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Observational Study
. 2025 Dec 23;41(1):79-91.
doi: 10.1093/ndt/gfaf086.

Genotype-phenotype correlations and clinical outcomes of genetic TRPC6 podocytopathies

Susan M McAnallen  1   2   3 , Elhussein A E Elhassan  1   3   4 , Sinead Stoneman  1   5 , Filippo Pinto E Vairo  6 , Marie C Hogan  7 , Julia Hoefele  8   9 , Michelle Clince  1 , Poemlarp Mekraksakit  7 , Silvia M Titan  7 , Sofia Jorge  10 , Joaquim Calado  11   12 , Stéphane Decramer  13   14 , Eloïse Colliou  15 , Stéphanie Tellier  13   14 , Telma Francisco  12 , Aude Servais  16 , Joséphine Cornet  16 , Jonathan de Fallois  17 , Claire Dossier  18 , Roberta Fenoglio  19 , Alessandra Renieri  20   21   22 , Anna Maria Pinto  22 , Sergio Daga  20   21 , Lorenzo Loberti  20   21   22 , Marc Fila  23 , Luis F Quintana  24 , Francesca Becherucci  25   26 , Nathalie Godefroid  27 , Astrid Dubrasquet  14   28 , Tory Kálmán  29 , Niamh Dolan  30   31 , Bushra Al Alawi  30   31 , Clodagh Sweeney  30   31 , Michael Riordan  30   31 , Maria Stack  30   31 , Atif Awan  30   31   32 , Ng Kar Hui  33 , Hugh J McCarthy  34   35 , Erik Biros  36   37 , Trudie Harris  37 , Kendrah Kidd  38 , Stefanie Haeberle  4   39 , Anthony J Bleyer  38 , Andrew J Mallett  36   37   40 , John A Sayer  41   42 , Franz Schafer  4   39 , Katherine A Benson  43 , Emma McCann  44 , Peter J Conlon  1   3   4
Affiliations
Observational Study

Genotype-phenotype correlations and clinical outcomes of genetic TRPC6 podocytopathies

Susan M McAnallen et al. Nephrol Dial Transplant. .

Abstract

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.

Keywords: TRPC6; CKD; FSGS; podocytopathy; steroid-resistant nephrotic syndrome.

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