New clues from genetic research may help explain what causes the most common heart defect present at birth. Researchers in Sweden have identified rare changes in DNA during fetal development that can lead to a condition known as bicuspid aortic valve (BAV).
Publishing in Nature Communications, a team of researchers from the KTH Royal Institute of Technology and the Karolinska Institutet identified nearly 30 times more potential BAV-linked genes than previously known. The aortic valve has three cusps (thin flaps of tissue) that open and close to control blood flow. The bicuspid aortic valve is a valve with only two leaflets.
The study offers a clearer picture of how heart valves are formed, says Pelin Sahlén, an associate professor at the KTH Royal Institute of Technology, whose former student Artemy Zhigulev led the study as his doctoral 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.”
Pelin Sahlén, Associate Professor, KTH Royal Institute of Technology
People born with BAV often develop complications, such as 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. Previous research has shown that a small number of cases are caused by changes in the genes that contain the instructions for making proteins – the molecules that do most of the work in a cell. This explains only about 10 percent of all cases, says study author Hanna Björck, associate professor at Karolinska Institutet.
“Most patients had no known genetic cause,” he says.
The new study turned attention to a different part of DNA – the regulatory regions of the genome that act like switches, turning important genes on or off during early development. The researchers studied tissues near heart valves from eight people with BAV and eight people with normal valves.
Instead of focusing on the genes themselves, Sahlén says they used a technique called HiCap, for targeted 3D genome mapping to examine how DNA is arranged within the cell and how regulatory regions are linked to key developmental genes.
They found that rare mutations in regulatory parts of DNA are likely to play an important 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 although 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 embryonic development, Sahlén says. Harmful changes that occurred before birth can be detected decades later. The finding shows that adult tissue samples can be used to study problems that first appeared early in life.
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