In a major scientific breakthrough, researchers at Mayo Clinic’s Center for Individualized Medicine have identified a rare genetic mutation that can directly cause a common liver condition—metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease.
This discovery changes what scientists have long believed. Until now, MASLD was thought to be caused by a mix of lifestyle and genetic factors.
But this new study, published in Hepatology, shows that for some people, a single inherited genetic change may be the main cause.
The mutation was found in the MET gene, which plays a key role in liver repair and how the body processes fat.
When this gene doesn’t work properly, fat builds up in the liver, causing inflammation. Over time, this can lead to scarring, known as fibrosis.
In more severe cases, the disease progresses to cirrhosis—serious liver damage that can result in liver failure or cancer.
MASLD affects about one-third of adults worldwide. Its more advanced form, metabolic dysfunction-associated steatohepatitis (MASH), is quickly becoming a leading cause of cirrhosis and liver transplants.
Dr. Filippo Pinto e Vairo, the study’s lead author and medical director of Mayo Clinic’s Program for Rare and Undiagnosed Diseases, explains that this finding gives us a new understanding of how the disease develops and points toward future treatment options. “This discovery opens a window into how rare inherited genetic variants can drive common diseases,” he said.
The research began with the case of a woman and her father who both had MASH but no common risk factors like diabetes or high cholesterol. Looking for answers, scientists studied over 20,000 genes in their DNA and found a single-letter mutation in the MET gene that disrupted fat metabolism in their liver.
To confirm the finding, the Mayo team partnered with the Medical College of Wisconsin. Led by Dr. Raul Urrutia, the team demonstrated how the tiny mutation scrambled the gene’s instructions, leading to a failure in liver fat processing. What’s remarkable is that this specific mutation had never been seen before in scientific databases.
“This study proves that rare diseases can hide in plain sight, buried in the more common health conditions we see every day,” said Dr. Urrutia. “This highlights the power of individualized medicine.”
To learn more about how widespread this problem might be, researchers turned to Mayo Clinic’s Tapestry study, a large-scale effort that has analyzed DNA from more than 100,000 people across the U.S. Among nearly 4,000 adults in the Tapestry study who had MASLD, about 1% had rare variants in the same MET gene.
Of these, 18% had mutations in the exact region as the family initially studied, strongly supporting the gene’s role in causing liver disease.
Dr. Konstantinos Lazaridis, another lead author and director of the Center for Individualized Medicine, emphasized the global significance: “This could potentially affect hundreds of thousands—or even millions—of people who have or are at risk for this liver disease.”
He added that this is one of the first major findings to come out of the Tapestry study and shows how powerful large-scale genetic databases can be when it comes to uncovering hidden causes of disease.
Mayo Clinic has been leading the way in using genomics to solve medical mysteries. Since 2019, its Program for Rare and Undiagnosed Diseases has helped over 3,200 patients and works closely with nearly 300 clinicians across different medical specialties. The goal is to bring precision diagnostics to people with rare or unexplained conditions—including those involving the liver.
Next steps include further research to understand how this genetic discovery can help create targeted treatments. By identifying people with these specific mutations early, doctors may eventually be able to offer more personalized care—and perhaps prevent the disease from progressing.
This finding not only sheds new light on MASLD but also shows how modern genetic tools can uncover hidden layers in common diseases. It’s a step toward a future where we can better treat—and even prevent—serious illnesses through personalized medicine.
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The research findings can be found in Hepatology.
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