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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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Conflict of interest statement

S.M.M., E.A.E.E., P.J.C., S.H. and F.S. are members of the European Rare Kidney Disease Reference Network. E.A.E.E. reports funds from the Royal College of Surgeons in Ireland StAR PhD. P.J.C. is co-founder of the Irish Kidney Gene Project. S.M.M. reports funding from the Royal College of Physicians of Ireland post-CSCST-ASPIRE Fellowship programme in Transitional Nephrology. J.A.S. is on the Genes and Kidney Board for the European Renal Association and is the Academic Vice President of the UK Kidney Association. A.J.M. is supported by a Queensland Health Advancing Clinical Research Fellowship and is on board of ANZSN. A.J.M. has reported association with research bodies NHMRC, MRFF and Aus Gov, QLD Gov. F.B. reports association with Alnylam and Chiesi. S.J. reports association with Alnylam for lumasiran use and from Dioscope for an educational course on nephrogenetics. J.C. is a coordinator of the nephrogenetics working group, Portuguese Society of Nephrology. The remaining authors have no conflicts of interest to declare.

Figures

Graphical Abstract
Graphical Abstract
Figure 1:
Figure 1:
Flow diagram illustrating the survey distribution, literature review, exclusion criteria and final cohort of patients with LP/P non-synonymous TRPC6 variants. ERKNet, the European Rare Kidney Disease Reference Network; LB, likely benign; n, number; VUS, variants of uncertain significance; pLOF, protein loss-of-function variants.
Figure 2:
Figure 2:
Distribution and functional effects of TRPC6 variants. Lollipop plot illustrating the position of non-synonymous TRPC6 variants in relation to a schematic representation of three protein regions: the ankyrin repeat region, transient receptor potential 2 region and ion transporter region (see key region below). Non-synonymous likely pathogenic/pathogenic TRPC6 variants are annotated according to their functional impact on calcium channel function and are categorised into three groups: GOF (red solid circles), LOF (blue solid circles) and variants that were not functionally evaluated (black solid circles). The lollipop was created utilizing plot template of proteinpaint.stjude.org. aa, amino acid; TRP, transient receptor potential.
Figure 3:
Figure 3:
Kidney survival estimates of patients with LP/P non-synonymous TRPC6 variants. The Kaplan–Meier survival curves show survival probability according to: (A) family history; (B) age at disease onset (adulthood vs childhood); (C) initial presentation with SRNS/NS; (D) pattern of clinical presentations; (E) functional impact on TRPC6 variants on calcium channel function; and (F) TRPC6 prevalent variants [c.523C>T p.(Arg175Trp) (R175W-TRPC6) variant, c.2683C>T p.(Arg895Cys) (R895C-TRPC6) compared with other TRPC6 variants]. P-value from the log-rank test is given to compare the survival distributions among subgroups.
See this image and copyright information in PMC

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