Until recently, patients and doctors relied on well-established family histories of heart problems as a predictor—and not always an accurate one—of risk. If you knew your paternal grandfather had died suddenly from an undiagnosed heart condition, or your father went through life with a fluttering heartbeat that a cardiologist would call an arrhythmia, there were few things you could do to protect yourself. You could eat healthy and stay active. Or opt to have your heart function checked every few years with an echocardiogram. The options were pretty much limited to "watch and wait."
But, as researchers learn more about genetic mutations linked to heart disease, patients with extensive family histories of heart problems may now have another option: genetic sequencing.
"Until recently, we didn't have the technology to connect genes to specific heart diseases," says Arya Mani, MD, founding director of Yale Medicine's Cardiovascular Genetics Program. "Now we have identified many genes associated with one disease."
Genetic sequencing gives patients a chance to learn if they have a genetic mutation that is strongly associated with a heart condition, such as hypertrophic cardiomyopathy. That's one of the more commonly inherited diseases related to the heart muscle. A patient who knows that she has a genetic mutation may benefit from early, and potentially life-saving, treatment, rather than going through unnecessary tests and the psychological stress of the unknown.
Many genes have been identified for inherited rhythm and heart muscle disorders. At the same time, in the still-burgeoning field of cardiovascular genetics, it's sometimes difficult to link a single mutated gene with a cardiovascular disease, unlike the case of, for example, cystic fibrosis (CF). In 1989, researchers discovered that CF is caused by mutations in the CFTR gene. If a child inherits a CF mutation from both parents, he is guaranteed to have the disease. Widespread prenatal screening for CF began in the early 2000s and has been routine ever since.
Still early in the game
Genetic sequencing for cardiovascular diseases (CVDs) in adults could reap enormous benefits. CVDs remain the top cause of death for men and women globally, and include everything from stroke to coronary artery disease to irregular heartbeats. They arise from a constellation of risk factors: smoking, blood pressure, family history, age, gender, physical activity, or diet.
Even before the Human Genome Project—which sought to map every gene in the human body—wrapped up in 2003, former Yale geneticist Richard Lifton, MD, PhD, now president of Rockefeller University in New York, was using genetic tools to study the causes of high blood pressure. As genetic sequencing technology rapidly advanced, a new kind of genetic test became readily available: whole exome sequencing (WES). Unlike whole genome sequencing, the WES method detects only protein-coding genes, which make up less than 2 percent of the human genome. But researchers estimate the exome contains about 85 percent of disease-related mutations.
Dr. Mani, who previously worked as a postdoctoral researcher in Dr. Lifton’s lab, decided in 2010 to put WES technology to clinical use. He founded the Cardiovascular Genetics Program, the first in the country to use WES to directly treat patients.
When he began, Dr. Lifton and his colleague, Allen Bale, MD, a clinical geneticist at Yale Medicine, helped him by sharing use of what were then a small number of sequencing machines on Yale’s campus. The program sequenced only a handful of patient exomes in the first few years. Now, Dr. Mani says, his team sequences an average of 250 patient exomes each year.
One of those patients is William.
A father who suffered from heart trouble
William, whose name has been changed for privacy, knew as an adult that he could have inherited the same mysterious heart condition his father, a Korean war veteran, endured. "My dad would have to sleep sitting up in a recliner at night," William says. "They tested him for all kinds of things, but at the time they didn't know what was causing him trouble."
Almost two years ago, Lawrence Young, MD, William's cardiologist at Yale Medicine, who also treated his father, recommended that William join a cardiovascular genetics study. "When I first met Bill, I thought his diagnosis would be familial, non-ischemic cardiomyopathy," Dr. Young says. Cardiomyopathy refers to any acquired or inherited heart muscle disease and "non-ischemic" means not caused by blocked arteries or heart attacks. In the meantime, Dr. Young diagnosed William with ventricular tachycardia, a condition that originates in the heart's ventricles and results in occasional bouts of extremely fast heart beats. (William has an implantable cardioverter defribillator [ICD] in his chest that sends electric shocks if his heart begins to beat too fast.)
"I referred Bill to the genetics study here because I felt that even if it didn't reveal a genetic mutation that was currently known to be definitively disease-causing, we would have his information to revisit in the future," Dr. Young says.
The researchers found that William had two genetic mutations that were considered "of uncertain significance," according to genetic databases and past research at that time. Now, just over a year later, after Dr. Mani's study and additional research, it appears likely these two mutations led to William's arrhythmia problems and cardiomyopathy. "We are learning that single mutations may lead to subtle disease, but, in combination with other mutations, they can cause profound disease," he says. As part of the study, William's children have the option to also have their exome sequenced. They will be able to find out if they have no mutations, one mutated gene, or both, which could lead to a profound disease like their father’s.
"It's a relief. I'm happy that I know the results and that my kids can know theirs, too," William says. "I want my children to get an early heads-up on it if they can," he says. The research team also alerted William's brothers and sisters to the genetic results, in case they want to take further action.
Meanwhile, Dr. Mani and his colleagues have continued to make progress on identifying genetic mutations that can be directly linked to cardiovascular diseases. The team has published data on five genes, and is studying 20 others.
"As we get more sophisticated in understanding the heart's biology, we can target disease mechanisms directly," Dr. Young says. The role that genetic sequencing plays in diagnosing and treating familial heart disease will only increase, he adds.
And may someday make "watching and waiting" a thing of the past.