Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly one in three adults around the globe. It starts when fat builds up inside the liver’s cells. Over time, this buildup can cause swelling, scarring, and even liver failure.

Doctors used to believe this disease was caused by a mix of inherited traits and environmental factors. Now, a groundbreaking study suggests that, at least in some people, a single tiny genetic mistake might be enough to cause it.

A Rare Gene Variant with Big Consequences

At the Mayo Clinic’s Center for Individualized Medicine, scientists recently uncovered a rare change in a single gene that may trigger this common liver disease. The gene is called MET, and it helps the liver repair itself and control how it handles fat.

When the MET gene doesn’t work right, fat starts to pile up inside liver cells. This extra fat causes the liver to swell and become inflamed. Over time, this can lead to fibrosis, which stiffens the liver, and eventually turns into cirrhosis. That’s when the liver becomes so damaged it can no longer function properly. In some people, this can even lead to liver cancer.

A tiny genetic glitch in the liver’s repair gene may silently trigger disease in millions across the globe. (CREDIT: iStock)

This discovery was published in the journal Hepatology. It represents a major shift in how scientists think about the causes of MASLD. “This discovery opens a window into how rare inherited genetic variants can drive common diseases,” said Dr. Filippo Pinto e Vairo, lead author of the study and medical director of Mayo’s Program for Rare and Undiagnosed Diseases. “It provides new insights into this disease pathogenesis and potential therapeutic targets for future research.”

A Family Case Sparks the Discovery

The research began with a puzzling case: a woman and her father both had a severe form of MASLD, called metabolic dysfunction-associated steatohepatitis, or MASH. Neither of them had diabetes or high cholesterol, which are usually major risk factors for the disease. Their doctors couldn’t explain the cause of their condition using typical tests. So, the researchers went deeper — into their DNA.

Using advanced genomic sequencing, the team scanned over 20,000 genes in each person. That’s when they found it — a small but important mistake in the MET gene. Genes are built from a long string of chemical letters that act like instructions. In this case, one of those letters had been swapped. This tiny change scrambled the gene’s message and kept the liver from processing fat correctly.

“This study demonstrates that rare diseases are not rare but often hidden in the large pool of complex disorders,” said Dr. Raul Urrutia, from the Medical College of Wisconsin. His team helped confirm the role of the MET gene mutation. “It underscores the immense power of individualized medicine in identifying them, and enabling the design of advanced diagnostics and targeted therapies.”

Larger Genetic Study Finds the Mutation in Others

To see if this same genetic error showed up in other people, the researchers turned to the Mayo Clinic’s Tapestry study. This massive research project looks at genetic information from more than 100,000 people in the U.S. Scientists use it to search for gene changes that cause diseases.

Out of nearly 4,000 adults in the Tapestry study with MASLD, about 1% carried rare changes in the MET gene. Of those, nearly 18% had changes in the same important region of the gene as the woman and her father. That might not sound like a lot at first, but when you consider how many people have MASLD, it could mean that hundreds of thousands — or even millions — of people carry a genetic risk they don’t know about.

The discovery emerged from the genomic data of a woman and her father with metabolic dysfunction-associated steatohepatitis. They had no history of diabetes or high cholesterol, two common risk factors for fat buildup in the liver. (CREDIT: iStock)

“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,” said Dr. Konstantinos Lazaridis, a senior leader of the Mayo research team.

Dr. Lazaridis explained that these findings are helping scientists understand how a disease that seems common and random may, in some cases, be driven by hidden genetic factors. “Once a pathogenic variant is discovered, interrogating our Tapestry data repository is giving us a clearer lens into the hidden layers of disease,” he said. “This discovery is one of the first to demonstrate its scientific significance.”

Moving Toward Better Treatment

This discovery does more than just explain a rare case. It could change how doctors treat and screen for MASLD in the future. Understanding how a single letter change in DNA can cause the disease may help doctors catch it earlier, before the liver becomes seriously damaged.

Discovery of a MET-driven monogenic cause of steatotic liver disease. (CREDIT: Filippo Pinto e Vairo, et al.)

It could also open the door to new treatments that are designed to correct or work around that genetic problem. These kinds of personalized treatments — often called precision medicine — are a growing part of modern healthcare. They aim to tailor therapies to each patient’s unique biology, rather than using a one-size-fits-all approach.

Mayo Clinic has been a leader in this field. Since 2019, its Program for Rare and Undiagnosed Diseases has helped over 3,200 patients with complex conditions get genetic testing. The program brings together doctors and researchers from many specialties to solve difficult medical puzzles — and often, those puzzles lead to discoveries that help more than just one patient.

The scientists plan to share their data publicly, so other researchers can use it to study liver disease and other conditions. By working together and sharing knowledge, scientists hope to find more of these hidden causes and turn them into new ways to prevent or treat disease.

A Common Disease with a Hidden Trigger

MASLD is one of the most common chronic liver diseases in the world. Experts expect it to soon become the number one cause of liver cirrhosis and the top reason for liver transplants. Yet until recently, doctors had no clear answers for why so many people developed it — especially those who didn’t have the usual risk factors.

MASLD may soon become the number one cause of liver cirrhosis and the top reason for liver transplants. (CREDIT: Northwestern University)

This new discovery offers part of that answer. It shows that even a single rare genetic change can have a big impact. It also reminds us that common diseases may not be so simple after all. What looks like one disease may actually be many different ones, each with its own cause and treatment path.

By looking at both individual cases and large-scale genetic data, scientists are finally peeling back the layers of MASLD. And as they do, they’re giving hope to people living with liver disease — and pointing the way to a healthier future.