Scientists have identified the crucial genetic mutations that cause a common heart condition called dilated cardiomyopathy (DCM), paving the way for more accurate diagnosis and screening of high-risk patients.
In a study of more than 5,000 people, researchers sequenced the gene encoding the muscle protein titin, known to be linked to this leading cause of inherited heart failure, to try to find which variations in it caused problems.
"These results give us a detailed understanding of the molecular basis for dilated cardiomyopathy," said Stuart Cook, a professor at Imperial College London who led the study. "We can use this information to screen patients' relatives to identify those at risk of developing the disease, and help them to manage their condition early."
DCM is thought to affect about 1 in 250 people. It causes the heart muscle to become thin and weak and often leads to heart failure.
Mutations in the titin gene that make the protein shorter are the most common cause of DCM, accounting for about a quarter of cases. But truncations in the gene are very common — about 1 in 50 people has one — and most of them are not harmful, making it difficult to develop an accurate genetic test.
For their study, published Wednesday in the journal Science Translational Medicine, Cook's team sequenced the titin gene from 5,267 people, including healthy volunteers and patients with DCM, and analyzed levels of titin in samples of heart tissue. Their results showed that mutations that cause DCM occur at the far end of the gene sequence, while mutations in healthy people tend to be in parts of the gene that aren't included in the final protein, allowing titin to remain functional.
"This study defines ... a comprehensive list of mutations in the titin gene, which of these are associated with dilated cardiomyopathy and which are harmless,'' said Jeremy Pearson, associate medical director at the British Heart Foundation charity, which contributed funding to the research. He said this information would prove "extremely valuable" for future diagnosis and treatment "as we enter an era when many people's genes will be sequenced."
The findings could also help researchers develop therapies to prevent or treat heart disease caused by titin mutations.