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Lookup NU author(s): Dr Janewit Wongboonsin, Zac Sentell, Dr Juliana Arcila GalvisORCiD, Professor John SayerORCiD
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© 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
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
PubMed id: 41453490
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