Mayo Clinic Researchers Identify Rare Inherited Gene Mutation Linked to Fatty Liver Disease

Healthcare

Mayo Clinic Researchers Identify Rare Inherited Gene Mutation Linked to Fatty Liver Disease

In a major advancement in liver disease research, Mayo Clinic's Center for Individualized Medicine has identified a rare inherited mutation in the MET gene that can directly cause metabolic dysfunction-associated steatotic liver disease (MASLD) — formerly known as nonalcoholic fatty liver disease (NAFLD). This discovery, published in the journal Hepatology, redefines scientific understanding by showing that, in some patients, a single genetic mutation—rather than a combination of lifestyle and environmental factors—may be the root cause of the disease.

The breakthrough stems from the genomic analysis of a patient and her father, both diagnosed with metabolic dysfunction-associated steatohepatitis (MASH)—the advanced and inflammatory form of MASLD—despite having no common risk factors such as diabetes or high cholesterol.

A Rare Mutation with Widespread Implications

Researchers found a small but impactful error in the MET gene, which is essential for liver repair and fat metabolism. The mutation impairs the liver’s ability to process fat, leading to its accumulation, inflammation, and eventually fibrosis, scarring, or cirrhosis, which can progress to liver cancer.

“This discovery opens a window into how rare inherited genetic variants can drive common diseases,” said Dr. Filippo Pinto e Vairo, lead author and Medical Director of the Program for Rare and Undiagnosed Diseases at Mayo Clinic. “It provides new insights into this disease’s pathogenesis and potential therapeutic targets for future research.”

The mutation had not been previously reported in scientific literature or global databases, indicating it is both rare and novel.

Large-Scale Genomic Insights from the Tapestry Study

To assess the broader impact of this MET gene variant, researchers turned to Mayo Clinic’s Tapestry study, which involves exome sequencing of over 100,000 participants across the U.S. Among nearly 4,000 participants with MASLD, about 1% carried rare MET gene variants, and nearly 18% of those had mutations in the same functional region as the family originally studied.

“This could affect hundreds of thousands, if not millions, of people worldwide,” said Dr. Konstantinos Lazaridis, co-lead author and Executive Director of the Center for Individualized Medicine. “Our Tapestry data repository is proving invaluable in revealing the hidden genetic drivers of complex diseases.”

Collaboration and Precision Medicine at Work

The research was conducted in collaboration with the Medical College of Wisconsin's John & Linda Mellowes Center for Genomic Sciences and Precision Medicine, led by Dr. Raul Urrutia. He emphasized that this study highlights how rare diseases can be hidden within more common conditions, and how individualized genomic analysis can unveil critical diagnostic and therapeutic pathways.

Since its launch in 2019, Mayo Clinic’s Program for Rare and Undiagnosed Diseases has served over 3,200 patients with complex medical conditions, partnering with nearly 300 clinicians across 14 divisions to integrate genomic sequencing into clinical care.

A Turning Point in Liver Disease Diagnosis and Treatment

MASLD currently affects about one-third of adults worldwide, with its advanced form, MASH, poised to become the leading cause of liver transplants globally. The newly discovered MET mutation could pave the way for targeted therapies, early screening, and personalized interventions for individuals at risk.

“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,” Dr. Lazaridis concluded.

Future research will focus on how this genetic insight can be translated into therapeutic innovations for liver disease, offering hope to millions affected by this growing global health challenge.