Study Finds Gene Behind Inherited Cases of Enlarged Heart

Mutation in TTN gene affects ability of heart muscle fibers to work properly, researchers say

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Wednesday, February 15, 2012

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WEDNESDAY, Feb. 15 (HealthDay News) -- Researchers have discovered a defective gene that's responsible for more than one-quarter of cases of inherited dilated cardiomyopathy, a serious heart muscle disease that often leads to heart failure by middle age.
In the study, published in the Feb. 16 issue of the New England Journal of Medicine, researchers analyzed the DNA of 312 people with dilated cardiomyopathy, 231 people with another form of heart muscle disease (called hypertrophic cardiomyopathy) and 249 people with healthy hearts.
The study patients with dilated cardiomyopathy had no obvious cause for their disease -- such as alcoholism, heart attacks and other infections -- so the researchers believed there was a genetic origin for the disease in these patients.
About 27 percent of the dilated cardiomyopathy patients had mutations on the TTN gene that shortened the length of the gene.
Only 1 percent of the patients with the other form of cardiomyopathy and 3 percent of patients with healthy hearts had similar mutations, the investigators found.
Further analysis of family members' DNA revealed that up to half of the dilated cardiomyopathy patients had first-degree relatives (including parents and siblings) who also had the TTN mutation by age 40, and of those, nearly all (95 percent) had some sign of heart disease, said study co-leader Jonathan Seidman, a professor of genetics at Harvard Medical School.
Seidman's wife, Dr. Christine Seidman, a professor of genetics and a cardiologist at Harvard, was the other study co-leader.
The researchers also estimate that about 20 percent of sporadic cases of the disease, that is, dilated cardiomyopathy that isn't passed down from parents, involve a TTN mutation.
In dilated cardiomyopathy, the chambers of the heart become enlarged, the walls thin and the ability of the heart to pump is impaired. When the heart can't squeeze properly, it can't circulate enough blood, leading to heart failure and landing many people on heart transplant lists.
Prior research has found genetic causes for dilated cardiomyopathy, but collectively those genes account for only about one-fifth of cases, Seidman said.
TTN is a very large gene, which made it difficult to analyze until recently, Seidman explained. The protein that TTN makes contains 30,000 amino acids, while the average protein contains about 1,000 amino acids. Only with the advent of next-generation gene sequencing -- which allows for more genetic data to be analyzed more quickly and for less money -- did it become possible to effectively analyze TTN, he said.
In people with a shortened TTN gene, the protein that's produced causes problems with the filaments inside the muscle fibers that allow the heart to contract.
The few people with healthy hearts who had a similar mutation and didn't have the disease had the shortening on a different location of the gene.
"Not only do they [the people with dilated cardiomyopathy] have the shortened mutation, it has to occur in just the right place," Seidman said.
The analysis also found that men with the TTN mutation are affected more severely than women. "We don't know why," Seidman said, noting that for other causes of heart failure, men also tend to get sicker younger and more severely than women.
To develop dilated cardiomyopathy, children have to inherit just one copy of the mutated TTN gene from a parent, the researchers noted.
Dr. Gordon Tomaselli, president of the American Heart Association and chief of cardiology at Johns Hopkins Medicine in Baltimore, said the study is important for both researchers and patients.
"Of the cases that are inherited [dilated cardiomyopathy], it looks like a substantial proportion are due to mutations in the TTN gene," Tomaselli said.
Currently, genetic tests are available that screen for the other known causes of cardiomyopathy. Soon, possibly within months, expect to see TTN testing added to genetic panels, Tomaselli said.
Although there is no cure for dilated cardiomyopathy, patients who know early on that they are susceptible can take steps to keep their hearts healthier longer, he noted. That may include taking certain heart failure medications, maintaining blood pressure control and other lifestyle changes.
An estimated one-third to one-half of dilated cardiomyopathy cases have a genetic cause, Tomaselli added. The others have an environmental trigger, such as drug or alcohol abuse or infections. For those patients, TTN would likely not play a role in the disease.

SOURCES: Jonathan Seidman, Ph.D., professor, genetics, Harvard Medical School, Boston; Gordon Tomaselli, M.D., president, American Heart Association, and chief, cardiology, Johns Hopkins Medicine, Baltimore; Feb. 16, 2012, New England Journal of Medicine

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