The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease
Authors: Elhassan Elhussein A. E. , Collins Kane E. , Heneghan Sophia , Gilbert Edmund , Yang Hana , Senum Sarah R. , Schauer Rachel S. , Elbarougy Doaa E. , Madden Stephen F. , Murray Susan L. , Sadeghi-Alavijeh Omid , Carmichael Joshua , Gale Daniel , Osman Shohdan M. , Kennedy Claire , Griffin Matthew D. , Casserly Liam , Moloney Brona , O’Hara Paul , Mallawaarachchi Amali , Ciurli Francesca ,   Genomics England Consortium, Ambrose John C. , Arumugam Prabhu , Bleda Marta , Boardman-Pretty Freya , Boustred Christopher R. , Brittain Helen , Caulfield Mark J. , Chan Georgia C. , Fowler Tom , Giess Adam , Hamblin Angela , Henderson Shirley , Hubbard Tim J. P. , Jackson Rob , Jones Louise J. , Kasperaviciute Dalia , Kayikci Melis , Kousathanas Athanasios , Lahnstein Lea , Leigh Sarah E. A. , Leong Ivonne U. S. , Lopez Javier F. , Maleady-Crowe Fiona , Moutsianas Loukas , Mueller Michael , Murugaesu Nirupa , Need Anna C. , O’Donovan Peter , Odhams Chris A. , Patch Christine , Perez-Gil Daniel , Pereira Mariana B. , Pullinger John , Rahim Tahrima , Rendon Augusto , Rogers Tim , Savage Kevin , Sawant Kushmita , Scott Richard H. , Siddiq Afshan , Sieghart Alexander , Smith Samuel C. , Sosinsky Alona , Stuckey Alexander , Tanguy Melanie , Thomas Ellen R. A. , Thompson Simon R. , Tucci Arianna , Walsh Emma , Welland Matthew J. , Williams Eleanor , Witkowska Katarzyna , Wood Suzanne M. , Graziano Claudio , Wolff Constantin A. , Schönauer Ria , LaManna Gaetano , Durand Axelle , Limou Sophie , Halbritter Jan , Capelli Irene , McCann Emma , Harris Peter C. , Cavalleri Gianpiero L. , Benson Katherine A. , Conlon Peter J. 
Published: January 2025

Abstract

Background
Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by pathogenic variants in the PKD1 and PKD2 genes. Although the type of ADPKD variant can influence disease severity, rare, hypomorphic PKD1 variants have also been reported to modify disease severity or cause biallelic ADPKD. This study examines whether rare, additional, potentially protein-altering, non-pathogenic PKD1 variants contribute to ADPKD phenotypic outcomes.

Methods
We investigated the prevalence of rare, additional, potentially protein-altering PKD1 variants in patients with PKD1-associated ADPKD. The association between rare, additional, potentially protein-altering variants and phenotypic outcomes, including progression to kidney failure, age at onset of hypertension and urological events, height-adjusted total kidney volume, and predicting renal outcomes in PKD (PROPKD) score, were examined.

Results
Rare, additional, potentially protein-altering variants were detected in 6% of the 932 ADPKD patients in the study. The presence of rare, additional, potentially protein-altering variants was associated with 4 years earlier progression to kidney failure (hazard ratio (HR): 1.66; 95% confidence interval (CI): 1.18–2.34; P = 0.003), with in-trans rare, additional, potentially protein-altering variants (n = 13/894) showing a greater risk of kidney failure (HR: 1.83; 95% CI 1.00–3.33; P = 0.049). We did not detect statistically significant differences between rare, additional, potentially protein-altering variants and other phenotypic outcomes compared to those without rare, additional, potentially protein-altering variants.

Conclusions
In patients with PKD1-associated ADPKD, our findings suggest that rare, additional, potentially protein-altering variants in PKD1 may influence disease severity. These findings have potential clinical implications in counselling and treating patients with rare, additional, potentially protein-altering variants, but further investigation of such variants in larger, longitudinal cohorts with detailed, standardised phenotype data is required.

Graphical abstract