A congenital heart defect is explained by new genetic clues.

The x-ray of the chest of an infant with Fallot's tetralogy, a congenital heart defect.

A deep blue tint in a newborn's skin is the first sign that something's wrong. Blood cells that should be bright red and full of oxygen, creating a baby's typically rosy hue, instead lack oxygen due to a congenital heart defect. Known colloquially as blue baby syndrome, tetralogy of Fallot (TOF) occurs in one in 3,000 live births and accounts for nearly 10 percent of all serious congenital heart defects. Its cause has largely been a mystery, as the parents of babies born with TOF usually show no signs of heart defect. Now, HHMI investigator Christine Seidman of Brigham and Women's Hospital and Harvard Medical School has found a genetic cause for some cases of TOF.

After hitting dead ends when trying to pinpoint specific mutations linked to TOF, Seidman's lab group hypothesized that TOF might have its root in the number of copies of particular genes. This kind of genetic change can lead to incorrect amounts of protein being made by a cell. Down syndrome, one extreme example of a copy number variation, is caused by an entire duplicated chromosome.

Seidman's team searched the genomes of 114 TOF patients and found 11 segments of DNA that were present in too many or too few copies. They then looked at these regions in the DNA of another 398 TOF patients and confirmed that seven of the copy number variations were linked to TOF. The regions did not show incorrect copy number in the unaffected parents of the babies born with TOF, the scientists report in the August issue of Nature Genetics.

The team is now studying those seven regions to explore what particular genes may be implicated in TOF. Seidman also thinks that variation in copy number could be at play in other congenital heart defects, where researchers have been unable to pinpoint specific mutations.

“Our work really reiterates the theme that the dosage of certain genes is vital,” says Seidman.

Photo: Zephyr / Photo Researchers, Inc.