New genetic breakthrough will help doctors to more accurately diagnose heart muscle disease patients, and predict the severity of their disease.

Hypertrophic (HCM) and dilated cardiomyopathies (DCM) are heart muscle diseases and are leading causes of sudden death in young people who are otherwise healthy. Despite both conditions having problems with the sarcomere – the part of a muscle cell that makes it contract – these diseases present almost as opposites. Individuals with HCM have a thickened heart muscle, whereas the heart muscle in those with DCM becomes stretched and thin. Both results make it difficult to pump blood around the body, and can result in heart failure and heart rhythm problems.

“Bigger really is better for this approach. The more data we can collect, the more we can find the different regions of the genome that are contributing to risk of cardiomyopathy" Dr James Ware Senior author

One of the big puzzles with these conditions, however, is that after genetic testing, roughly half of those with the condition don’t have any mutations in the genes that help to build the sarcomere. To further add to the mystery, even when you do find a cause, other family members can carry the same genetic mutation, but not all develop disease. Among those family members that do develop disease, some will develop mild symptoms whereas others will suffer from advanced disease. As a result of all of these levels of complexity, it is unsurprising that managing treatment is very difficult and can be very worrying for families who are affected by the conditions.

However, a new genetic breakthrough will help doctors to more accurately diagnose HCM and DCM patients, and predict the severity of their disease. Research led by the Cardiovascular Genomics and Precision Medicine group, in collaboration with teams at the University of Amsterdam, Université de Montréal, University of Oxford and others, has revealed that these heart conditions may not always be single gene disorders as originally thought. Alongside rare mutations that disrupt the sarcomere and contractile machinery, they found that many more common perturbations in the genome act in combination to influence susceptibility to heart disease.

The researchers performed genome-wide association studies (GWAS) to scan the entire genome from many people to look for genetic variants that influence the risk of disease. Data from 1733 patients with HCM from London, the Netherlands, and Montreal was compared to a group of healthy individuals to assess which mutations would contribute to HCM risk. They then compared this with data from 5,521 patients with DCM, and almost 20,000 people from the general population who had their hearts assessed using cardiac MRI scans.

The genetic analysis reveals that a proportion of HCM does not behave like a single gene disorder. The GWAS shows many more locations in the genome that are associated with risk of developing HCM. Interestingly, many of these locations in the genome were involved in both HCM and DCM patients despite the opposing nature of the conditions. This means that there is some fascinating new biology to investigate to unravel more of the mysteries associated with these heart diseases, and that the genes at these locations could prove to be promising new treatment options.

The results of this study could also have a more immediate impact. When someone has HCM due to common variants alone it is much less likely to be passed on to their children, than when it is due to a single mutation in the sarcomere. This will influence whether they need regular clinical check-ups, and will lead to reassurance for many.

The results from this genetic analysis can also be used to calculate diagnostic risk scores which can be used in two ways. The first is with diagnosis. Creating a risk score could be helpful to figure out which family members may or may not develop the disease. The second is to predict disease severity. As these conditions are associated with sudden cardiac death, then any information that can help to predict who might need more advanced treatment is going to be hugely valuable to families.

James Ware, Head of the Cardiovascular Genomic and Precision Medicine group at the LMS and one of the senior authors in this paper, shared more about this research:

“Bigger really is better for this approach. The more data we can collect, the more we can find the different regions of the genome that are contributing to risk of cardiomyopathy. We are already doubling our sample size by pooling our data with other groups to do that. But I feel this is just the beginning for this work on these conditions. We need to explore each of the genomic regions we find linked to these diseases to understand which particular gene is responsible, to understand what that gene is doing, and to consider whether there is a new opportunity to treat cardiomyopathy by modifying that process. Also, we need to further test the value of our new genetic risk scores in the clinic. Our work so far is very promising, but there is still lots to do and understand before they will be a routine part of our assessment in the cardiomyopathy clinic".

‘Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect’ was published on 25 January in Nature Genetics. Read the full article here.

Article written be Dr Sophie Arthur - MRC London Institute of Medical Sciences - first published 12 February 2021 on the MRC LMS news site.