Editorials

Genetic Testing



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Am Fam Physician. 2000 Feb 15;61(4):950-956.

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In questioning whether we are undergoing a genetic revolution, in the “Medicine and Society” article in this issue,1 Wulfsberg argues that people will not soon be obtaining “genetic profiles” that will predict their risks of future disease, nor he says, will primary care providers use genetic tests to screen for “disorders for which some claim there is compelling therapeutic intervention.”2 “The lack of effective interventions,” Wulfsberg concludes, “and public resistance suggest that genetic technologies will indeed be slow to be adopted into primary care medicine.”

Certainly, primary care providers are not going to be deluged with tests that will indicate increased susceptibilities to a host of different diseases, each of which will call for a different intervention. As Wulfsberg1 points out, “The technical and biologic complexities of genetic diseases has been far greater than expected.” The complexity is actually much greater for gene-influenced, common diseases, usually of adult onset (e.g., cancer, hypertension, bipolar disorder and type 2 diabetes [formerly known as non–insulin-dependent diabetes]) than it is for single-gene (Mendelian) diseases (e.g., cystic fibrosis, hemophilia, Marfan's syndrome and thalassemia).

A few years ago, molecular biologists believed that alleles at a single gene locus would prove to be major determinants of the common, adult-onset disorders; however, it is now thought that alleles at several gene loci, often acting in concert and interacting with environmental factors, must be present before disease appears. Finding contributing loci, however, is extremely difficult.

Once a gene is found, tests for susceptibility alleles at that locus will have low predictive value until several of the other inherited and environmental contributing factors are discovered and tests and other methods are devised to detect their presence. Even when alleles at a single gene locus significantly increase susceptibility (as several BRCA1 and BRCA2 alleles increase the risk of breast cancer), future disease is uncertain. Another problem is that different combinations of genetic and environmental factors contribute to the occurrence of a specific disease; tests that detect only one or a few of these combinations will identify only a small proportion of persons who will develop the disease.

In contrast to the common, complex disorders, extraordinary progress in discovering single-gene (Mendelian) diseases has been made in the past decade. Mendelian disorders are characterized by complete or high penetrance of alleles at single gene loci. When the genotype capable of resulting in disease is present, the disease will almost always appear although its severity may vary.

When tests become available for identifying disease-related alleles, the question then arises, will primary care providers offer them when “lack of intervention”1 is the rule? Clinical laboratories can offer predictive genetic tests without having to demonstrate their clinical validity or utility.3 Thus, without more stringent regulation,4 providers should be skeptical of the promotional materials made available by their developers. Situations do arise when offering genetic testing to a patient is appropriate.

One of the benefits of predictive testing for breast or colon cancer—in persons in whom an affected first-degree relative has been found to have a susceptibility-conferring mutation—is sparing patients with negative results from early, periodic monitoring or prophylactic surgery, and removing the uncertainty of whether or not their risk is increased. In healthy relatives with a positive result, the benefits of early monitoring or prophylaxis have not been fully established.

Therapies are available for a few single-gene disorders but, more often, families who unexpectedly have an affected child and ask, “why us?” can be given an answer based on inheritance. Genetic testing also gives parents the opportunity, through prenatal diagnosis and other strategies, to avoid the conception or birth of another affected child. Not all patients or families will want genetic testing for this purpose. Nevertheless, physicians have an obligation to make their at-risk patients aware of the options.

Wulfsberg1 concludes by predicting that genetics will impact primary care practices “in an evolutionary rather than revolutionary manner.” “Primary care physicians who keep current,” he adds,“by reading the medical literature and attending professional meetings will not be left in the dust.” Although primary care providers will not be flooded with genetic tests, reading and attending professional meetings have not, as innovations have appeared in the past,5 proved effective in altering physician practice, and I doubt they will in the future.

Primary care physicians might be spurred into action more readily by a revolution if every patient was eligible for screening. This is unlikely to happen until the benefits are clearly established and far exceed the risks. Instead, physicians will be challenged to recognize which handful of their patients are likely to benefit from genetic testing and other interventions. Sometimes this will entail eliciting a family history of those common disorders for which predictive genetic testing could be of benefit. Sometimes the patient's ethnic background will suggest increased risk. Occasionally, when confronted with unusual symptoms or signs that are refractory to standard therapy, referral may be indicated. A novel approach to improve physicians' understanding is to make them active partners in clinical trials that assess the safety and effectiveness of genetic tests and therapies.

Genetic discoveries are influencing medical practice in a more subtle but important way than the tests and therapies to which they may ultimately lead. Discovering the marked heterogeneity underlying the same complex of symptoms and signs suggests that seldom is there a prototypal case of any disease.6 The lesson is that patient management must be individualized. Whether, as the pharmaceutical companies hope, this will mean tailoring drugs to genotypes remains to be seen. But understanding what makes our patients unique, including their social environment, is more likely to improve health than the drugs we prescribe.

Neil A. Holtzman, M.D., M.P.H., is professor of pediatrics at the Johns Hopkins University School of Medicine, of Health Policy and Epidemiology at the Johns Hopkins School of Hygiene and Public Health and director of Genetics and Public Policy Studies at the Johns Hopkins Medical Institutions. Dr. Holtzman is actively engaged in research on the policy implications of genetic tests. He was the chair of the NIH-Department of Energy's Task Force on Genetic Testing.

Address correspondence to Neil A. Holtzman, M.D., Johns Hopkins Medical Institutions, 550 N. Broadway, Baltimore, MD 21205-2004.

REFERENCES

1. Wulfsberg EA. The impact of genetic testing on primary care: where's the beef?[Medicine and Society] Am Fam Physician. 2000;61:971–8.

2. Beaudet AL. 1998 ASHG Presidential Address: making genomic medicine a reality. Am J Hum Genet. 1999;64:1–13.

3. Holtzman NA, Watson MS, editors. Promoting safe and effective genetic testing in the United States: final report of the Task Force on Genetic Testing. Baltimore: Johns Hopkins University Press, 1998.

4. Holtzman NA. Are genetic tests adequately regulated? Science. 1999;286:409.

5. Davis DA, Thomson MA, Oxman AD, Haynes RB. Changing physician performance. A systematic review of the effect of continuing medical education strategies. JAMA. 1995;274:700–5.

6. Childs B. Genetic medicine: a logic of disease. Baltimore: John Hopkins University Press, 1999.



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