Genetic testing brings new hopes, hard choices

In 1961, when Michael Downing was just 3, his seemingly healthy father got up in the middle of the night, coughed, and died. He left a wife and nine children. A massive heart attack at age 44, they were told.

In 2003, Downing's seemingly healthy brother, Gerard, the district attorney of Berkshire County, got up one wintry morning, went outside to pick up his newspaper and brush off his car, and fell dead in his driveway. The diagnosis was the same: massive heart attack, this time at 52.

Downing, an author and popular Tufts University writing teacher, did not have to wait for the same thing to happen to him.

A simple blood test based on new gene science enabled him to discover that he carried the same gene defect that probably doomed his father and brother.

The test result did not necessarily mean he would die young from a heart attack - some people with such mutations live to old age. But that genetic knowledge helped to persuade him, though he was in excellent health, to opt for a major intervention: a defibrillator implanted in his chest, to zap his heart back to normal rhythm if it stopped beating properly.

Doctor after doctor "leaned a little forward in their chairs and said the words 'Sudden death' to me," Downing recalled. As in, his first symptom could be his own sudden death.

Downing exemplifies a generation of patients who are beginning to make medical decisions bolstered by new genetic tests that can help determine whether they, personally, carry a family "curse" - mutations that can lead to a history of cancer, heart disease, or other illness. In his case, he carried a gene that causes hypertrophic cardiomyopathy, a dangerous thickening of heart muscle that caused athletes - such as Boston Celtics player Reggie Lewis, Spanish soccer star Antonio Puerta, and major league pitcher Joe Kennedy - to drop dead suddenly.

The heart gene tests allow "predictive medicine and preventative therapy," said Dr. Christine Seidman, a cardiologist and researcher at Harvard Medical School.

The tests' predictive power is not usually perfect, however. A negative test can reassure by ruling out risk of a disease. But a positive test result often cannot definitively predict trouble ahead, it merely means added risk. And the interventions may have significant downsides.

So the choices that patients face may still not be simple.

Downing, for example, has had a series of complications since his 2004 operation, including an infection so virulent he had to have the defibrillator removed and a different one implanted.

At 50, he has gone from a healthy athlete, confident that if he took good care of himself he would be fine, to a lifelong patient who needs regular monitoring and care. Even if his surgery had gone perfectly, the defibrillator would have required regular maintenance and vigilance.

Nonetheless, "this is progress," he said.

Currently, the best-known such decisions stem from knowledge of the BRCA genes that convey vastly higher risks of breast and ovarian cancer. Some women who test positive choose to have their breasts and ovaries removed before cancer can develop, reducing their risk of breast or ovarian cancer by 90-plus percent.

But many less dramatic medical choices like Downing's are on the way, genetics specialists say.

An overweight person whose genes suggest a high risk for diabetes might lean more toward weight-loss surgery. Someone with an identifiable gene for colon cancer might choose to begin colonoscopy screening as a 20-something, rather than at 50, and have every tiny growth removed.

For all the difficult questions it raises, the new genomic knowledge about diseases already represents real progress, specialists say. And, as in the case of hypertrophic cardiomyopathy, it holds out the promise that in the future, gene tests will predict far better who will get a disease, and also help determine which treatments might work best.

In recent years, researchers have found that mutations in any one of 10 genes can cause hypertrophic cardiomyopathy, or HCM. The most common cause of fatal heart failure in people under 40, it kills about 6,000 young people per year in the United States, usually out of the blue, and often on a playing field.

Ideally, all young athletes could be screened for HCM genes and such deaths prevented. As many as 1 million Americans may have one of the potentially dangerous gene variants.

But "at the current price" - about $3,000 - "I don't think anybody is going to do any screening" of the general population for them, said Jon Seidman, who researches HCM at Harvard Medical School.

Rather, he said, the gene tests can help families like Downing's sort out who is really at risk, and better prevent tragedy.

The test is sometimes covered at least partially by insurance, and only the first test in the family is so expensive; subsequent members can be tested for just $250. The test is able to identify a patient's specific mutation, which can help doctors recommend the best treatment.

The implanted defibrillator makes the most sense if a patient has a strong family history of sudden death and signs of thickening heart muscle, Christine Seidman said. For those at lower risk, it may be enough to simply have their heart carefully checked each year. In some cases, patients are advised to give up competitive athletics.

The Seidmans are trying to understand the HCM mutations better. In April, their team reported in the New England Journal of Medicine that the same HCM mutations that endanger adults like Downing, by affecting the muscle filaments that contract and relax their hearts, threaten young children as well.

And in June, other researchers reported in the Mayo Clinic Proceedings that among patients with HCM, those who had the known muscle-filament mutations were at greater risk of sudden death, stroke and heart deterioration, suggesting that they might be particularly good candidates for defibrillators.

Working in both animals and humans, the Seidmans and others are also trying to figure out ways to use drugs to prevent the known HCM genes from actually deforming hearts and causing deaths. Clinical trials of such drugs are already under way at Harvard and elsewhere.

"There's a potential here to save a lot of lives," said Dr. Raju Kucherlapati, director of the Harvard Medical School-Partners Center for Genetics and Genomics.

Downing's decision to get a defibrillator turned him into a patient all too intimately acquainted with the flawed world of modern medicine, a journey he describes in his book in progress, tentatively titled "Heart of my Heart."

But he would absolutely make the same decision again, Downing said. His father's premature death was the defining fact of his childhood, and it awes him that in his own lifetime, such a death has become preventable.

"I'd much rather be given a hard choice than none at all," he said.

Carey Goldberg can be reached at goldberg@globe.com.