Study Finds Gene Behind Inherited Cases of Enlarged
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
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
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
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
"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
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
U.S. National Heart, Lung, and Blood Institute has
more on cardiomyopathy.
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