@article{discovery10205787,
            note = {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/.},
           title = {The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease},
           month = {January},
            year = {2025},
         journal = {Journal of Nephrology},
       publisher = {SPRINGER HEIDELBERG},
            issn = {1121-8428},
             url = {https://doi.org/10.1007/s40620-025-02211-x},
        keywords = {Science \& Technology, Life Sciences \& Biomedicine, Urology \& Nephrology, Genetic burden, PKD, ADPKD, Disease severity, Prognosis, MUTATION},
        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.},
          author = {Elhassan, Elhussein AE and Collins, Kane E and Heneghan, Sophia and Gilbert, Edmund and Yang, Hana and Senum, Sarah R and Schauer, Rachel S and Elbarougy, Doaa E and Madden, Stephen F and Murray, Susan L and Sadeghi-Alavijeh, Omid and Carmichael, Joshua and Gale, Daniel and Osman, Shohdan M and Kennedy, Claire and Griffin, Matthew D and Casserly, Liam and Moloney, Brona and O'Hara, Paul and Mallawaarachchi, Amali and Ciurli, Francesca and Genomics England Consortium, John C and Graziano, Claudio and Wolff, Constantin A and Schonauer, Ria and LaManna, Gaetano and Durand, Axelle and Limou, Sophie and Halbritter, Jan and Capelli, Irene and McCann, Emma and Harris, Peter C and Cavalleri, Gianpiero L and Benson, Katherine A and Conlon, Peter J}
}