For a long time, researchers considered an inherited mutation that causes a severe heart muscle disease to be “typically Dutch.” New international research led by UMC Utrecht now shows that the mutation spread to more than 20 countries across four continents via historical trade routes beginning in the 17th century.
In cardiomyopathy, the heart is less able to pump blood throughout the body. In some people, the disease is caused by an inherited genetic variant, such as a mutation in the PLN gene (p.(Arg14del)). People who carry this mutation have a higher risk of developing severe cardiomyopathy, life-threatening heart rhythm disorders, and heart failure. For many years, researchers believed this mutation was found almost exclusively in the Netherlands. New research, published in the Journal of Cardiovascular Translational Research, now shows that this is not the case.
Professor of Clinical Genetics Peter van Tintelen of UMC Utrecht, together with PhD candidates Esmée van Drie and Freyja van Lint, mapped the global distribution and history of the mutation. They discovered that nearly all carriers—except for one Greek family—share a common ancestor who likely lived between 275 and 425 years ago, during the era of the Dutch East India Company (VOC).
According to the researchers, the mutation spread through Dutch trading networks in Asia. Dutch merchants lived for more than two centuries on the small island of Dejima, isolated from the rest of Japan but permitted to establish families there. Trade connections with countries including Iceland, Norway, Russia, and Spain also helped spread the mutation from the Baltic Sea to the Mediterranean.
Researchers first described this specific mutation in 2006 in a large Greek family. Shortly afterward, they found that the mutation was also relatively common in the northern Netherlands. “That led researchers to believe for many years that this mutation was typically Dutch,” says Peter van Tintelen. “We now know that the same variant is also found in countries including Canada, the United States, Australia, France, Italy, Norway, and Russia. It has now been identified in 21 countries across four continents. So it is no longer just a Dutch mutation.”
The mutation remains most common in the Netherlands, where researchers have identified more than 1,300 carriers. In some regions of the northern Netherlands, an estimated one in every 500 people carries this inherited variant.
The discovery is not only historically significant but also important for patient care. People with the mutation have an increased risk of life-threatening heart rhythm disorders and heart failure, often developing later in life. However, the severity of the disease varies widely between individuals. Researchers therefore want to better understand why some carriers become seriously ill while others experience few or no symptoms.
“By working together internationally, we hope to better predict which patients will benefit from treatments such as an implantable defibrillator or emerging gene therapies,” says Van Tintelen. “This study helps us identify patients around the world and better understand why the disease progresses differently from one person to another.”
Furthermore, recent international guidelines for genetic testing now include the PLN gene. As a result, physicians can identify carriers of this mutation when patients undergo genetic testing for other conditions. This is expected to lead to the identification of many more carriers worldwide.
