Cause of common heart valve defect revealed in genetic study

Publishing in Nature Communications, a team of researchers from KTH Royal Institute of Technology and Karolinska Institutet identified nearly 30 times more potential genes linked to BAV than previously known. The aortic valve has three cusps (thin flaps of tissue) that open and close to control blood flow. A bicuspid aortic valve is a valve with only two cusps.

The study offers a clearer picture of how heart valves form, says Pelin Sahlén, an associate professor at KTH Royal Institute of Technology whose former student Artemy Zhigulev led the study as his PhD project.

“These findings expand our understanding of the genetic complexity of BAV and raise hope for new ways to improve how genetic risk is assessed,” Sahlén says. 

People born with BAV often go on to develop complications, such as a narrowing of the valve or enlargement of the aorta. More than half will undergo surgery at some point in their lives.

But the underlying causes have long remained unclear. Earlier research showed a small number of cases are caused by changes in genes that contain the instructions for making proteins — the molecules that carry out most of the work in a cell. This explained only about 10 percent of all cases, says the study’s c0-author Hanna Björck, associate professor at Karolinska Institutet. 

“Most patients had no known genetic cause,” she says.

The new study shifted attention to a different part of the DNA — the regulatory regions of the genome that act like switches, turning important genes on or off during early development. The researchers studied tissues close to heart valves from eight people with BAV and eight people with normal valves. 

Rather than focus on genes themselves, Sahlén says they used a technique called HiCap, for targeted 3D genome mapping to examine how the DNA is arranged inside the cell and how regulatory regions connect to key developmental genes.

They found that rare mutations in the regulatory parts of DNA are likely to play a major role in causing BAV. Each patient in the study had different mutations, but many of these mutations disrupted the same important genes that shape the aortic valve in the fetus, Zhigulev says. 

“This suggests that even though the mutations vary, they interfere with the same developmental processes,” he says.

One of the surprising discoveries is that adult tissues retain traces of what went wrong during fetal development, Sahlén says. Harmful changes that happened before birth can be detected decades later. The finding indicates adult tissue samples can be used to study problems that originally occurred in the early stages of life.