Scientists Hone In On Genetic Culprit in Heart Birth Defects

From the WebMD Archives

Feb. 22, 2001 -- A mutation in at least one gene -- and possibly two -- has been cornered as the probable culprit for a range of heart birth defects generically referred to as DiGeorge syndrome, according to three separate reports in scientific journals.

Jonathan Epstein, MD, co-author of a report in the Feb. 23 edition of Cell, tells WebMD that a mutation in a gene known as Tbx1 appears to account for DiGeorge syndrome, which affects one in every 4,000 children.

The syndrome can involve heart birth defects, head and facial deformities and other problems. "The most common and devastating aspect of the syndrome is heart disease," says Epstein, a cardiologist at the University of Pennsylvania Medical Center in Philadelphia.

Isolation of the same gene was simultaneously reported by other research groups in the journals Nature Genetics and Nature.

All of the researchers used mouse models to isolate the gene, and Epstein says the next step is to replicate the work in humans. "The first major outcome from all of these papers will be to spur the human genetics field to look very hard for mutations in patients," he tells WebMD. "We have to extend these studies to determine how many patients with congenital heart disease have the mutation in Tbx1."

When a test for the gene mutation is developed, it can be used to screen parents who may be carrying it to determine the risks for their children, and in prenatal screening, Epstein says.

Epstein tells WebMD it has been known for some time that DiGeorge syndrome is associated with deletions of large blocks of DNA on chromosome 22. Not known until now is the precise gene in that region responsible for the defect, he says.

The strategy for pinpointing Tbx1 used by the researchers is a remarkable example of genetic detective work. Epstein explains that genes comparable to those on the human chromosome 22 are found in mice on another chromosome -- number 16. By deleting the region on that chromosome believed to be associated with symptoms of DiGeorge syndrome, the researchers were able to breed a line of mice with conditions that mimicked the syndrome.

Next, the scientists replaced the genes in groups of four to determine whether resulting mice offspring would still have the DiGeorge syndrome symptoms. In this way, they were able to hone in on the culprit Tbx1, Epstein explains.

And he notes that Tbx1 is a member of a family of related genes implicated in other heart defects. "The importance of the finding goes beyond [DiGeorge syndrome]," he says.

Knowledge of the genetic component in heart birth defects can aid in understanding how those components work with other factors. "Diet and environment contribute to congenital heart disease, but we need to understand the genes that contribute and how they interact," he says.

As if to complicate matters, another report by researchers at the University of Chicago and Oregon Health Sciences University that appears in the journal Nature Genetics found another gene in the same region of chromosome 22 also implicated in symptoms of DiGeorge syndrome. That finding may reflect some difference between mice and humans, or it could indicate that DiGeorge syndrome requires a mutation in both genes, according to researchers.

However, the isolation of Tbx1 by three independent laboratories lends credence to its important association with DiGeorge syndrome in humans, says pediatric cardiologist Gail D. Pearson, MD, ScD.

"We won't know with certainty what the role of analogous genes in humans is until that human work is done," Pearson tells WebMD. "These findings are exciting and we hope they will shed some light on the gene or genes involved in the human condition."

Pearson is leader of the heart development, function and failure scientific research group in the division of heart and vascular diseases at the National Heart, Lung, and Blood Institute of the National Institutes of Health. The National Heart, Lung, and Blood Institute supported the work by Epstein as well as some others, she says.

Pearson notes that nearly three-fourths of all people with DiGeorge syndrome have "significant cardiovascular disease requiring one or more surgical interventions, in childhood and later on." And she adds that cardiovascular disease associated with the syndrome can be fatal.

She notes that the syndrome can also include problems with the immune system, abnormalities in the urinary tract and genitals, and even behavioral and psychiatric problems. "This seems to be a syndrome that affects a number of organ systems," Pearson tells WebMD. The recent genetic findings may "shed a lot of light on how one or more genetic defects can lead to this complex constellation of problems."

And she echoes Epstein in stating that the Tbx1 gene may hold the key to heart defects beyond DiGeorge syndrome. In particular, the family of genes related to Tbx1 appears to be implicated in Holt-Oram syndrome, which involves a defect in the upper chambers of the heart, Pearson says.