Improved gene test analysis for cardiomyopathy

29th August 2016

A study, led by experts from the University of Oxford and Royal Brompton Hospital, has discovered better ways to interpret the significance of gene mutations in people with cardiomyopathy.

Researchers, including PhD student Kate Thomson and Prof Hugh Watkins, compared genetic data from nearly 8,000 cardiomyopathy patients with more than 60,000 samples from the general population. The aim was to reassess the role that mutations in different genes play in causing the condition.

The cardiomyopathy data, from the Oxford Molecular Genetics Laboratory and the Laboratory of Molecular Medicine, Partners HealthCare in Boston, USA, is the biggest ever analysed. Researchers compared this with a large volume of raw genetic data from the general population, available from a new database known as ExAC, compiled by an international consortium in the USA.

Variants in genes that are typically associated with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), were examined.

The results, published in the journal Genetics in Medicine, found that rare variants in some of these genes were not any more common in the cardiomyopathy patients than the general population. This shows they are unlikely to be valid disease-causing genes and that having rare gene variants is collectively more common than previously thought.

The study found that only eight out of 48 genes previously implicated in DCM, and two thirds of genes that are regularly screened for HCM, were found to be much more common among the cardiomyopathy patients. This means they are more likely to be disease-causing and therefore most relevant for genetic testing. As a result, clinical scientists can take a more targeted approach and have increased confidence to provide a positive diagnosis if one of these gene variants is found. In the past clinical labs may have taken a more conservative approach, meaning that patients might have received an inconclusive result.

Relatives of cardiomyopathy patients often undergo heart tests because the condition can be genetic. Those found to have no symptoms may have a genetic test to confirm they have the same gene variant as their family member, meaning they can be monitored and treated, often before the condition can be detected on conventional tests. Those who do not have the faulty gene can be reassured and avoid long-term follow-up, saving the NHS money. Currently, if genetic testing is inconclusive, relatives usually receive life-long care in case they later develop the condition. It is hoped the new research findings will lead to an increase in the number of conclusive diagnoses.

Researcher Roddy Walsh, from the NIHR Royal Brompton Cardiovascular Biomedical Research Unit, and a lead author of the paper, said: The huge reference data set gives us an unprecedented understanding of gene variation in a normal population, while the large collection of data from cardiomyopathy patients has allowed us to make new insights into the disease.

'Overall, the database has found higher levels of gene variants in the general population than previously thought, but many of these do not cause disease. So it is about knowing what is significant and what isn't, and communicating that to clinicians so they know how best to interpret genetic tests.'

Professor Stuart Cook, director of genetics at Royal Brompton & Harefield NHS Foundation Trust and another senior author, said: “For the first time, we can really look at what is important and what is not. This helps us pinpoint the variants that are causing the disease and identify parts of protein that are hotspots for the mutations. When we can be firmer in our diagnosis we no longer have to carry out follow-up tests for those who don't need it.”

Cardiomyopathy UK support nurse Robert Hall said: “Doctors will be more confident about dismissing some genetic findings and be able to focus more on what gene mutations clearly cause cardiomyopathy.”