Genetic Mutation Identified as Cause of Fatty Liver Disease

Researchers at Mayo Clinic's Center for Individualized Medicine have uncovered a rare inherited genetic mutation that can directly lead to metabolic dysfunction-associated steatotic liver disease, previously known as nonalcoholic fatty liver disease (NAFLD). This groundbreaking discovery challenges the previous understanding that the disease primarily results from a combination of genetic and environmental factors, highlighting that in some instances, a single genetic variant can be the main cause.

The identified mutation occurs in the MET gene, which plays a crucial role in liver repair and fat metabolism. When this gene malfunctions due to the mutation, it causes an abnormal buildup of fat within liver cells. This accumulation triggers inflammation and, over time, leads to fibrosis and scarring, ultimately stiffening the liver tissue. If untreated, this process can progress to cirrhosis, which may cause irreversible liver damage or even liver cancer.

Metabolic dysfunction-associated steatotic liver disease affects approximately one-third of adults worldwide. Its severe form, known as metabolic dysfunction-associated steatohepatitis, is poised to become the leading cause of cirrhosis and a major reason for liver transplants in the near future.

The discovery was made through analysis of genomic data from a woman and her father, both affected by the disease but without common risk factors such as diabetes or high cholesterol. By examining over 20,000 genes, scientists identified a tiny, yet impactful, error in the MET gene—a single letter change in the DNA sequence—that disrupted normal fat processing in the liver. This mutation was unique and had not been documented before in existing literature or databases.

In collaboration with the Medical College of Wisconsin, researchers found that this genetic error affected a critical biological process, preventing the liver from metabolizing fat properly. This finding emphasizes that rare genetic variants can profoundly influence common diseases, often remaining hidden within complex disorders.

Further investigations using Mayo Clinic’s extensive genomic database, the Tapestry study, revealed that about 1% of individuals with this liver condition carry similar rare variants in the MET gene. Nearly 18% of those studied displayed variants in the same region, reinforcing the gene's role in disease development.

This research underscores the importance of integrating genomics into clinical care, as it allows for the identification of genetic causes of diseases that were previously considered multifactorial. Since 2019, Mayo Clinic's Program for Rare and Undiagnosed Diseases has provided advanced genomic testing to over 3,200 patients with complex conditions, supporting this precision medicine approach.

Future studies aim to explore how understanding these genetic factors can lead to targeted therapies and more effective disease management strategies. Overall, this discovery opens new avenues for diagnosing and treating fatty liver disease based on an individual’s genetic makeup, offering hope for personalized therapeutic options.