Study Leads to Improved Diagnosis of Inherited Heart Muscle Disease

In a groundbreaking study of Mendelian gene pathogenicity, using comparative population genetics, researchers have developed more accurate diagnostics for inherited cardiomyopathy. The approach improves interpretation of the medical significance of gene mutations in patients being tested for a genetic condition.

In the study, experts from the University of Oxford (Oxford, England, UK) and Royal Brompton Hospitale (London, UK) compared genetic data from nearly 8,000 patients who have cardiomyopathy (CM) with over 60,000 reference samples from the general population. The aim was to reassess the role that variants in different genes play in causing the condition.

The large CM patient data set was from the Oxford Molecular Genetics Laboratory and the Laboratory of Molecular Medicine, Partners HealthCare (Boston, USA) and was compared with a large general population data set from ExAC, a new database compiled by an international consortium led by the MacArthur Lab (USA).

Rare variants in genes that are typically associated with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVCM), were examined. The study found that rare variants in some of these genes were not more common among the CM 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.

Only 8 of 48 genes previously implicated in DCM, and 2/3 of genes that are regularly screened for HCM, were found to be much more common among the CM patients, thus more likely to be disease-causing genes. As a result, a more targeted approach can be taken with increased confidence to provide a CM 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.

CMs are the most common cause of sudden death in otherwise healthy young people. Since the condition can be genetic, relatives of CM patients often undergo heart tests. Those found to have no symptoms but have the same gene variant as their family member can be monitored and treated, often before the condition can be detected by currently used tests. Also currently, if genetic testing was inconclusive for a patient, immediate relatives usually receive life-long follow-up care.

Lead author Roddy Walsh, NIHR Royal Brompton Cardiovascular Biomedical Research Unit, said: “This study has major implications for other diseases with strong genetic components as researchers can apply the same techniques to other studies using the ExAC database. The huge reference data set gives us an unprecedented understanding of gene variation in a normal population, while the large collection of data from CM patients has allowed us to make new insights into the disease.”

BHF Professor Hugh Watkins, head of Radcliffe Department of Medicine, University of Oxford (UK), said: “These results will help diagnostic laboratories avoid testing genes that can't be interpreted reliably, and be more confident in interpreting variants in the genes that we have shown to be valid.”

Professor Stuart Cook, SingHealth Duke-NUS Academic Medical Centre in Singapore, and director of genetics, Royal Brompton & Harefield NHS Foundation Trust, said: “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.”

The study, by Walsh R et al, was published online August 17, 2016, in the journal Genetics in Medicine.

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