New Mutations Linked to Inherited Heart Condition Uncovered

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Human heart with bronchial tree, illustration

A study carried out at the University of Oxford has uncovered 12 regions of the genome that have significant levels of mutation in people with hypertrophic cardiomyopathy, a common, inherited heart condition.

The researchers used their findings to create a genetic risk score based on 27 different single nucleotide polymorphisms (SNPs), which was able to accurately predict cases of hypertrophic cardiomyopathy across three independent cohorts comprising more than 40,000 people.

Hypertrophic cardiomyopathy causes unexplained thickening of the heart muscle, which can cause circulation and electrical conduction problems. It impacts about 1 in 500 people and is a common cause of sudden cardiac death in undiagnosed individuals, for example, after endurance events such as marathons.

It is known to be a genetic condition, often inherited in an autosomal dominant manner. However, there is considerable variability of inheritance and symptoms, which can make diagnosis and predictions about future prognosis difficult. It can be hard to understand why some individuals with the condition have few symptoms and some die young as a result.

As described in the journal Nature Genetics,  Hugh Watkins, M.D., Radcliffe Professor of Medicine and Director of the British Heart Foundation Centre of Research Excellence, University of Oxford, and colleagues initially carried out a genome-wide association study of 2780 cases of the cardiac condition and 47,486 controls. They identified 12 specific areas in the genomes of those with hypertrophic cardiomyopathy that were particularly susceptible to mutation.

The team found 27 SNPs that were all significantly associated with risk for hypertrophic cardiomyopathy and its associated symptoms, but to differing degrees. They created a ‘weighted’ genetic risk score to take these differences into account and assess an individual’s risk of having hypertrophic cardiomyopathy and also evaluate the severity of symptoms they were likely to experience.

The genetic risk score was validated in three independent cohorts in the Netherlands including 1769 cases and 39,828 controls. Those with the lowest score (bottom fifth of the group) had half the risk for hypertrophic cardiomyopathy and those with the highest score (top fifth) more than double the risk compared with the 60% of the group in the middle of the scoring range.

The researchers also found that patients with sarcomeric hypertrophic cardiomyopathy, which is caused by myofilament gene mutations and inherited in an autosomal dominant fashion, tended to have more severe symptoms if they also had specific risk score variants.

Notably risk for sarcomere-negative hypertrophic cardiomyopathy, which tends to be more polygenic in origin than the sarcomeric variant, diastolic blood pressure was linked to increased disease risk. A 1 standard deviation increase in blood pressure was linked with an almost fourfold increase in risk for hypertrophic cardiomyopathy.

“We now have a new genetic tool that we believe will better predict which members of affected families will have a bad form of the disease, identifying those who need early intervention,” says Watkins.

“It will also take away the worry for many families as it enables us to identify those who are unlikely to pass faulty genes onto their children. This will reduce the need for unnecessary genetic testing and regular follow-ups.”

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