New clues from genetic research may help explain the cause of the most common heart defects present at birth. Researchers in Sweden have identified a rare DNA change during fetal development that can cause a condition known as bicuspid aortic valve (BAV).
A team of researchers from KTH Royal Institute of Technology and Karolinska Institutet, published in Nature Communications, identified nearly 30 times more genes potentially associated with BAV than previously known genes. The aortic valve has three leaflets (thin flaps of tissue) that open and close to control blood flow. A bicuspid aortic valve is a valve with only two leaflets.
This study provides a clearer picture of how heart valves form, said Perrin Sahlen, associate professor at KTH Royal Institute of Technology. His former student Artemy Zhigulev led the research as a doctoral project.
These findings expand our understanding of the genetic complexity of BAV and raise expectations for new methods to improve how genetic risk is assessed. ”
Perrin Sahlen, Associate Professor, KTH Royal Institute of Technology
People born with BAV often develop complications such as narrowing of the valve and enlargement of the aorta. More than half will have surgery at some point in their lives.
However, the underlying cause remained unknown for a long time. Previous research has shown that a small number of cases are caused by changes in genes that contain instructions for making proteins (the molecules that perform most of the work in cells). Study co-author Hanna Bjork, associate professor at Karolinska Institutet, says this only explains about 10% of all cases.
“Most patients had no known genetic cause,” she says.
The new study has shifted attention to another part of DNA, the regulatory regions of the genome that act like switches, turning important genes on and off early in development. The researchers studied tissue near the heart valves of eight patients with BAV and eight patients with normal valves.
Rather than focusing on the genes themselves, Sahlen said they used a technology called HiCap for targeted 3D genome mapping to examine how DNA is arranged in cells and how regulatory regions connect to important developmental genes.
They found that rare mutations in regulatory parts of DNA may play a major role in the cause of BAV. Although each patient in the study had a different mutation, many of these mutations disrupted the same key gene that forms the fetal aortic valve, Zhigulev said.
“This suggests that even though the mutations are different, they interfere with the same developmental process,” he says.
One surprising discovery, Sahlen says, is that adult tissue retains traces of what happened during fetal development. Adverse changes that occur before birth can be detected decades later. This finding indicates that adult tissue samples can be used to study problems that originally occurred early in life.
sauce:
KTH Royal Institute of Technology
Reference magazines:
Zhigulev, A. others. (2026). A rare regulatory mutation disrupts the mesenchymal molecular program that promotes endocardial cushion formation in the bicuspid aortic valve. Nature Communications. Doi: 10.1038/s41467-026-71758-5. https://www.nature.com/articles/s41467-026-71758-5
