Researchers Discover Heart Defect Gene Mutation

Discovery could eventually lead to better prevention or treatment

(HealthDay is the new name for HealthScoutNews.)

MONDAY, July 7, 2003 (HealthDayNews) -- Researchers have identified another gene that plays a role in the development of congenital heart defects.

The gene, known as GATA4, is only the second gene that's been identified as a possible cause of congenital heart defects, one of the most common birth defects in the United States.

"This gene is in a class of master regulators. It turns other genes on or off," says study author Dr. Deepak Srivastava, an associate professor of pediatrics and molecular biology at the University of Texas Southwestern in Dallas. A mutation in this gene affects its function, says Srivastava, which prevents GATA4 from turning on other genes that are responsible for tasks such as forming a baby's heart walls early in pregnancy.

The result is a congenital heart defect, often literally a hole in the heart or a problem with the heart's valves. Slightly less than 1 percent of American babies, or about 35,000 annually, have a congenital heart defect, according to the American Heart Association. Congenital heart defects remain the leading birth defect-related cause of death in infants, according to the March of Dimes.

Results of the study appear in the July 6 issue of Nature.

To locate a mutation in GATA4, the researchers examined two large families with a strong history of congenital heart defects. The first family was from Dallas and included five generations. Sixteen members of that family were born with congenital heart defects. The researchers performed a test known as a linkage scan that looks for differences in the genes of those who are affected by a disorder and those who are not.

All of the family members with heart defects had a mutation in GATA4, while the healthy family members did not.

To confirm their findings, the researchers collaborated with Japanese researchers who had discovered a family spanning four generations with eight members with congenital heart defects. The results were the same as they were in the Dallas family.

Using data from the Dallas group, the researchers found the GATA4 mutation interfered with the gene's ability to interact with another gene responsible for early heart formation, TBX5, pointing to a possible cause for the heart defect.

Knowing the cause may eventually lead to therapies for prevention in much the same way that folic acid has helped reduce neural tube defects, another class of birth defects, says Srivastava.

"The most immediate application is for families that have the mutation," he says. "We can provide very accurate genetic counseling and can test for the mutation. If the parents have the mutation, the risk of passing it on is 50 percent. If they don't have the mutation, the risk is zero percent."

Two pediatric cardiology experts, Dr. Bruce Gelb from Mt. Sinai School of Medicine in New York City and Dr. Michael Artman from New York University School of Medicine, are both excited by the study's findings, but caution that any practical applications from this work are likely years away.

"This is the first time that anybody has shown that mutations in GATA4 can cause congenital heart defects. This is an important new finding," says Artman, who is the director of pediatric cardiology. But, he adds this is a basic science study: "We're still a long way from screening for genetic cardiac defects or applying that knowledge to treat heart disease."

"The open question is, while this was true for these rare families, how often would you see this mutation in children who have a congenital heart defect when no one else in their family does?" asks Gelb.

That, according to Srivastava, is one of the next steps in the research, along with trying to come up with an animal model that could be used for testing possible preventive therapies.

Even if a genetic screening test does become available, Gelb points out it's not the type of screening that would cause prospective parents to decide not to conceive, because these types of defects are easy to correct. Fixing a hole in the heart no longer requires open surgery; it's done through catheterization now.

More information

To learn more about congenital heart defects, go to the American Heart Association or the March of Dimes.

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