When 2 rights make a wrong: Combating childhood heart disease

When the body can't distinguish its right side from its left during development, a child can develop a condition called heterotaxy in which the heart is severely malformed, leading to congenital heart disease. To improve survival in these children, researchers at Yale School of Medicine sought to identify the genes that cause heterotaxy. They have shown in a new study that patients with heterotaxy have considerably more copy number variations (CNVs) on their genomes than do control patients.

The findings are published January 31 in Proceedings of the National Academy of Sciences (PNAS) Early Edition. Mustafa Khokha, M.D., assistant professor of pediatrics and genetics at Yale, and co-authors studied over 200 patients with heterotaxy as well as a large number of control subjects. They identified and analyzed genome-wide CNVs in humans and then tested these genes in a frog model called Xenopus tropicalis. Copy number variations are insertions or deletions of regions of the genome, so parts of the genome might be deleted or a region might be duplicated.

Khohka said that the frog is a good model for testing genes identified from patients with heterotaxy because the developmental program to establish the left-right axis is nearly identical in frogs compared to humans.

"Five of the seven genes we identified in heterotaxy patients also cause left-right axis abnormalities in frogs when CNV genes were reduced," said Khohka. "Therefore, we have shown that children with heterotaxy have a higher burden of CNVs that also cause abnormalities in frogs."

Khokha explained that while humans may appear symmetric across our right and left sides externally, internally our organs are not symmetric. For example, our heart sits on the left side of our body along with the stomach and spleen. Our liver sits on the right. Also, the left and right side of the heart perform very different functions; the right side pumps blood to lungs while the left pumps blood to the body. In children with heterotaxy, because the body cannot properly place the organs on the left or right sides, the heart in particular is severely malformed and can lead to severe disease. In fact, about 90 percent of these children have complex congenital heart disease, which requires surgery to reconstruct their hearts for the child to survive.

Heterotaxy syndrome is a rare birth defect that involves the heart and other organs. The beginning of the word (hetero-) means “different” and the end (–taxy) means “arrangement.”

In heterotaxy syndrome, paired organs, such as the lungs or kidneys, are often mirror images of one another instead of having the unique characteristics of right and left that are normally present.

There are different forms of heterotaxy. All usually involve heart defects, of varying type and severity. In addition, organs such as the stomach, intestines, liver and lungs may be in abnormal places in the chest and abdomen. The intestines may have malrotation, which is when the loops of bowel are lined up incorrectly. With this problem the bowel can twist on itself (volvulus), so many children with malrotation need abdominal surgery to correct it. Some children with heterotaxy can have a very serious condition of the liver called biliary atresia. This also may require surgical intervention. There may also be irregularities with the skeleton, central nervous system and urinary tract.