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Cardiac genetic mutation may not always predict heart disease

July 02, 2019

PHILADELPHIA - More than 750,000 people in the United States have dilated cardiomyopathy, a potentially life-threatening condition in which the heart's main pumping chamber, the left ventricle, enlarges and grows increasingly weak. Research has shown that one in 10 people with this condition were born with a mutation in the TTN (titin) gene, but - until now - it has been unclear whether everyone with these mutations will inevitably develop dilated cardiomyopathy. In a new study published today in Circulation, researchers at Penn Medicine and Geisinger reviewed gene sequences of more than 70,000 people, and found that 95 percent of patients who had the genetic mutations did not have heart disease or signs of cardiac decline. However, they did find subtle differences in the hearts ability to pump efficiently, compared to those without the mutation.

"It's clear that these gene mutations have a real effect on one's heart, and yet, there are a lot of people carrying the deleterious mutations right now who are fine," said the study's corresponding author Zoltan Arany, MD, PhD, a professor of Cardiovascular Medicine in the Perelman School of Medicine at the University of Pennsylvania. "While our study moves us one step closer to being able to predict, based on one's genes, who will get this disease, there is still a difference between these two populations that we don't yet understand. The next step will be to identify the specific variable causing some of these patients to get heart disease."

The TTN gene, which codes the body's largest protein, acts as a spring inside the heart muscle and helps limit how much it can be stretched. Mutations in this gene - which affect about 1 percent of the global population - are commonly found in people with dilated cardiomyopathy, when cardiologists order a genetic test to determine if the disease stems from a genetic variant.

In this study, researchers sought to reverse the process, and determine if pinpointing the mutations could predict whether people carrying the faulty genes would develop the disease. To do so, researchers reviewed the exome sequence data of 61,040 from the Geisinger MyCode Community Health Initiative and 10,273 from the Penn Medicine BioBank to identify individuals with the gene mutations. From there, they examined corresponding information, including diagnoses, imaging and test results - available via linked electronic health records - to determine whether the patients had heart disease or showed signs of declined cardiac function.

Researchers found that patients with cardiomyopathy who have the mutations fare worse, even on treatment, than patients with the condition who don't have a mutation. The finding, researchers say, underscores the value of ordering a genetic test for patients who have been diagnosed with cardiomyopathy. That said, Arany cautions against patients who don't have heart disease undergoing genetic tests for titin variants.

"For now, I would not recommend people get genetic testing for the titin variants because that will just make them anxious for something that's highly unlikely," Arany said. "That may change, for example, if we were to find that the combination of a TTN gene mutation and a mutation in another gene causes people to get the disease, then we'd recommend genetic testing for both of the variants. But right now we still don't know enough."
-end-
This work was supported, in part, by grants from the National Institutes of Health (HL126797 and R01HL141901), the U.S. Department of Veterans Affairs (IK1-CX001780) and the U.S. Department of Defense (PR171741).

Additional Penn authors on the study include Scott Damrauer, Michael G. Levin, David Birtwell, Renae Judy, Rachel Kember, Lusha Liang, Chris McDermott-Roe, Apoorva Babu, Michael Morley, Aeron Small, Heather Williams, Kenneth Margulies, Thomas Cappola, Anurag Verma, Xinyuang Zhang, Marylyn Ritchie and Daniel Rader.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $425 million awarded in the 2018 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center--which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report--Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation's first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Home Care and Hospice Services, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 40,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2018, Penn Medicine provided more than $525 million to benefit our community.

University of Pennsylvania School of Medicine

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