The diagnosis of a serious heart condition known as dilated cardiomyopathy often can lead doctors to run genetic tests that help determine whether the disease stems from a faulty gene.
But a group of researchers wondered: What if they reversed the process and first looked for the faulty genes? Could pinpointing those mutations help predict whether the people carrying them would develop cardiomyopathy?
That "genomics first" approach is the premise of a new study that looked at mutations in a gene called titin, which makes the body's largest protein known by the same name. The titin protein acts as a spring inside the heart muscle and helps limit how much it can be stretched out. But its immense size allows for thousands of possible genetic variants.
Flawed titin genes are commonly found in people with dilated cardiomyopathy, which causes the heart's main pumping chamber, the left ventricle, to enlarge and become increasingly weak. About 750,000 people in the United States have the condition, and roughly half of those cases have genetic roots, according to the U.S. National Library of Medicine.
For the new study, researchers tapped into two large Pennsylvania biobanks and examined gene sequence information of 81,000 people. Looking for titin mutations, they examined electronic health records to see whether people with the mutations were more likely to have abnormal hearts.
Their study showed having a titin truncating mutation – a kind of premature stop sign in the gene that results in a shorter protein – puts people at significantly higher risk for developing cardiomyopathy. People with cardiomyopathies are at greater risk for heart failure or irregular heartbeats called arrhythmias than the general public.
But most of the people they pinpointed with titin-variant genes had no record of a heart problem in their medical files, said Dr. Zoltan Arany, lead author of the study published Thursday in the American Heart Association journal Circulation.
"The first thing we learned is that 95% of these people, when you go and look in their electronic health records, have no identifiable cardiac disease. That's pretty striking," he said. "That means that there's a lot of people walking around with these mutations that we think are very deleterious and yet they're fine."
But he said a close look at the echocardiograms, or heart ultrasounds, conducted on these same people did show subtle changes in their heart's ability to pump efficiently.
"That means that having these mutations does actually do something to your heart for real, but for some reason some people end up getting bad disease and some don't," said Arany, a professor at the University of Pennsylvania's Perelman School of Medicine and the director of its cardiovascular metabolism program.
"There's a difference between these two populations that we don't understand," he said. "That's fodder for future studies."
Cardiologist and geneticist Dr. Elizabeth McNally said mutations affect people differently.
"Every one of these mutations is a variable in how it expresses itself from person to person. Sometimes they're really mild, sometimes they're really severe, sometimes they present with sudden death at the age of 20," said McNally, director of the Center for Genetic Medicine at Northwestern University's Feinberg School of Medicine in Chicago.
"You have this huge range of what you see," she said, "yet you know having the gene change, the mutation, is a clear marker for disease risk."
While having a titin mutation doesn't guarantee development of dilated cardiomyopathy, it should encourage doctors and patients to take an assertive and personalized approach in controlling risk factors, said McNally, who was not involved in the new study but frequently treats people with genetic heart diseases.
"If I knew you were at genetic risk of developing this, I'd be all over better blood pressure management," she said.
She'd also keep a more watchful eye on expectant women through their pregnancies, a time that places tremendous stress on the heart and vascular system, and make sure they get appropriate treatment.
Arany said the findings may prompt some people to turn to commercially available DNA tests, but he said those genetic kits are not designed to test for these types of titin gene mutations. That's because home tests look for common variants found in the general population and don't provide full gene sequencing.
"From a scientific point of view, (the study) gets us one step closer to doing what we would love to do, which is to predict who's going to get (cardiomyopathy) or not," he said. "We're not quite there yet, but it moves us closer to the finish line."
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