Novel Genetic Variant May Drive MASLD
In an article published in Hepatology , Filippo Pinto e Vairo, MD, PhD, and colleagues described their discovery of a single inherited variant of the mesenchymal-epithelial transition ( MET ) gene in a familial case of MASLD involving a father and daughter with no apparent additional risk factors.
MASLD remains one of the world's most common diseases and will likely become the leading cause of liver cirrhosis worldwide, the researchers wrote. MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD), likely stems from a combination of genetic and environmental factors, they said.
Their discovery of the gene variation prompted the researchers to investigate whether that variation and others on the MET gene were linked to steatotic liver disease.
They used Mayo Clinic's Tapestry study, a large-scale genetic sequencing project, to analyze the exome sequencing data of 3904 adults with MASLD to identify other cases and analyze them. About 1% (45 individuals) had rare variants of the MET gene potentially associated with MASLD, and 8 of the 45 (18%) had genetic variants in the same area as the index patient and her father.
Pinto e Vairo, medical director of the Program for Rare and Undiagnosed Diseases in the Mayo Clinic's Center for Individualized Medicine, explained the potential implications of the findings in a Q&A with Medscape Medical News .
What prompted you to conduct this research? How did you identify the original patient?
Pinto e Vairo: The original patient was identified through clinical care and underwent liver biopsy due to elevated liver enzymes. Her histology confirmed MASH [metabolic dysfunction–associated steatohepatitis], and subsequent exome sequencing revealed a novel heterozygous MET variant, inherited from her affected father, which led to a deeper investigation into the genetic basis of her condition.
Were you surprised by any of the findings? Why or why not?
Pinto e Vairo: The findings were surprising in several ways. First, variants in MET had not previously been implicated as a germline monogenic cause of MASLD or MASH in humans. Its known roles had largely been confined to cancer. Second, the discovery that rare, loss-of-function variants in the MET kinase domain could underlie liver steatosis and inflammation ran counter to the usual oncogenic MET variants, which are typically gain-of-function.
The confirmation that the MET variants impaired downstream signaling further reinforced a novel mechanism. The lack of high polygenic risk scores in patients with these MET variants also highlighted that monogenic drivers might be underrecognized contributors to MASLD/MASH.
Based on your research and other research, how might genetics play into MASLD?
Pinto e Vairo: Genetics play a significant role in MASLD by modulating both susceptibility and disease progression. While large-scale genome-wide association studies have identified common variants — such as those in PNPLA3 , TM6SF2 , GCKR , MBOAT7 , and HSD17B13 — that confer risk or protection, this study adds evidence that rare monogenic variants can also independently drive the disease.
This suggests a genetic spectrum in MASLD, ranging from polygenic, environmentally modulated forms to monogenic cases with high penetrance. The interplay between these rare variants and broader metabolic context will be crucial to understand personalized risk.
Is there a practical application for this research now? What might the future clinical applications be?
Pinto e Vairo: The immediate practical application lies in the potential for early identification of individuals at high risk for MASLD/MASH through exome or genome sequencing, particularly in families with a strong history of liver disease. Clinically, this could justify enhanced surveillance or earlier lifestyle and therapeutic interventions in at-risk individuals.
In the future, this research may support the development of targeted therapies that can restore or bypass defective MET signaling. Moreover, it opens the door to personalized medicine strategies that consider a patient's unique genetic profile when choosing interventions or preventive strategies.
What are the next steps?
Pinto e Vairo: The next steps include functional validation of other rare MET variants to better understand their pathogenic potential and variability in phenotypic expression; longitudinal cohort studies to monitor disease progression in individuals with MET variants and to define genotype-phenotype correlations more precisely; and ultimately therapeutic exploration, including in vitro and in vivo modeling, to determine whether restoring MET signaling could reverse or mitigate disease.
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