TY  - INPR
ID  - discovery10205787
N2  - 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.
SN  - 1121-8428
UR  - https://doi.org/10.1007/s40620-025-02211-x
PB  - SPRINGER HEIDELBERG
JF  - Journal of Nephrology
KW  - Science & Technology
KW  -  Life Sciences & Biomedicine
KW  -  Urology & Nephrology
KW  -  Genetic burden
KW  -  PKD
KW  -  ADPKD
KW  -  Disease severity
KW  -  Prognosis
KW  -  MUTATION
A1  - Elhassan, Elhussein AE
A1  - Collins, Kane E
A1  - Heneghan, Sophia
A1  - Gilbert, Edmund
A1  - Yang, Hana
A1  - Senum, Sarah R
A1  - Schauer, Rachel S
A1  - Elbarougy, Doaa E
A1  - Madden, Stephen F
A1  - Murray, Susan L
A1  - Sadeghi-Alavijeh, Omid
A1  - Carmichael, Joshua
A1  - Gale, Daniel
A1  - Osman, Shohdan M
A1  - Kennedy, Claire
A1  - Griffin, Matthew D
A1  - Casserly, Liam
A1  - Moloney, Brona
A1  - O'Hara, Paul
A1  - Mallawaarachchi, Amali
A1  - Ciurli, Francesca
A1  - Genomics England Consortium, John C
A1  - Graziano, Claudio
A1  - Wolff, Constantin A
A1  - Schonauer, Ria
A1  - LaManna, Gaetano
A1  - Durand, Axelle
A1  - Limou, Sophie
A1  - Halbritter, Jan
A1  - Capelli, Irene
A1  - McCann, Emma
A1  - Harris, Peter C
A1  - Cavalleri, Gianpiero L
A1  - Benson, Katherine A
A1  - Conlon, Peter J
TI  - The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease
EP  - 11
AV  - public
Y1  - 2025/01/01/
N1  - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
ER  -