Researchers have discovered a gene critical to heart development and learned that mutations lead to isolated congenital heart defects, according to a study published on the Nature website that will appears in a future print issue.

The gene, GATA4, is only the second that has been identified as a cause of congenital heart disease not associated with medically identified syndromes. The researchers identified mutations in the gene GATA4 as a cause of cardiac septal defects.

“In terms of identifying genetic etiologies, there are not many discoveries that have been made,” said Vidu Garg, MD, study lead author. “This is one of the genes responsible, and we are working to identify others.”

Deepak Srivastava, MD, senior author, said that the discovery may enable doctors in the future to prevent or repair some congenital heart defects before birth: “We cannot change the fact that parents are going to pass along the mutation, but we might be able to develop a way to keep the disease from occurring.”

In the current study, researchers examined an American and a Japanese family affected by congenital heart defects. The American family pedigree spanned 5 generations and included 16 affected members, and the Japanese family pedigree spanned 4 generations, including 8 affected members.

Genomic DNA from white blood cells was used for analysis, and researchers studied medical records of deceased family members. Linkage analysis showed that GATA4 mutations were present in all family members with heart disease but not in unaffected family members or in 3,000 unrelated healthy people.

The gene may be responsible for defects through its interaction with TBX5, a protein that causes a subset of syndromic cardiac septal defects. An investigator found that when a single amino acid of the GATA4 protein was altered in the American family, it prevented that protein from interacting with the TBX5 protein, suggesting that the 2 proteins interact in some way to divide the developing heart into 4 chambers.

Srivastava said the next step is to determine the prevalence of GATA4 mutations in the general population of children with heart defects and to use that information to devise approaches to prevention. Eventually, broad screenings of individuals with congenital heart defects may help in preconception counseling, Garg said. The risk of an affected child if either parent has a GATA4 mutation is 50 percent. In general, the risk for an infant with congenital heart disease is about 1 percent, increasing to 5 percent for parents who already have a baby with congenital heart disease.