Nephrotic syndrome genomic discovery in the Mass General Brigham Biobank identifies monoallelic MEFV variants as a risk factor for focal segmental glomerulosclerosis
Issued Date
2026-01-01
Resource Type
ISSN
00852538
eISSN
15231755
Scopus ID
2-s2.0-105029974184
Pubmed ID
41453490
Journal Title
Kidney International
Rights Holder(s)
SCOPUS
Bibliographic Citation
Kidney International (2026)
Suggested Citation
Wongboonsin J., Gibson K.M., Ke J., Sentell Z.T., Arcila-Galvis J.E., Koyama S., Greenberg A., Reynolds K.M., Montini G., Magistroni R., Mitrotti A., Gesualdo L., Pezzuto A., Peruzzi L., Caliskan Y., Onuchic-Whitford A.C., Bunlungsup S., McNulty M., Gbadegesin R., Saleem M.A., Pollak M.R., Hildebrandt F., Natarajan P., Lee D., Nigwekar S.U., Sayer J.A., Sanna-Cherchi S., Sampson M.G. Nephrotic syndrome genomic discovery in the Mass General Brigham Biobank identifies monoallelic MEFV variants as a risk factor for focal segmental glomerulosclerosis. Kidney International (2026). doi:10.1016/j.kint.2025.12.013 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/115188
Title
Nephrotic syndrome genomic discovery in the Mass General Brigham Biobank identifies monoallelic MEFV variants as a risk factor for focal segmental glomerulosclerosis
Author(s)
Wongboonsin J.
Gibson K.M.
Ke J.
Sentell Z.T.
Arcila-Galvis J.E.
Koyama S.
Greenberg A.
Reynolds K.M.
Montini G.
Magistroni R.
Mitrotti A.
Gesualdo L.
Pezzuto A.
Peruzzi L.
Caliskan Y.
Onuchic-Whitford A.C.
Bunlungsup S.
McNulty M.
Gbadegesin R.
Saleem M.A.
Pollak M.R.
Hildebrandt F.
Natarajan P.
Lee D.
Nigwekar S.U.
Sayer J.A.
Sanna-Cherchi S.
Sampson M.G.
Gibson K.M.
Ke J.
Sentell Z.T.
Arcila-Galvis J.E.
Koyama S.
Greenberg A.
Reynolds K.M.
Montini G.
Magistroni R.
Mitrotti A.
Gesualdo L.
Pezzuto A.
Peruzzi L.
Caliskan Y.
Onuchic-Whitford A.C.
Bunlungsup S.
McNulty M.
Gbadegesin R.
Saleem M.A.
Pollak M.R.
Hildebrandt F.
Natarajan P.
Lee D.
Nigwekar S.U.
Sayer J.A.
Sanna-Cherchi S.
Sampson M.G.
Author's Affiliation
Harvard Medical School
Columbia University
Massachusetts General Hospital
Università degli Studi di Milano
Brigham and Women's Hospital
University of Bristol
Newcastle University
Beth Israel Deaconess Medical Center
Boston Children's Hospital
Università degli studi di Bari Aldo Moro
Vanderbilt University Medical Center
Duke University School of Medicine
Università degli Studi di Modena e Reggio Emilia
University of G. d'Annunzio Chieti and Pescara
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Saint Louis University School of Medicine
Broad Institute
Siriraj Hospital
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Azienda Ospedaliero - Universitaria di Modena
Ospedale Infantile Regina Margherita
Bumrungrad International Hospital
NIHR Newcastle Biomedical Research Centre
Columbia University
Massachusetts General Hospital
Università degli Studi di Milano
Brigham and Women's Hospital
University of Bristol
Newcastle University
Beth Israel Deaconess Medical Center
Boston Children's Hospital
Università degli studi di Bari Aldo Moro
Vanderbilt University Medical Center
Duke University School of Medicine
Università degli Studi di Modena e Reggio Emilia
University of G. d'Annunzio Chieti and Pescara
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Saint Louis University School of Medicine
Broad Institute
Siriraj Hospital
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Azienda Ospedaliero - Universitaria di Modena
Ospedale Infantile Regina Margherita
Bumrungrad International Hospital
NIHR Newcastle Biomedical Research Centre
Corresponding Author(s)
Other Contributor(s)
Abstract
Introduction: Health system-based biobanks with genetic data provide a unique opportunity for nephrotic syndrome (NS) genomic discovery. This is predicated on finding cases in the electronic health record. Methods: We tested three strategies to identify focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) cases in the 130,000 members of Mass General Brigham Biobank (MGBB). We analyzed a “synthetic proteinuria panel” of 192 Mendelian genes and the APOL1 kidney risk variants in those with exome sequencing (ES). We studied the associations between patients with Mendelian variants (MV), APOL1-HR genotype (APOL1) and outcomes. Validation of a novel gene-FSGS association was done in the Genomics England 100,000 Genome Project (100KG) and a global NS case-control cohort. Results: 319 MGBB participants had FSGS or MCD and ES data; reviewing pathology reports was the most accurate screening strategy. 31 (9.7%) of patients had MV and 24 (7.5%) had APOL1. 61% of genetic NS with a kidney biopsy report were classified as secondary FSGS. MV and APOL1 patients had a 3.1 (1.1–8.7) and 6.5 (1.3–32.3) increased odds of developing kidney failure, respectively. Unexpectedly, monoallelic pathogenic variants in MEFV (Mendelian gene for Familial Mediterranean Fever [FMF]) were found in 6 MGBB participants with FSGS, all of whom had features of collapsing glomerulopathy and thrombotic microangiopathy. 8 glomerular disease cases in the 100KG, unsolved via genome sequencing, had monoallelic pathogenic MEFV variants. Finally, a case-control study found a 3.8 increased odds of SRNS in individuals with pathogenic or likely pathogenic MEFV alleles (P = 7.8 × 10<sup>–5</sup>). Conclusions: 17.2% of unselected adults with NS in the MGBB had a well-established genetic form, each associated with an increased risk of kidney failure. A biopsy read of secondary FSGS should not be used to rule out testing for genetic disease. Monoallelic pathogenic variants in MEFV may be a novel and underappreciated cause or susceptibility factor for SRNS/FSGS with distinct histologic features, even in the absence of clinical FMF.