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Lookup NU author(s): Dr Janewit Wongboonsin, Zac Sentell, Dr Juliana Arcila GalvisORCiD, Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 International Society of Nephrology. 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 × 10–5). 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.
Author(s): Wongboonsin J, Gibson KM, Ke J, Sentell ZT, Arcila-Galvis JE, Koyama S, Greenberg A, Reynolds KM, Montini G, Magistroni R, Mitrotti A, Gesualdo L, Pezzuto A, Peruzzi L, Caliskan Y, Onuchic-Whitford AC, Bunlungsup S, McNulty M, Gbadegesin R, Saleem MA, Pollak MR, Hildebrandt F, Natarajan P, Lee D, Nigwekar SU, Sayer JA, Sanna-Cherchi S, Sampson MG
Publication type: Article
Publication status: Published
Journal: Kidney International
Year: 2026
Pages: Epub ahead of print
Online publication date: 24/12/2025
Acceptance date: 09/12/2025
Date deposited: 07/03/2026
ISSN (print): 0085-2538
ISSN (electronic): 1523-1755
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.kint.2025.12.013
DOI: 10.1016/j.kint.2025.12.013
ePrints DOI: 10.57711/3ymj-q964
Data Access Statement: The data for this study were obtained from the Mass General Brigham Biobank, which restricts the sharing of genetic and clinical data to Institutional Review Board–approved investigators within Mass General Brigham. Additional Mass General Brigham Biobank data are not currently publicly available due to restrictions on the data. Access to sequence data for the Genome England 100K Genome Project is described at https://www.genomicsengland.co.uk/initiatives/100000-genomes-project.
PubMed id: 41453490
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