If the biotechnology company called Myriad Genetics has its way, thousands of healthy women in the U.S. will hear doubly bad news. First, a close relativeperhaps a sisterwill announce that she has breast cancer. Second, the patient’s physician thinks this particular cancer has probably been caused by a mutation that the healthy relative has an even chance of also carrying. This patient has been advised to suggest to all her female relatives that they be tested for the mutation. How likely? Hard to saythe mutation has not yet been thoroughly studiedbut the likelihood could be as much as 85 percent.

The oncoming tidal wave of genetic data has not yet affected most people. That will change. Workers are now routinely isolating genetic mutations associated with such widespread illnesses as cancer, Alzheimer’s disease and some types of cardiovascular disease. Devising tests for mutations in a known gene has become a comparatively straightforward matter. Genzyme, a biotechnology company in Cambridge, Mass., announced in 1995 a diagnostic technology that can simultaneously analyze DNA from 500 patients for the presence of 106 different mutations on seven genes.

When enough is known about the effects of mutations, test results can be a medical boon: they can indicate how likely a person is to develop illnesses and perhaps suggest life-enhancing medical surveillance or therapy. But learning about the effects of mutations requires lengthy study. And genetic data can cause immediate and life-sapping harm. In particular, it can precipitate detrimental psychological changes, and it can open the door to discrimination.

In the past, genetic discrimination has been largely confined to members of families afflicted with rare conditions showing a clear pattern of inheritance. For example, members of families with Huntington’s disease, a fatal neurodegenerative disorder that develops in middle age, have long found it difficult or impossible to obtain health insurance. So far a few hundred of people who are at risk of future illness because of their genetic makeup are known to have lost jobs or insurance, Collins states. Most suffered because a family member had been diagnosed with a condition long known to have a genetic basis. But as the number of genetic tests grows, Francis S. Collins predicts, “we are going to see it happen on a larger scale, since we’re all at risk for something.”

What’s Your Genotype?

Testing for cancer-associated mutations, for example, is at present carried out only in research studies at large medical centers, because interpreting the results is fraught with uncertainty. But some grim facts are clear. In families with hereditary breast cancerwhich accounts for less than 10 percent of all casesmutations in the BRCA1 gene confer an 85 percent lifetime risk of the disease, as well as a 45 percent chance of ovarian cancer. Some women in such families who have learned that they carry a mutated BRCA1 have elected to undergo a prophylactic mastectomy and ophorectomy (removal of the ovaries)a procedure that may reduce but does not eliminate the risk of cancer.

More uncertainty arises, however, with women who have a mutated BRCA1 gene but do not have a family history of breast cancer. For them, the danger is uncertain, but it may be smaller. Nor is it known whether the danger is different for members of different ethnic groups (although Ashkenazi Jews are more likely than others to carry one specific mutation in BRCA1, and a gene that can cause neurobromatosis has more severe effects in whites than in blacks). These and other uncertainties pose an agonizing treatment dilemma. The choice between radical surgery and intensive surveillancein the form of frequent mammogramsmight be crucial. The identification of a second breast cancer gene, BRCA2, complicates matters even more.

Although further advances in understanding the genome might conceivably one day eliminate such dilemmas, most scientists do not expect them to evaporate in the foreseeable future. For a woman who has already been diagnosed with breast cancer, the significance of a positive BRCA1 test for treatment is murky. And even with a negative test result, a woman still faces the same one-in-eight lifetime risk that all women in the U.S. do. These factors have led the American Society of Human Genetics and the National Breast Cancer Coalition, an advocacy group, to urge that for now, testing for BRCA1 mutations be carried out only in a research setting. “We will fight any sale of this test before there is consensus on how it should be used,” says coalition member Mary Jo Ellis Kahn, a breast cancer survivor with a family history of the disease.

Some women who know that they carry a mutated BRCA1 gene have gone to elaborate lengths to conceal that information from their insurance carriers, says Barbara B. Biesecker of the NCHGR. One fear is that insurers will classify the mutations as a preexisting condition and so refuse to cover treatments related to the condition. That concern is hardly irrational: health insurance companies often decline to cover policies, or offer inflated premiums, to individuals who have a significant family history of cancer. The National Breast Cancer Coalition was rejected several times for health insurance for its Washington, D.C., staff of eight, because the staff includes some breast cancer survivors. To find coverage, it had to join a larger organization.

The trend toward secrecy in genetic testing seems to be catching on. At a meeting in 1995 of the American Society of Human Genetics, Thomas H. Murray of Case Western Reserve University asked his audience whether they knew of patients who had requested testing for a genetic trait anonymously or under a false name. Hands shot up all over the room. In many clinical studies, patients are now formally warned that test results could lead to insurance complications if they get into the patient’s medical records. Researchers sometimes obtain special legal documents called “certificates of confidentiality” that prevent the courts from gaining access to data gathered for a study.

Keep a Secret?

Other patients are simply avoiding taking genetic tests, thus forgoing whatever medical benefit they might bring. People with vonHippelLindau (VHL) disease, a rare hereditary condition that can cause brain and kidney tumors, often find it hard to obtain health insurance because of the expensive surgeries they might need. Although no prophylactic therapy can prevent the tumors, people with VHL disease can extend their lives by undergoing regular magnetic resonance imaging scans followed by surgical removal of tumors. According to William C. Dickson, research management chair of the VHL Family Alliance, many parents with the syndrome avoid having their children tested for mutations in the recently discovered gene for VHL because they fear that a genetic diagnosis will make their offspring uninsurable.

