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‘Titin’ gene mutations will help identify patients at risk of heart failure

15 January 2015


Researchers from Royal Brompton & Harefield NHS Foundation Trust and Imperial College London have identified genetic mutations that cause the heart condition, dilated cardiomyopathy (DCM), paving the way for more accurate diagnosis.

Titin gene mutations were previously associated with DCM, a leading cause of inherited heart failure. Around one in 250 people are estimated to have DCM. It causes the heart muscle to become thin and weak, often leading to heart failure. By sequencing the gene encoding the muscle protein, titin, scientists have worked out which variations are linked to disease, providing information that will help screen high-risk patients. For many people, variations in the genetic code are completely harmless and do not damage the heart.

The new study, published in Science Translational Medicine, sorts the harmful from the harmless mutations, giving doctors a comprehensive list to interpret patients’ DNA sequences. Researchers are hopeful that this information could also help them develop therapies to prevent or treat heart disease caused by titin mutations.

Mutations in the titin gene that make the protein shorter, or truncated, are the most common cause of DCM, accounting for about a quarter of cases. But truncations in the gene are common – around one in 50 people have one – and most are not harmful, making it difficult to develop a useful genetic test.

The researchers sequenced the titin gene from 5,267 people, including healthy volunteers and patients with DCM, and analysed the levels of titin in samples of heart tissue. The results showed that mutations causing DCM occur at the far end of the gene sequence. Mutations in healthy individuals tend to occur in parts of the gene that are not included in the final protein, allowing titin to remain functional.

Professor Stuart Cook, from the Medical Research Council (MRC) Clinical Sciences Centre at Imperial College London, who led the study, said: “These results give us a detailed understanding of the molecular basis for dilated cardiomyopathy. 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.”

Professor Dudley Pennell, director of the NIHR Royal Brompton Cardiovascular Biomedical Research Unit, said: “This research reveals which genetic mutations are bad and which are there purely as bystanders. It will benefit patients with cardiomyopathy and enable us to reassure relatives who do not have the disease, allowing them to be discharged from clinic and preventing needless anxiety and unnecessary expensive tests.”

The research was funded by the MRC, the British Heart Foundation, Fondation Leducq, the Wellcome Trust, the National Institute for Health Research (NIHR) Royal Brompton Cardiovascular Biomedical Research Unit and the NIHR Imperial Biomedical Research Centre.

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