Mayo Clinic discovers rare gene mutation that causes fatty liver disease

Researchers previously believed this condition developed mainly from a mix of genetic susceptibility and lifestyle or environmental influences. However, findings published in Hepatology show that in certain cases, a single inherited mutation can play a central role in triggering the disease.

The team traced the variant to the MET gene, which plays an important role in liver repair and how the body processes fat. When this gene does not function properly, fat begins to build up inside liver cells. This buildup can lead to inflammation. Over time, inflammation can progress to fibrosis and scarring that stiffens the liver. In more advanced stages, the condition can develop into cirrhosis, which may cause permanent liver damage or even liver cancer.

Metabolic dysfunction-associated steatotic liver disease affects roughly one-third of adults worldwide. Its more severe form, metabolic dysfunction-associated steatohepatitis, is expected to become the leading cause of cirrhosis and the primary reason for liver transplants in the near future.

"This discovery opens a window into how rare inherited genetic variants can drive common diseases," says 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. "It provides new insights into this disease pathogenesis and potential therapeutic targets for future research."

Family Case Reveals the Genetic Clue

The discovery began with genomic analysis of a woman and her father who both had metabolic dysfunction-associated steatohepatitis. Interestingly, neither of them had diabetes or high cholesterol, two of the most common risk factors associated with fat accumulation in the liver.

Because the usual explanations did not apply, researchers performed an extensive genetic analysis, examining DNA across more than 20,000 genes. During this search, they identified a small but potentially meaningful alteration in the MET gene.

Working together 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 research team confirmed that this mutation interfered with a critical biological process.

Genes are made up of chemical letters that carry instructions for how the body functions. In this case, a single swapped letter within the DNA sequence disrupted the message, preventing the liver from properly processing fat. This rare genetic variant found in the family has not previously been documented in scientific literature or public genetic databases.

"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 in identifying them, and enabling the design of advanced diagnostics and targeted therapies," Dr. Urrutia says.

Large Genomic Study Finds Similar Variants

To understand whether this mutation might appear in other patients, researchers analyzed data from Mayo Clinic's Tapestry study. This large exome sequencing initiative aims to identify genetic factors that influence disease.

The Tapestry project has examined germline DNA from more than 100,000 participants across the United States, creating an extensive genomic database that supports research into both established and emerging health conditions.

Among nearly 4,000 adults in the Tapestry study who had metabolic dysfunction-associated steatotic liver disease, about 1% carried rare variants in the same MET gene that may contribute to the condition. Nearly 18% of these variants occurred in the same key region identified in the original family, strengthening the evidence that this gene plays a role in liver disease.

"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," says Konstantinos Lazaridis, M.D., a lead author and the Carlson and Nelson Endowed Executive Director for the Center for Individualized Medicine.

Dr. Lazaridis also emphasized the importance of the Tapestry study in revealing hidden genetic factors behind disease.

"Once a pathogenic variant is discovered, interrogating our Tapestry data repository is giving us a clearer lens into the hidden layers of disease, and this discovery is one of the first to demonstrate its scientific significance," Dr. Lazaridis says. "This finding highlights the profound value of studying familial diseases and the merit of large-scale genomic datasets, which can reveal rare genetic variations with broader implications for population health."

Precision Genomics Helps Solve Medical Mysteries

The findings also highlight the growing role of genomic medicine in clinical care at Mayo Clinic. Researchers and clinicians are increasingly using advanced genetic technologies to help uncover the causes of complex diseases.

Since it launched in 2019, the Program for Rare and Undiagnosed Diseases has provided more than 3,200 patients with access to comprehensive genomic testing. The program works with nearly 300 clinicians across 14 divisions at Mayo Clinic to deliver precision diagnostics for patients with difficult-to-diagnose conditions, including rare liver diseases.

Researchers say future studies will examine how this discovery involving metabolic dysfunction-associated steatotic liver disease could guide the development of targeted treatments and improve how the disease is diagnosed and managed.