eprintid: 10205787 rev_number: 7 eprint_status: archive userid: 699 dir: disk0/10/20/57/87 datestamp: 2025-03-10 08:56:06 lastmod: 2025-03-10 08:56:06 status_changed: 2025-03-10 08:56:06 type: article metadata_visibility: show sword_depositor: 699 creators_name: Elhassan, Elhussein AE creators_name: Collins, Kane E creators_name: Heneghan, Sophia creators_name: Gilbert, Edmund creators_name: Yang, Hana creators_name: Senum, Sarah R creators_name: Schauer, Rachel S creators_name: Elbarougy, Doaa E creators_name: Madden, Stephen F creators_name: Murray, Susan L creators_name: Sadeghi-Alavijeh, Omid creators_name: Carmichael, Joshua creators_name: Gale, Daniel creators_name: Osman, Shohdan M creators_name: Kennedy, Claire creators_name: Griffin, Matthew D creators_name: Casserly, Liam creators_name: Moloney, Brona creators_name: O'Hara, Paul creators_name: Mallawaarachchi, Amali creators_name: Ciurli, Francesca creators_name: Genomics England Consortium, John C creators_name: Graziano, Claudio creators_name: Wolff, Constantin A creators_name: Schonauer, Ria creators_name: LaManna, Gaetano creators_name: Durand, Axelle creators_name: Limou, Sophie creators_name: Halbritter, Jan creators_name: Capelli, Irene creators_name: McCann, Emma creators_name: Harris, Peter C creators_name: Cavalleri, Gianpiero L creators_name: Benson, Katherine A creators_name: Conlon, Peter J title: The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease ispublished: inpress divisions: UCL divisions: B02 divisions: C10 divisions: D17 divisions: G93 keywords: Science & Technology, Life Sciences & Biomedicine, Urology & Nephrology, Genetic burden, PKD, ADPKD, Disease severity, Prognosis, MUTATION 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/. 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. date: 2025-01-01 date_type: published publisher: SPRINGER HEIDELBERG official_url: https://doi.org/10.1007/s40620-025-02211-x oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2360170 doi: 10.1007/s40620-025-02211-x medium: Print-Electronic pii: 10.1007/s40620-025-02211-x lyricists_name: Sadeghi-Alavijeh, Omid lyricists_name: Gale, Daniel lyricists_id: OSADE31 lyricists_id: DGALE18 actors_name: Gale, Daniel actors_id: DGALE18 actors_role: owner funding_acknowledgements: [National Institute for Health Research]; [NHS England]; [Wellcome Trust]; [Cancer Research UK]; [Medical Research Council]; [Irish Research Council]; EPSPD/2019/213 [Punchestown Kidney Research Fund]; HRCI-HRB-2020-032 [Health Research Board]; HRCI-HRB-2020-032 [Irish Nephrology Society]; [Irish Kidney Association]; [Beaumont Foundation, Dublin, Ireland]; [RCSI StAR MD programme, Royal College of Surgeons in Ireland, Dublin, Ireland]; 18/CRT/6214 [Science Foundation Ireland (SFI)]; [SFNDT PKD-France 2018 funding]; [Hospital-engineering 2018 funding (CHU-ECN)]; [NIH]; [IReL Consortium]; DK058816 full_text_status: public publication: Journal of Nephrology pages: 11 event_location: Italy issn: 1121-8428 citation: Elhassan, Elhussein AE; Collins, Kane E; Heneghan, Sophia; Gilbert, Edmund; Yang, Hana; Senum, Sarah R; Schauer, Rachel S; ... Conlon, Peter J; + view all <#> Elhassan, Elhussein AE; 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, John C; Graziano, Claudio; Wolff, Constantin A; Schonauer, 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; - view fewer <#> (2025) The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease. Journal of Nephrology 10.1007/s40620-025-02211-x <https://doi.org/10.1007/s40620-025-02211-x>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10205787/1/2025%20Elhassan%20et%20al%20Impact%20of%20second%20PKD1%20variants%20J%20Nephrol.pdf