Further advances in our understanding of the genetic basis of hypertrophic cardiomyopathy

Two back to back papers, published in Nature Genetics, jointly led by Prof Hugh Watkins (Oxford) and Prof James Ware (Imperial College London), have further advanced our understanding of the genetic basis of hypertrophic cardiomyopathy (HCM).

Hypertrophic cardiomyopathy (HCM), one of the most prevalent cardiomyopathies, was once considered a monogenic disorder and around a third of cases are due to rare genetic faults in a single gene, usually inherited through families. More recently, the teams involved in this current work discovered that HCM is also a polygenic disease where 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 can significantly increase the chances.

In the first of the two papers, Tadros et al conducted analysis that identified 50 novel loci associated with HCM and identified a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin. They demonstrated that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM.

In the second paper, Zheng et al 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. They 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 that “Together, these two papers help us understand how common genetic variation causes HCM to develop variably in different family members and the way we can use that to predict which affected individuals are likely to develop severe forms and so may need closer follow up and earlier treatment, including genetic therapies in the future.”

Professor James Ware said “Our patients and their families want to know what the future holds after a diagnosis of HCM, but it is extremely difficult to advise because it is such a variable condition. The same genetic change can lead to a fatal heart rhythm problem or a need for heart transplantation in some people, while others don’t manifest any problems at all. Thanks to this research, we’re an important step closer to being able to provide much needed clarity and reassurance.”

This work is fundamental to CureHeart as it will help to stratify patients, identifying those most at risk of developing severe disease and hence those most in need of the cures and therapies we are developing.