Researchers at Mayo Clinic have discovered a rare mutation in the MET gene that directly causes metabolic dysfunction-associated steatotic liver disease, a condition affecting about one-third of adults worldwide. The finding, based on a family case without typical risk factors, suggests similar variants may contribute to the disease in many others. Published in Hepatology, the study highlights the role of genomic analysis in uncovering hidden genetic causes.
Scientists at Mayo Clinic's Center for Individualized Medicine identified a rare genetic variant in the MET gene that triggers metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease. The MET gene is crucial for liver repair and fat processing; when mutated, it leads to fat buildup in liver cells, inflammation, fibrosis, scarring, and potentially cirrhosis or liver cancer.
The discovery stemmed from genomic analysis of a woman and her father, both diagnosed with the more severe form, metabolic dysfunction-associated steatohepatitis, but lacking common risk factors like diabetes or high cholesterol. Researchers examined DNA across more than 20,000 genes and found a novel alteration in the MET gene—a single change in the DNA sequence that disrupts fat processing. This variant had not been previously documented in scientific literature or public databases. Collaboration with the Medical College of Wisconsin's John & Linda Mellowes Center for Genomic Sciences and Precision Medicine confirmed the mutation's impact on biological processes.
"This discovery opens a window into how rare inherited genetic variants can drive common diseases," said lead author 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 this disease pathogenesis and potential therapeutic targets for future research."
To assess broader relevance, the team analyzed Mayo Clinic's Tapestry study, which sequences germline DNA from over 100,000 U.S. participants. Among nearly 4,000 adults with MASLD, about 1% carried rare MET gene variants, with nearly 18% in the same key region as the family's mutation. "This finding could potentially affect hundreds of thousands, if not millions, of people worldwide with or at risk for metabolic dysfunction-associated steatotic liver disease," noted Konstantinos Lazaridis, M.D., executive director of the Center for Individualized Medicine.
MASLD affects roughly one-third of adults globally, and its severe form is projected to become the leading cause of cirrhosis and liver transplants. The Program for Rare and Undiagnosed Diseases, launched in 2019, has provided genomic testing to over 3,200 patients. Raul Urrutia, M.D., emphasized, "This study demonstrates that rare diseases are not rare but often hidden in the large pool of complex disorders, underscoring the immense power of individualized medicine."
Future research will explore how this finding could inform targeted treatments and diagnostics.
