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Genotype-phenotype correlations and clinical outcomes of genetic TRPC6 podocytopathies

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...

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Main Authors: McAnallen, Susan (Author) , Elhassan, Elhussein A E (Author) , Stoneman, Sinead (Author) , Pinto e Vairo, Filippo (Author) , Hogan, Marie C (Author) , Hoefele, Julia (Author) , Clince, Michelle (Author) , Mekraksakit, Poemlarp (Author) , Titan, Silvia M (Author) , Jorge, Sofia (Author) , Calado, Joaquim (Author) , Decramer, Stéphane (Author) , Colliou, Eloïse (Author) , Tellier, Stéphanie (Author) , Francisco, Telma (Author) , Servais, Aude (Author) , Cornet, Joséphine (Author) , de Fallois, Jonathan (Author) , Dossier, Claire (Author) , Fenoglio, Roberta (Author) , Renieri, Alessandra (Author) , Pinto, Anna Maria (Author) , Daga, Sergio (Author) , Loberti, Lorenzo (Author) , Fila, Marc (Author) , Quintana, Luis F (Author) , Becherucci, Francesca (Author) , Godefroid, Nathalie (Author) , Dubrasquet, Astrid (Author) , Kálmán, Tory (Author) , Dolan, Niamh (Author) , Alawi, Bushra Al (Author) , Sweeney, Clodagh (Author) , Riordan, Michael (Author) , Stack, Maria (Author) , Awan, Atif (Author) , Hui, Ng Kar (Author) , McCarthy, Hugh J (Author) , Biros, Erik (Author) , Harris, Trudie (Author) , Kidd, Kendrah (Author) , Häberle, Stefanie (Author) , Bleyer, Anthony J (Author) , Mallett, Andrew J (Author) , Sayer, John A (Author) , Schaefer, Franz (Author) , Benson, Katherine A (Author) , McCann, Emma (Author) , Conlon, Peter J (Author)
Format: Article (Journal)
Language:English
Published: 2025
In: Nephrology, dialysis, transplantation
Year: 2025, Pages: 1-13
ISSN:1460-2385
DOI:10.1093/ndt/gfaf086
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/ndt/gfaf086
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Author Notes:Susan M. McAnallen, Elhussein A.E. Elhassan, Sinead Stoneman, Filippo Pinto e Vairo, Marie C. Hogan, Julia Hoefele, Michelle Clince, Poemlarp Mekraksakit, Silvia M. Titan, Sofia Jorge, Joaquim Calado, Stéphane Decramer, Eloïse Colliou, Stéphanie Tellier, Telma Francisco, Aude Servais, Joséphine Cornet, Jonathan de Fallois, Claire Dossier, Roberta Fenoglio, Alessandra Renieri, Anna Maria Pinto, Sergio Daga, Lorenzo Loberti, Marc Fila, Luis F. Quintana, Francesca Becherucci, Nathalie Godefroid, Astrid Dubrasquet, Tory Kálmán, Niamh Dolan, Bushra Al Alawi, Clodagh Sweeney, Michael Riordan, Maria Stack, Atif Awan, Ng Kar Hui, Hugh J. McCarthy, Erik Biros, Trudie Harris, Kendrah Kidd, Stefanie Haeberle, Anthony J. Bleyer, Andrew J. Mallett, John A. Sayer, Franz Schafer, Katherine A. Benson, Emma McCann and Peter J. Conlon
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Summary: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.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.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].Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.
Item Description:Vorab veröffentlicht: 19. Mai 2025
Gesehen am 29.10.2025
Physical Description:Online Resource
ISSN:1460-2385
DOI:10.1093/ndt/gfaf086

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