Researchers tested more than 5,200 people to tease apart when mutations really are harmful or are just bystanders. The work could help in screening families prone to heart failure but also has broader implications as more people undergo genetic tests that can turn up unnecessarily worrying results.
Heart failure, when the heart cannot pump blood properly, is caused by a variety of conditions, including damage from heart attacks. But one trigger is dilated cardiomyopathy, a condition that makes the heart's muscle walls stretch out of shape, becoming progressively weaker. It can run in families, but often there's no obvious cause.
Titin is a protein that gives muscle tissue, including heart muscle, its elasticity. In 2012, researchers reported that gene mutations that make that protein shorter, or truncated, were a common cause of dilated cardiomyopathy, accounting for a quarter of cases. The problem: A lot of healthy people also harbour mutations in that stretchy muscle protein, yet some gene tests already look for the glitches.
So a British-led research team mapped the titin-producing gene in 5,267 people, ranging from the healthy to the seriously ill. Where the DNA glitches are located in this huge gene is key, the team reported Wednesday in the journal Science Translational Medicine.
Mutations that caused dilated cardiomyopathy are located at one end of the gene sequence, while mutations in healthy people occur in other spots apparently less important for heart muscle, they reported.
Another discovery: Titin-caused cardiomyopathy is more severe than other forms of the disease, said lead researcher Angharad Roberts of Imperial College London. Those patients are more likely to suffer life-threatening irregular heartbeats, suggesting doctors might use genetic testing to guide therapy including when to implant defibrillators.
Somehow, this truncated protein is poisoning heart muscle cells, the researchers concluded.
When cardiomyopathy runs in the family, close relatives get regular heart screening to see whether they're developing it, too. The researchers said finding which kind of mutation family members harbour could help narrow who's really at risk — but it would take more in-depth genetic testing than is routine today.
"In an era where genetic testing and genome sequencing is increasingly available, more and more titin mutations will be identified, often as incidental findings," Roberts said. "Accurate interpretation of these results is vital to avoid unnecessary follow-up and anxiety."
While the findings are intriguing, the role of gene testing in this heart condition will take much more research to prove, cautioned Dr. Donna Arnett, a former American Heart Association president who wasn't part of the new study.
The broader context is that scientists must examine how subtle factors can affect the impact of mutations, said Dr. Christine Seidman of Harvard Medical School, a senior author of the study.
"We generally think the DNA provides us the answer: There's a mutation, it's a yes or a no," she explained. But the new finding "really changes the way in which we consider gene-based diagnostics."