Genetic Test Helps Spot Familial Cardiomyopathy

Marlene Busko

October 22, 2013

MONTREAL, QC — By sequencing the whole exome—the part of the genome that codes for protein—researchers found two new mutations on genes related to inherited dilated cardiomyopathy, which will improve the ability to detect people with the disease[1]. Dr Rafik Tadros (Montreal Heart Institute, QC) presented the study here at the Canadian Cardiovascular Congress (CCC) 2013 .

"It's important to identify and appropriately manage other family members who might also have this genetic mutation, which puts them at risk for heart failure [or heart transplant] or sudden cardiac death," he told heartwire .

By using this type of genetic screening—instead of only looking for mutations in five genes known to be related to this disease, as recommended in Canadian guidelines—they greatly improved the ability to detect individuals with dilated cardiomyopathy. They found that mutations in TTN and BAG3 , which were not part of the usual genetic screening, account for a significant proportion of familial dilated cardiomyopathy.

This is important because about one in three patients with cardiomyopathy has the inherited form of the disease, Tadros noted, and individuals with the mutations have a 50% risk of passing the disease on to their children.

Currently, individuals with family members who have cardiomyopathy might be screened by echocardiography, but the disease usually manifests when a person is in their 40s. The other screening method, genetic testing looking for mutations in five genes linked with the disease (LMNA, MYH7, TNNT2, SCN5A, MYBPC3), has a low, 20% detection rate.

The researchers, led by Drs Guillaume Lettre and Mario Talajic (Montreal Heart Institute), hypothesized that whole-exome sequencing would increase the ability to identify family members with inherited dilated cardiomyopathy.

They recruited 26 unrelated families that had two or more family members with dilated cardiomyopathy who were being seen in their cardiovascular genetics clinic: 61 individuals including 49 affected individuals.

Whole-exome sequencing was performed on DNA samples from 42 affected individuals—an equal number of men and women. At baseline, the individuals had an average age of 52 and had had cardiomyopathy for the past eight years. Their average left ventricular end diastolic diameter was 65 mm. Two-thirds had NYHA class 3-4 heart failure.

The genetic tests revealed that five families had expected mutations (in three of the five genes recommended for clinical testing), but the other nine families had mutations in TTN and BAG3. The remaining 11 families are still undergoing tests.

Unlike cystic fibrosis, which can be traced to mutations in one gene, several genes are implicated in dilated cardiomyopathy, but each explains less than 6% of the disease, except TTN,which might explain up to 20% of the cases of dilated cardiomyopathy, Tadros explained. Their work suggests that TTN and BAG3 ought to be sequenced in standard genetic testing for dilated cardiomyopathy in the Canadian population.

"It is a very important study," session chair Dr Dakshina Murthy (Regina Qu'Appelle Health Region, SK) commented. "We are moving toward personalized medicine." A few individuals with rare genotypes who have had a heart attack are resistant to certain medications, and this study is the type of research that will ultimately lead to more tailored care.

By identifying family members at high risk of cardiomyopathy, these patients can be encouraged to adopt healthy behaviors, "so that we don't add environmental factors to genetic predisposition," he said.

The authors have no relevant disclosures.

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