Increased genetic testing required to identify concealed cardiomyopathy

Genetic testing shows that concealed cardiomyopathy is an important cause of sudden cardiac death where no cause is found from autopsy, according to researchers from the Centenary Institute, Sydney University.

Dr Julia Isbister and colleagues at the institute performed genetic testing in  91 inconclusive autopsy cases where there was sudden cardiac death with no premorbid cardiac diagnosis.

They found that disease-causing variants in arrhythmogenic cardiomyopathy-associated genes were a common cause of concealed cardiomyopathy, and identification of these variants could alter management of surviving relatives.

In the study, the rate of concealed cardiomyopathy was found to be 15%; with higher rates (23%) in those with subdiagnostic histological alterations to the heart.

In 22% of cases a disease-causing gene linked to sudden cardiac death could be identified. Of these, 70% were clinically actionable gene variants associated with cardiomyopathy, the study investigators said in their paper published in the Journal of American College of Cardiology (link here).

Overall, 20 disease-causing gene variants were identified among the autopsy-inconclusive sudden death cases, in which the mean age of subjects was 25 years. Six of the 20 disease-causing variants identified were in genes implicated in arrhythmogenic cardiomyopathy.

When cascade testing and clinical assessment were offered to 47 first degree relatives of the deceased, 20 (43%) were positive for the familial variant, and two thirds of these genotype-positive patients had an observable phenotype. The remaining 27 genotype-negative first-degree relatives were released from follow-up.

Dr Julia Isbister said wider use of genetic testing for cardiomyopathy and inherited arrhythmia syndrome-associated genes in people with cases of unexplained sudden care death would increase diagnosis and provide closure for families.

Currently, genetic testing guidelines only recommend genetic testing for cardiomyopathy genes when physical signs of cardiomyopathy can be seen during the autopsy examination, she noted.

“The problem with this approach is that the deadly [arrhythmias] in these conditions can occur before changes to the heart muscle that would be detected at autopsy.”

“We believe that the genetic testing of sudden cardiac death cases which are unexplained after autopsy should be broader so that we can identify concealed cardiomyopathy. Identifying the cause of death also helps us provide optimal care for surviving relatives,” said Dr Isbister.

“Where a genetic cardiac condition is identified, family screening and targeted management of at-risk relatives can be undertaken to prevent further tragedy in the family, while unaffected family members can be reassured that they are not at risk and released from follow-up.”

Study co-author Professor Christopher Semsarian, Head of the Centenary Institute’s Agnes Ginges Centre for Molecular Cardiology and cardiologist at Royal Prince Alfred Hospital, Sydney, said the results showed the importance of genetic testing for surviving family members.

“Our research highlights the wide spectrum of genes implicated in autopsy-inconclusive sudden cardiac death and the importance of identifying concealed cardiomyopathy for the ongoing care of sudden cardiac death families,” he said.

“Sudden cardiac death is a tragedy but increased genetic testing can provide certainty and closure as to why the death occurred as well as guide us in taking appropriate next steps in looking after family members with the same genetic issues.”

An accompanying editorial said the results supported wider use of “molecular autopsy” for identifying occult cardiomyopathies and preventing sudden cardiac death in family members.

“By demonstrating a comparable yield between cardiomyopathy and channelopathy genes and presenting the results of cascade screening, the authors present a compelling argument for prioritising cardiomyopathy gene testing at the same level as channelopathy gene testing into current guidelines for the assessment of sudden cardiac death,” it concluded.

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