Researchers at the Yale School of Medicine may be one leap closer to reducing heart disease in children.
A recent study by Yale cardiology researchers has found a number of genes that can be used to diagnose and treat children who have a birth defect called heterotaxy, which causes the heart to be severely malformed. Their findings, published Jan. 31 in the scientific serial Proceedings of the National Academy of Sciences Early Edition, suggest that certain genes which affect human embryonic development can cause abnormalities leading to congenital heart disease. But experts interviewed said they think that more research needs to be done to determine how the study’s results can be used to provide better care for sick patients.
“This study is a big step towards understanding what causes congenital heart disease and hopefully will give us some idea of which genes lead to better or worse outcomes,” said Mustafa Khohka, assistant professor of pediatrics and genetics and a co-author of the paper. “We also hope to improve our understanding of the genes that affect left-right [axis] development and the mechanisms involved in determining your left side from your right side.”
The research showed that patients with heterotaxy have considerably more alterations of DNA that have been deleted or duplicated on certain chromosomes, called copy number variations. These variations are found in about 5 percent of the genome in most individuals, said Khalid Fakhro, another co-author of the study, but these do not have any significant effects.
In patients with heterodoxy, however, the body cannot properly place the organs on the left or right sides, which causes problems because normal human hearts sit on the left side of our bodies, Fakhro said. The left and right side of the heart also perform very different functions — the right side pumps blood to lungs while the left pumps blood to the body — so its correct placement is particularly important, he said.
“We leveraged the latest techniques in genetics to analyze a large number of unrelated patients,” Fakhro said. “We found that the burden of [copy number variations] in patients with heterodoxy was two times greater than in control patients, which was a strong indicator that some of these would be causative in disease.”
By examining the number of genetic copy variations in frogs, Khokha said, the scientists were able to identify genes that cause left-right axis mutations. Frogs make a good model for studying heterotoxy in human embryos, he explained, because the left-right axis develops similarly in both.
Nearly one percent of all newborns develop congenital heart disease, and most patients need surgery to survive, Fakhro said. But even with a procedure, Fakhro added, outcomes are poor and patients require constant medical supervision over the years.
“Congenital heart disease is very broad and complicated,” he said. “This research may not affect the quality of life of the patients studied, but it adds a significant amount to our understanding of the disease.”
Other heart disease experts said the research’s focus on five specific genes was unique, but added that the findings may not benefit children with heterotoxy for some time.
“Patients with heterotaxy defects include some of the most severely affected individuals we see,” said Dr. Anne M. Murphy, professor of pediatric cardiology at Johns Hopkins University. “While discovery of the root causes of the disorder will not immediately translate into better care, there are already emerging examples in our field where understanding the molecular pathways of disease affecting the heart could offer new therapies.”
The team’s research has opened doors to future study on the genetics of congenital heart disease.
The researchers were recently awarded a grant by the National Institutes of Health which will fund their studies for the next five years, Fakhro said. The group plans to identify more patients with congenital heart disease and the mutations that have caused it, he added.
“Without this research, Yale would not have won that grant,” he said. “Now, we have a strong foot in the door of understanding the genetics of congenital heart disease, and unlocking the major players in terms of genes and pathways affecting human cardiac development.”
The National Institutes of Health is a part of the U.S. Department of Health and Human Services and is the nation’s official medical research agency.