Flaws in the blueprint for the heart’s exquisite tapestry of sarcomere proteins cause most cases of hypertrophic cardiomyopathy in adults. In fact, in the vast majority of these patients, mutations in just two genes—cardiac beta-myosin heavy chain (MYH7) and cardiac myosin-binding protein C (MYBPC3)—account for thickening of the left ventricle, which can lead to pumping problems. HMS researchers have now determined that many children with unexplained cardiac hypertrophy harbor mutations in the same genes.
A team led by Christine Seidman, a Howard Hughes investigator and the Thomas W. Smith professor of medicine at HMS and Brigham and Women’s Hospital, and Jonathan Seidman, the Henrietta B. and Frederick H. Bugher Foundation professor of genetics at HMS, sequenced sarcomere genes in 84 affected children. The results, published online April 9 in The New England Journal of Medicine, provide the first evidence that unexplained cardiac hypertrophy can share common genetic roots, regardless of the age at which symptoms appear.
“Labs have done work on the genetic underpinnings of unexplained cardiac hypertrophy in adults, but few thought that research applied to children,” explained Christine Seidman, who is also a member of the HMS–Partners HealthCare Center for Genetics and Genomics. For years, doctors have assumed the two conditions are clinically distinct.
Younger Patients, Greater RisksAccording to the Seidmans, three to four percent of adults have cardiac hypertrophy, and data from the Framingham Heart Study suggest that mutations in 10 genes account for one fifth to one sixth of those cases. Most of the genes implicated encode sarcomere proteins, the building blocks of the heart’s contractile apparatus.
“Cardiac hypertrophy increases your risk of a variety of negative cardiovascular outcomes, including heart failure and sudden death,” said Jonathan Seidman, who is also a member of the HMS–Partners Center for Genetics and Genomics. “Although the condition is rare in children, the prognosis is even worse than in adults.”
Despite the greater severity of symptoms in children, the team suspected that defective sarcomere proteins might still be to blame. Amy Roberts, HMS assistant professor of pediatrics at Children’s Hospital Boston, and Jeffrey Towbin, professor of pediatric cardiology at Baylor College of Medicine, among other clinicians, located children with unexplained cardiac hypertrophy unrelated to systemic disease to test this hypothesis. Fifty-one of the pediatric patients included in the study had no family history of cardiomyopathy.
The team sequenced the suspect genes, using a novel chip technology developed by molecular geneticist and HMS instructor in pathology at BWH Heidi Rehm and others at the Center for Genetics and Genomics’ Laboratory for Molecular Medicine. The chip was originally designed as a diagnostic tool, efficiently screening for mutations implicated in adult-onset hypertrophic cardiomyopathy. It scans the exons of eight sarcomere genes and two metabolic genes for a fraction of the cost of traditional sequencing technologies. The price of the test has dropped to approximately $3,000 per patient.
“Advances in the chip technology allowed the type of deep sequencing required for this project,” explained Raju Kucherlapati, the Paul C. Cabot professor of genetics and scientific director of the Center for Genetics and Genomics. “Until recently, it just wasn’t affordable.”
As one might have expected, the team identified mutations in 21 of the 33 children with family histories of the disease. But they also found mutations in 25 of the 51 children without family histories.
The researchers took a closer look at the genes of these patients’ parents. Eleven pairs of parents agreed to participate in the study. In seven cases, one parent harbored the same mutation as his or her child. Though these adults assumed their hearts were fine, echocardiograms revealed thickening of the left ventricle in some cases.
“Every child who has isolated cardiomyopathy probably deserves to have this test whether or not there is a family history of cardiomyopathy,” observed Roberts, a pediatric cardiovascular geneticist. “We learned that it’s insufficient to just take a family history and draw a conclusion about the cause of the disease based on that.”
“We still don’t know why the children presented symptoms so much earlier than their parents,” added Jonathan Seidman. “We suspect that other genes must influence the disease presentation.”
Toward a CauseIn addition to finding mutations with a known role in hypertrophic cardiomyopathy, the team identified a number of novel missense mutations in the children. In fact, significantly more MYBPC3 missense mutations were detected than occur in adult-onset cardiomyopathy.
Perhaps this explains why children tend to present with more severe symptoms than adults, said Jonathan Seidman. Unlike nonsense mutations, missense mutations produce defects in proteins by changing a single amino acid in the chain. The cell recognizes and discards proteins with major defects, but these deviants may fly under the radar. Perhaps patients with truncation mutations have built-in coping mechanisms.
Steven Colan, chief of noninvasive cardiology at Children’s Hospital Boston and professor of pediatrics at HMS, who was not involved in the study, cautioned that it would not immediately change how pediatric cardiologists treat patients with unexplained cardiac hypertrophy.
“We need to go back and look at some of the novel mutations identified in this study to determine if they’re truly to blame,” said Colan. “We need to demonstrate causation.” Nonetheless, he said the study is interesting and important. Few data are available on cardiac hypertrophy in children, so the results begin to fill the void.
As Christine Seidman explained, “Rational treatment requires understanding the underlying causes of the disease. Recognizing that sarcomere gene mutations account for hypertrophy in some children is a first step. The next step is to elucidate the signals activated by mutations—knowledge that may help to explain the variable clinical expression of hypertrophy and, as well, to inform new approaches to prevent disease development.”
