Fatty liver disease has been climbing steadily as a global health concern, with its more severe form now positioned to become the leading driver of cirrhosis and liver transplants worldwide. Against that backdrop, a new genetic finding from Mayo Clinic reframes how the disease can originate in certain patients.
Researchers at Mayo Clinic’s Center for Individualized Medicine have identified a rare mutation in the MET gene that can directly cause metabolic dysfunction-associated steatotic liver disease — previously known as nonalcoholic fatty liver disease. The findings appear in Hepatology. Until now, the condition was understood to develop from a combination of genetic susceptibility and lifestyle or environmental factors. According to the announcement, this study shows that in some cases a single inherited mutation can play a central role in triggering the disease on its own.
The MET gene governs liver repair and how the body processes fat. When it malfunctions, fat accumulates inside liver cells. That buildup drives inflammation, which can progress to fibrosis and scarring. In advanced stages, the condition can become cirrhosis — potentially causing permanent liver damage or liver cancer.
A Family Case Opens the Door
The discovery began with two patients: a woman and her father, both diagnosed with the disease’s more severe form, metabolic dysfunction-associated steatohepatitis. Neither had diabetes or elevated cholesterol, the two most common risk factors linked to fat accumulation in the liver. That absence prompted researchers to conduct an extensive genomic analysis spanning more than 20,000 genes.
They found a single swapped chemical letter within the MET gene DNA sequence — enough to disrupt the liver’s ability to process fat correctly. The variant had never appeared in scientific literature or public genetic databases before. Working with scientists from the Medical College of Wisconsin’s John & Linda Mellowes Center for Genomic Sciences and Precision Medicine, led by Raul Urrutia, M.D., the team confirmed the mutation interfered with a critical biological process.
“This study demonstrates that rare diseases are not rare but often hidden in the large pool of complex disorders,” Dr. Urrutia says, “underscoring the immense power of individualized medicine in identifying them, and enabling the design of advanced diagnostics and targeted therapies.”
Scale: What the Tapestry Data Shows
To test whether this mutation appears more broadly, researchers turned to Mayo Clinic’s Tapestry study — a large exome sequencing initiative that has examined germline DNA from more than 100,000 participants across the United States. Analysis of nearly 4,000 participants in that dataset identified similar rare variants in the MET gene, suggesting the mutation may be quietly contributing to the disease in far more people than the initial family case implied.
The condition already affects roughly one-third of adults worldwide. Lead author Filippo Pinto e Vairo, M.D., Ph.D., medical director of the Program for Rare and Undiagnosed Diseases at Mayo Clinic’s Center for Individualized Medicine, says the findings “open a window into how rare inherited genetic variants can drive common diseases” and point toward “potential therapeutic targets for future research.”
The research team states the next step is using these findings to inform the design of advanced diagnostics and targeted therapies.
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