Researchers at Mayo Clinic’s Center for Individualized Medicine have identified a rare genetic mutation that can directly cause metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. This groundbreaking discovery challenges the long-held belief that the condition arises solely from a combination of genetic predisposition and environmental factors, showing that a single inherited genetic variant can, in some cases, be the primary driver of disease.
The Role of the MET Gene in Liver Health
The mutation was traced to the MET gene, a crucial regulator of liver repair and fat metabolism. Dysfunction in this gene prevents the liver from processing fat properly, leading to fat accumulation in liver cells. This triggers inflammation, which over time can progress to fibrosis, cirrhosis, and in severe cases, liver cancer.
MASLD affects approximately one-third of adults worldwide. Its more severe form, metabolic dysfunction-associated steatohepatitis (MASH), is projected to become a leading cause of cirrhosis and a primary indication for liver transplantation in the coming years.
“This discovery opens a window into how rare inherited genetic variants can drive common diseases,” said Filippo Pinto e Vairo, M.D., Ph.D., medical director of the Program for Rare and Undiagnosed Diseases at Mayo Clinic. “It provides new insights into disease pathogenesis and potential therapeutic targets.”
Discovery Emerges from a Family Case Study
The research originated from genomic analysis of a woman and her father, both diagnosed with MASH but lacking typical risk factors such as diabetes or high cholesterol. With conventional explanations ruled out, scientists examined over 20,000 genes and identified a rare error in the MET gene.
This mutation involves a single chemical “letter” in the gene that disrupts a critical biological process, impairing the liver’s ability to metabolize fat. According to Raul Urrutia, M.D., from the Medical College of Wisconsin, “Rare diseases are often hidden in a pool of complex disorders, highlighting the power of individualized medicine in identifying them and enabling targeted therapies.”
Broader Insights from the Tapestry Study
To determine the mutation’s prevalence, researchers analyzed data from Mayo Clinic’s Tapestry study, a large-scale exome sequencing initiative involving over 100,000 participants. Among nearly 4,000 adults with MASLD, about 1% carried rare MET gene variants, and 18% had mutations in the same critical region as the initial family.
“This finding could potentially affect hundreds of thousands, if not millions, of people worldwide,” said Konstantinos Lazaridis, M.D., executive director for the Center for Individualized Medicine. The discovery underscores the value of familial studies and large genomic datasets in revealing rare but impactful genetic variations.
Advancing Genomic Medicine
The integration of genomics into clinical care at Mayo Clinic has proven critical. Since 2019, the Program for Rare and Undiagnosed Diseases has provided comprehensive genomic testing to over 3,200 patients with complex conditions, collaborating with nearly 300 clinicians across 14 divisions.
Future research will focus on how this MET gene mutation can guide the development of targeted treatments and improve management strategies for MASLD, potentially offering new hope for millions affected by this increasingly prevalent liver disease.
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