Abstract: TH-PO0615
Novel Gene Disease Association Between MEFV and Nephrotic Syndrome
Session Information
- Monogenic Kidney Diseases: Glomerular
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Wongboonsin, Janewit, Mahidol University Faculty of Medicine Siriraj Hospital, Bangkok, Thailand
- Gibson, Kristen, Boston Children's Hospital, Boston, Massachusetts, United States
- Ke, Juntao, Columbia University, New York, New York, United States
- Sentell, Zachary T., Newcastle University, Newcastle upon Tyne, England, United Kingdom
- Nigwekar, Sagar U., Massachusetts General Hospital, Boston, Massachusetts, United States
- Sayer, John Andrew, Newcastle University, Newcastle upon Tyne, England, United Kingdom
- Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
- Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
Background
Pyrin, a protein encoded by the MEFV gene, plays a central role in innate immunity and is the known cause of Familial Mediterranean Fever (FMF), which is a genetically semidominant disorder. While FMF is classically associated with secondary amyloidosis affecting the kidneys, rare case reports have described non-amyloid kidney involvement, such as proteinuric kidney disease. However, the potential role of MEFV as a genetic risk factor for nephrotic syndrome remains unclear.
Methods
We analyzed adult patients with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) from the Mass General Brigham Biobank (MGBB) using whole-exome sequencing, focusing on the 192-gene panel related to proteinuric kidney disease. Individuals with monoallelic pathogenic or likely pathogenic (P/LP) variants were assessed for clinical and histological characteristics. Replication was performed using data from the 100,000 Genomes Project (100KG). A separate case-control analysis included 5,260 FSGS/MCD cases and 27,644 controls, with multivariable Firth logistic regression used to evaluate associations, stratified by steroid response.
Results
In MGBB, six unresolved cases had monoallelic MEFV P/LP variants. All showed diffuse podocyte injury and features resembling thrombotic microangiopathy on biopsy, but none had amyloidosis. In the 100KG cohort, nine individuals from seven unrelated families with unexplained glomerular disease also had monoallelic MEFV P/LP variants and no other monogenic findings. In the case-control study, 31 patients with nephrotic syndrome (0.6%) had monoallelic MEFV variants, with 28 (90%) being steroid-resistant—compared to 60% steroid resistance in the overall case group. With Firth regression analysis to account for population substructure, individuals with monoallelic P/LP variants had significantly higher odds of steroid-resistant disease (OR 3.48, p = <0.01).
Conclusion
Across three independent cohorts, our findings suggest a novel association between monoallelic MEFV variants and steroid-resistant nephrotic syndrome (SRNS), distinct from the gene’s traditional link to AA amyloidosis. This highlights MEFV as a potential contributor to podocytopathy and a new consideration in the genetic landscape of SRNS.