DNA analysis of two families affected by significant and early-occurring aortic valve disease identified different mutations in the same gene, NOTCH1, suggesting that it plays a vital role in developmental formation of the valve, according to an article published online by Nature.

The primary family involved in the research had five generations affected by aortic valve disease. American researchers scanned the DNA of 11 members of the family, ranging from children with severe aortic stenosis to 50- and 60-year-olds who had such severe calcification that they required replacement valves. All family members with some manifestation of aortic valve disease had a mutation in NOTCH1.

A second, smaller family affected by valvular disease had members with a second mutation in the same gene, providing convincing evidence that the researchers had found the genetic link to aortic heart disease, said Dr. Vidu Garg, assistant professor of pediatrics and molecular biology and lead author of the study.

“Mutations in NOTCH1 cause an early developmental defect in the aortic valve,” Garg said.

About 1 percent to 2 percent of the world’s population is born with a bicuspid aortic valve. The condition predisposes individuals to aortic valve stenosis, which may require surgery at birth.

The narrowing of the valve can be so severe while the fetus is still developing that blood cannot get out of the ventricle. In those cases, the ventricle does not grow, and the child is born with a condition called hypoplastic left heart syndrome.

“The left ventricle of these children is almost nonexistent, and they are born with one of the most severe types of congenital heart disease, which accounts for a quarter of all children who die from heart disease,” said Dr. Deepak Srivastava, senior author of the paper.

“We know that aortic valve problems cause those deaths, so we think NOTCH1 mutations are likely the cause of some cases of hypoplastic left heart syndrome as well,” said Srivastava.

“Our work suggests that calcification of the aortic valve may be a manifestation of a mutation in NOTCH1 or related genes,” Garg said. “In the long term, we may be able to use that information to screen those at risk, possibly giving patients the opportunity to make a pharmacological or lifestyle intervention to slow down the progression of the calcification. I think that’s where the clinical utility of this research will most likely be.”