Although the gene mutation responsible for causing HCM is inherited at the time of conception, it may take decades before there is clinical evidence of impaired heart function. The clinical spectrum of HCM ranges from asymptomatic individuals to those with exercise intolerance, chest pain, or disabling symptoms of heart failure.

Christine Seidman's interest in heart disease emerged early in her career. After graduating from medical school in 1978, she spent roughly a decade in medical and research fellowships at Johns Hopkins and Harvard, specializing in internal medicine. She became intrigued by the research and clinical implications of the heart's unique biology. For example, she says, the cells of the mature heart don't divide, as cells in other tissues do. In another quirk, the heart can be caused to change shape by a diversity of disorders, from HCM to hypertension to coronary artery disease. But the change actually occurs in only two ways—hypertrophy, in which the heart walls thicken, or dilation, whereby the heart's volume increases. Either change limits the heart's blood-pumping ability, threatening to stop it completely. "Here you have a variety of pathogenic stimuli, and they all activate one of these two pathways to disease," Seidman says. If we could prevent these changes from occurring, she adds, "we could really help patients."

Christine Seidman established her lab at Harvard Medical School about 20 years ago, and began recruiting families with a history of cardiac hypertrophy or dilation for research studies. The lab homed in on HCM, painstakingly mapping disease genes to specific chromosomes and then fingering the genes themselves.

Working together and with colleagues, the Seidmans have linked HCM to mutations in structural proteins—such as the cardiac B myosin heavy chain and cardiac myosin binding protein C—found in heart muscle cells. These proteins help form the sarcomere, the pumping part of heart muscle cells. When mutated, the proteins apparently short-circuit the cells' normal flow of calcium that is needed to regulate cellular activity. As a result, the muscle cells grow unchecked, swelling into dramatically thickened heart walls.

Among individuals carrying an HCM mutation, however, it's impossible to know just when—or if—a heart actually will become hypertrophic. "You're born with an HCM mutation, but its clinical signs could take years to evolve," Christine Seidman says. Yet on the positive side, she notes, "we have a huge window to intervene. That's why I'm keen on gene-based testing."

The Seidmans developed a test, based on direct DNA sequencing, that screens a patient's blood sample for mutations of the genes most commonly implicated in HCM. Made available to the public last year, the test is offered in two panels. The first, HCM-A, includes the five most common genes for HCM. Among patients with existing clinical symptoms, HCM-A offers a roughly 50 to 60 percent detection rate of a pathogenic mutation. The second panel, HCM-B, targets three other genes, adding another 5 to 10 percent to the detection rate of a pathogenic mutation. When both panels are analyzed, a disease-causing mutation is identified in 55 to 70 percent of individuals. The detection rate is highest among families in which clinical diagnosis is well established.

After developing the test, the Seidmans transferred the technology to the nonprofit Harvard Medical School—Partners Healthcare Center for Genetics and Genomics. The center's laboratory of molecular medicine actually performs the test, as one of many genetic tests—including a different test for unexplained cardiac hypertrophy—available to the public. (The Seidmans do not receive any profit from these tests.) But the center has a broader mission: to incorporate genetics and genomics into clinical medicine. To that end, the center maintains a computer database with the medical records, including HCM test results, of patients in the Partners Healthcare system, which includes Massachusetts General and Brigham and Women's hospitals.

Tapping this database, participating cardiologists can easily weave a patient's HCM diagnosis into his or her clinical care. Ultimately, the center's goal is to learn whether genetic test results improve that care. "Many labs provide genetic testing, but we're different because we're also interested in incorporating the knowledge of genetics and genomics into the practice of clinical medicine," explains Raju Kucherlapati, scientific director of the center and a geneticist at Harvard. "This same attitude is what makes Christine's work special. She not only discovers genes, but also understands patients and clinical outcomes. So she's in a good position to assess how genetic tests for cardiovascular conditions can change the practice of medicine."

Photo: Getty Images

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