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Lookup NU author(s): Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s).Background and hypothesis Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype-phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. Methods In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan-Meier analyses investigated the associations between genetic variants and disease progression. Results Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17-40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P =. 001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85-10.15); P =. 001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P =. 004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40-5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01-2.81), respectively, log-rank P =. 005]. Conclusion Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.
Author(s): Mcanallen SM, Elhassan EAE, Stoneman S, Vairo FPE, Hogan MC, Hoefele J, Clince M, Mekraksakit P, Titan SM, Jorge S, Calado J, Decramer S, Colliou E, Tellier S, Francisco T, Servais A, Cornet J, De Fallois J, Dossier C, Fenoglio R, Renieri A, Pinto AM, Daga S, Loberti L, Fila M, Quintana LF, Becherucci F, Godefroid N, Dubrasquet A, Kalman T, Dolan N, Alawi BA, Sweeney C, Riordan M, Stack M, Awan A, Hui NK, Mccarthy HJ, Biros E, Harris T, Kidd K, Haeberle S, Bleyer AJ, Mallett AJ, Sayer JA, Schafer F, Benson KA, Mccann E, Conlon PJ
Publication type: Article
Publication status: Published
Journal: Nephrology Dialysis Transplantation
Year: 2026
Volume: 41
Issue: 1
Pages: 79-91
Print publication date: 01/01/2026
Online publication date: 19/05/2025
Acceptance date: 11/04/2025
Date deposited: 06/01/2026
ISSN (print): 0931-0509
ISSN (electronic): 1460-2385
Publisher: Oxford University Press
URL: https://doi.org/10.1093/ndt/gfaf086
DOI: 10.1093/ndt/gfaf086
Data Access Statement: The data underlying this article will be shared on reasonable request to the corresponding and named senior author.
PubMed id: 40388293
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