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Cardiomyopathies are a group of conditions that affect the structure of the heart, reducing its ability to pump blood around the body. They cause an increased risk of arrhythmia, heart failure, stroke and sudden death. Cardiomyopathies are the leading cause of sudden death in the young and account for about half of all cardiac transplants. They are among the most common severe genetic diseases, occurring with a prevalence of 1 in 250 across all populations.
Hypertrophic cardiomyopathy (HCM), one of the most prevalent cardiomyopathies, was once considered only a monogenic disorder – a disease caused by a mutation in a single gene – and around a third of cases are due to rare genetic faults in a single gene. In monogenic forms of the disease, different family members could have the same inherited mutation, but can develop different severities of the disease or develop the disease at different ages. This makes it difficult for clinicians to advise affected family members on what to expect. More recently, the research teams involved in this latest work discovered that HCM can also be a polygenic disease whereby multiple so-called 'common genetic variants' can also cause disease. A single common variant will have little impact on an individual's risk of developing HCM, but the combined impact of many variants can significantly increase the chances of developing the disease. It is the combined effect of these multiple genetic variants that be used to predict the risk of the disease in patients.
50 new genetic locations associated with HCM and novel HCM gene identified
In the first paper, researchers conducted analysis that pinpointed 50 new locations in the genome found to be associated with HCM. They also discovered that a gene known as SVIL is relevant to HCM. SVIL encodes a protein called supervillin. Supervillin binds to another protein called actin, which helps cells maintain their shape, move and contract. Researchers found that the presence of an uncommon genetic mutation within the SVIL gene, known as a truncating variant, which significantly impacts the genes function, is associated with roughly a tenfold increased risk of HCM.
Disease prediction could allow for earlier treatment
In the second paper, researchers demonstrated that calculating a polygenic risk score based on an individual's genetic profile could help predict the likelihood of them developing HCM, and also predict important disease complications. The team demonstrated that in patients with a single rare genetic fault, the presence of common variants can also add to their already increased risk of developing HCM.
Professor Hugh Watkins stated: 'Together, these two papers help us understand how common genetic variation causes HCM to develop variably in different family members. We can use this information to predict which affected individuals are likely to develop severe forms of the disease. This could allow us to follow-up with patients more closely or provide earlier treatment, including genetic therapies in the future.'
Findings are fundamental to CureHeart progress
CureHeart is a cutting-edge research project funded by the British Heart Foundation which aims to develop cures for cardiomyopathies using advanced genetic therapies.
'These two latest papers, involving many CureHeart researchers in Oxford and Imperial College London, is fundamental to the work of CureHeart,' adds Professor Hugh Watkins, who leads the project.
'The findings will help to classify patients into risk groups, identifying those most at risk of developing severe disease and hence those most in need of the therapies being developed.'