Routine Genetic Testing May Impact Patient Outcomes, Survival

April 28, 2021 - Many cardiomyopathies in children are the result of genetic mutations, making a strong case for routine genetic testing to improve patient outcomes, according to a study published in the Journal of the American Heart Association.

The study, led by researchers at the University of Buffalo (UB), revealed wide variations in genetic testing, with some institutions conducting routine screening and others conducting none.

Pediatric cardiomyopathy is a genetically heterogeneous disease with significant morbidity and mortality. While current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, practice variations exist.

Researchers conducted the study at 14 centers and included 152 children with cardiomyopathy. The team found that only half had undergone genetic testing. Of those who hadn’t undergone genetic testing, 21 percent were found to have a genetic cause for the disease after undergoing genetic testing as part of the study.

"Even in families without a family history of cardiomyopathy, we found that many children with cardiomyopathy have a genetic cause that we can establish," said Steven E. Lipshultz, MD, the study's senior author and principal investigator and A. Conger Goodyear Professor and Chair of the Department of Pediatrics in the Jacobs School of Medicine and Biomedical Sciences at UB.

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For the study, researchers performed whole exome sequencing on a large number of children with cardiomyopathy. Whole exome sequencing is a more comprehensive way to identify gene mutations, the group stated.

"With whole exome sequencing, a much broader range of pathologic mutations are able to be identified, and novel new mutations that may be associated with cardiomyopathy can be identified," Lipshultz said.

The results have significant implications for treating and potentially curing this sometimes-fatal disease, the group noted.

"We had assumed that many of the life-threatening cardiomyopathies in children resulted from genetic mutations," said Lipshultz. "This research confirms that assumption. When we know the cause, we can more effectively treat, and in some cases even cure, these children with therapies targeted to the specific mutation causing their disease."

With routine genetic testing, providers could deliver crucial, possibly life-saving information to children and their families.

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"Since some mutations are associated with rapidly progressive fatal outcomes, genetic screening could allow children with these mutations to be identified and prioritized for a lifesaving cardiac transplant," said Lipshultz.

Knowing which mutation is involved in a patient’s disease can also make a major difference in the type of treatment prescribed, as well as the outcome. The UB team has published research showing that children whose cardiomyopathy results from certain mutations that cause heart failure will deteriorate and even die if treated with therapies commonly prescribed for heart failure.

"This is because those therapies push the child's genetically impaired mitochondria to work harder," said Lipshultz.

"This, tragically, can hasten the demise of these children. But by knowing that these types of mutations are present, alternative therapies that preserve and protect mitochondrial function can be employed. This is one of many examples where knowing the genetic cause of cardiomyopathy could make the difference between the life or death of a child."

Researchers were also able to identify novel gene mutations associated with cardiomyopathy.

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While the study was conducted at major children’s hospitals with renowned cardiomyopathy programs, the team found that only some of them used genetic screening as a routine part of care delivery.

In the US, a minority of children and their families with cardiomyopathy have the opportunity to undergo genetic screening. Researchers expect that the results of this study may begin to change that.

However, leveraging the potential of routine genetic testing for cardiomyopathy will require centers to have certain resources in place – and most children with the disease are not receiving care in specialized centers.

"One hurdle is having cardiologists and geneticists interested in ordering these genetic tests and then counseling the families about the results," said Lipshultz. "The testing for the most common gene mutations associated with cardiomyopathy can be done pretty much anywhere, since laboratory companies provide the kits for collected patient samples."

The study’s findings support existing guidelines for pediatric cardiomyopathy, but these recommendations are not widely followed.

"Our results show that with routine clinical judgment, a high percentage of children with genetic causes for their cardiomyopathy are missed. If you don't look, you don't know," Lipshultz said.

The results also offer additional evidence for cardiac surveillance, where all immediate family members of a child with cardiomyopathy and an associated gene mutation are screened to find out if they also have the same mutation and cardiomyopathy.

With gene therapies increasingly emerging as viable methods of treatment, genetically screening these patients is only becoming more important.