Parents with polycystic kidney disease, which may be the most common simply inherited, life-threatening condition, also frequently decide for insurance-related reasons not to subject their children to testing, reports Gregory G. Germino, an investigator at the Johns Hopkins University School of Medicine. Approximately 600,000 Americans have the illnessmany unknowingly. A gene causing many cases, PKD1, was identified in 1994 using technologies developed under the genome project. Testing of PKD1 can sometimes improve medical therapy for a child, Germino says.

Such reports have prompted alarm among health officials. (Collins admits to being passionate on the subject.) A working group on the ethical, legal and social implications of the Homo sapiens genome program, together with the National Action Plan on Breast Cancer, a presidential initiative, recommended that insurance providers be prohibited from using genetic information, or an individual’s request for testing, as a basis for limiting or denying health insurance.

Currently insurers do not usually ask directly for results of genetic tests; inquiries about the health or cause of death of a person’s parents are sufficient to identify many of those at high risk. But insurers may consider genetic data for an individual policy. They don’t ask now about genetic testing, but that will change, says Nancy S. Wexler, president of the Hereditary Disease Foundation, who has herself a 50 percent risk of Huntington’s disease.

Because patients with genetic diseases are often reluctant to identify themselves, gauging the extent of discrimination is difficult. But new data strengthen earlier anecdotal reports suggesting the phenomenon is widespread. In one of the first extensive surveys, Lisa N. Geller of Harvard Medical School and her co-authors describe how they sent questionnaires to people who, though free of any symptoms, are at risk for acquiring a genetically based illness. Of the 917 who responded, a total of 455 asserted that they had been discriminated against after they revealed a genetic diagnosis.

Follow-up interviews by the researchers provided details of health and life insurers who refused or canceled coverage, adoption agencies that required prospective parents to pass a genetic test (but on one occasion misunderstood the results) and employers who fired or refused to hire on the basis of a treatable genetic condition or the mere possibility of one. Paul R. Billings of the Veteran’s Affairs Medical Center in Palo Alto, Calif., one of the study’s authors, declares that the public will reject genetic testing out of fear of discrimination. In a separate study by E. Virginia Lapham of Georgetown University and others, 22 percent of a group of 332 people who had a genetic illness in their families reported having been refused health insurance.

Several European countries have taken steps to prevent abuse of genetic data. Basic medical insurance is not a major concern in Europe, because it is guaranteed by governments. Yet France, Belgium and Norway all have laws preventing the use of genetic information by life and medical insurance companies and by most employers. The Netherlands guarantees basic life insurance, and Germany has some protections. In the U.S. several states have enacted legislation that limits discrimination based on genetic data. Employment discrimination is prohibited by federal law, and several bills now before Congress would discourage or prevent gene-based insurance discrimination nationally. But their prospects are uncertain.

The potential for psychological harm from DNA testing is receiving growing attention. Because a test may have implications for all the members of an extended family, powerful feelings of guilt and sadness can disrupt relationships. Fear of such consequences may explain the unexpectedly low utilization of a test that has been available for some years to identify most carriers of cystic fibrosiswho are not themselves at risk.

Genetic counselors have formed a strong consensus that because of the potential for harm, children should not be tested for mutations predicting diseases that will not develop until adulthood, unless there are possible medical interventions. That principle rules out testing children for Huntington’s, because there is no preventive therapy against developing the rocking motions and mental impairment that characterize the illness. Yet parents do seek testing of their children: in one case, to avoid paying for a college education if the youngster was likely to succumb.

The principal U.S. network of testing laboratories is known as Helix. According to a survey by Dorothy C. Wertz and Philip R. Reilly of the Shriver Center for Mental Retardation in Waltham, Mass., 23 percent of the network’s labs technically capable of checking for the Huntington’s mutation have done so in children younger than 12 years. More than 40 percent of Helix laboratories had performed tests for patients directly, with no physician involved. Yet the public can easily misunderstand the meaning of genetic diagnoses, Wertz notes. Moreover, she says, many physicians are not well enough informed to be giving genetic advice.

On the credit side of the ledger, it is clear that some patients in families afflicted with hereditary colon cancer, and possibly breast cancer, too, have already made wise medical choices as a result of discoveries facilitated by the genome program. Some with a mutation predisposing them to colon cancer, for example, have had their colons removed as soon as threatening changes started to occura procedure that probably saved their lives. Eagerly awaited novel therapies, though, are further in the future.

Collins notes that only six years after a team that he co-led found the gene associated with cystic fibrosis in 1989, drugs developed to counter effects of the mutated gene were already being tested in patients. How soon a definitive treatment will emerge, however, is anyone’s guess.

The treatment prospect that has most gripped the public imagination is gene therapyan approach that would be better described as gene transplantation. But attempts to treat familial hypercholesterolemia, cystic fibrosis and Duchenne’s muscular dystrophy have each resulted in failures over the past year, apparently because patients’ cells did not take up enough of the transplanted genes. The earlier treatment of adenosine deaminase deficiency by W. French Anderson showed at best a modest effect. In December 1995, a NIH review concluded that clinical efficacy has not been definitively demonstrated at this time in any gene therapy protocol.