier testing can be performed with linkage analysis in addition to mutation analysis when there is a DNA sample available from an affected person in a family. Therefore, testing should be offered to all individuals and couples with a family history of cystic fibrosis. This makes it more important than ever for providers of medical care to obtain family histories, particularly for patients of reproductive age.
In contrast, for a number of reasons there is a consensus that under the current circumstances population-based screening should not be recommended for individuals and couples with a negative family history. First among these reasons is the fact that currently the test will detect only 70 to 75 percent of carriers. Therefore, only about half the couples at risk can be identified. Second, the frequency of the disease and the different mutations vary according to racial and ethnic background, so that important laboratory and counseling modifications would be required in different populations. Third, there are substantial limitations on the ability to educate people regarding the use of an imperfect test. Fourth, without more definitive tests, about one in 15 couples those in which one partner has a positive test and the other has a negative test would be left at increased risk (approximately one in 500) of bearing a child with cystic fibrosis.
These difficulties would be substantially reduced if testing could detect at least 90 to 95 percent of carriers. There is a consensus that population-based screening for carriers could be offered to all persons of reproductive age if a 95 percent level of carrier detection were achieved. The offering of population-based screening would still require that substantial educational and counseling guidelines be satisfied. Benefits and risks of population-based screening and its feasibility are uncertain if this level of carrier detection cannot be achieved. When people without a family history of cystic fibrosis request testing, the physician should explain the risks and benefits of the test, either directly or through a center for genetic counseling.
Regardless of when or whether population-based screening becomes widespread, there is consensus on a number of screening guidelines. First, screening should be voluntary, and confidentiality must be assured. Second, screening requires informed consent. Pretest educational material should explain the hazards (for example, psychosocial effects and the loss of insurability) and benefits of choosing to be tested or choosing not to be tested. Third, providers of screening services have the obligation to ensure that adequate education and counseling are included in the program. Fourth, quality control of all aspects of the laboratory testing, including systematic proficiency testing, is required and should be implemented as soon as possible. And finally, there should be equal access to testing.
In view of the importance of the voluntary nature of screening and anticipated rapid changes in current information, legislative action to require cystic fibrosis screening is undesirable at present. There is consensus, however, that cystic fibrosis carriers should not be discriminated against with regard to insurability or employment. If evidence of discrimination emerges corrective legislative action should be considered.
When population-based screening becomes available, who should be offered testing and in what setting? The most appropriate group for population-based screening comprises those of reproductive age. Although it is recognized that testing will often be provided to couples during pregnancy, it is preferable to offer screening before conception. Preconception testing offers a couple that has a one-in-four risk of having an affected child a broader range of reproductive options.
The optimal setting for carrier testing is through primary health care providers. Community-based screening programs provide an alternative setting. At present. newborn screening primarily to detect carriers is inappropriate as are screening programs direct ed at children below reproductive age.
Education of the lay community and health care providers concerning the disease, its genetic transmission, and carrier testing is an important goal. Both traditional and innovative methods should be used for community education. Education regarding carrier testing for cystic fibrosis could have a major effect on the level of genetic knowledge in the population.
In addition to obtaining informed consent, providers of carrier screening must ensure the availability of appropriate genetic counseling. Those with a negative carrier test should require minimal counseling but should be reminded of the limitations of the test. Those identified as carriers should be informed of the personal and family implications of their status. Group and individual counseling services should be available. After specialized training, physicians, nurses, social workers and other health care personnel could provide much of this counseling service. A range of teaching devices to be shared with family members should be developed and evaluated as an adjunct to counseling.
Couples found to have a one-in-four risk require comprehensive individual genetic counseling by a qualified professional. This counseling should be non-directive and should help the couple to make reproductive decisions consonant with their own beliefs. Educational materials that present a range of views and options should be developed.
Pilot programs investigating research questions in the delivery of population-based screening for cystic fibrosis carriers are urgently needed. These programs should address clearly defined questions, including the effectiveness of educational materials, the level of utilization of screening, laboratory aspects, counseling issues, costs, and the beneficial and deleterious effects of screening. One important issue is to determine the effect on couples who are at increased risk because only one partner has an identified cystic fibrosis mutation. Pilot programs should examine alternative models of delivery that could be generalized. Federal funds are critically needed to carry out these programs.
The development of carrier-screening programs for cystic fibrosis should not detract from the current scientific efforts to improve the treatment of this disease. Currently, about 30,000 Americans have cystic fibrosis, and additional children with the disease are born every day. The ability to identify couples at risk will continue to be important even if more successful treatments are developed.
Members of the workshop were as follows: Cochairmen Arthur L. Beaudet, M.D., Baylor College of Medicine, and Haig H. Kazazian, Jr., M.D., Johns Hopkins University: Panel Members James E. Bowman M.D., University of Chicago: Aravinda Chakravarti, Ph.D., University of Pittsburgh; Francis S. Collins. M.D., Ph.D., Universitv of Michigan; Jessica C. Davis, M.D., Cornell Medical Center; Pamela B. Davis M.D., Ph.D., Case Western Reserve University; Robert J. Desnick, M.D., Ph.D., Mount Sinai Medical Center; Sherman Elias, M.D., Universitv of Tennessee, Memphis; Norman Fost, M.D., M.P.H., University of Wisconsin; Neil A. Holtzman. M.D., M.P.H., Johns Hopkins University; Michael Kaback, M.D., Universitv of California, San Diego; Katherine Klinger, Ph.D., Integrated Genetics; Philip R. Reilly, M.D., Shriver Center, Waltham, Mass.: Beryl Rosenstein, M.D., Johns Hopkins University: Peter T. Rowley, M.D., University of Rochester; Elizabeth M. Short, M.D., Amencan Society for Human Genetics, Ann C.M. Smith, M.A., Children's Hospital. Denver; James R. Sorenson, Ph.D., University of North Carolina; Lap-Chee Tsui. Ph.D., Hospital for Sick Children, Toronto; and Robert Williamson, Ph.D., St. Mary's Hospital, London; Staff coordinator Nancy Lamontagne, Ph.D., National Insutute of Diabetes and Digestive and Kidney Diseases; and Cosponsors National Center tor Human Genome Research, National Center for Nursing Research. National Heart, Lung, and Blood Institute, National Institute Of Child Health and Human Development. National Institute of Diabetes and Digestive and Kidney Diseases, and Office of Medical Applications Of Research.