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Lookup NU author(s): Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Autosomal Dominant Polycystic Kidney Disease (ADPKD), caused by pathogenic variants in PKD1 and PKD2, is the most common monogenic cause of kidney failure. Approximately 10% of ADPKD patients remain undiagnosed after coding-region focused genomic testing. Non-coding variants in regulatory regions are not an established cause of disease in ADPKD. We performed regulatory region analysis in a primary cohort of undiagnosed ADPKD patients (n = 20) and then extended this analysis to patients with undiagnosed cystic kidney disease within the Australian KidGen cohort (n = 42) and the Genomics England rare disease cohort (n = 1320). Through this genomic analysis we identified two rare, potentially disease-causing variants in the PKD1 5′untranslated region (UTR). We then designed a PKD1 5′UTR-luciferase translation assay to characterise these variants in vitro, which showed that a PKD1 variant c.−69dupG, reduced the translation efficiency of the main PKD1 open reading frame by ~87% compared to wildtype (p < 0.0001). The human PKD1 5′UTR contains two upstream open reading frames (uORFs). Using our model, we knocked-out the upstream open reading frames of the wildtype PKD1 5′UTR sequence, which increased expression of wildtype polycystin-1 (130%, p < 0.0001). We show that PKD1 5′-UTR variants are a currently overlooked rare cause of disease in ADPKD and that analysis of this region should be included in variant analysis pathways to increase diagnostic rates. In addition, we show that manipulation of the wildtype 5′UTR sequence can increase polycystin-1 expression, providing insights into regulation of PKD1 and suggested new approaches for therapeutic intervention in this haplo-insufficient disease.
Author(s): Wedd L, Hort Y, Patel C, Sayer JA, Rius R, Mallett AJ, Cottle DL, Smyth IM, Furlong T, Shine J, Mallawaarachchi A
Publication type: Article
Publication status: Published
Journal: European Journal of Human Genetics
Year: 2025
Pages: epub ahead of print
Online publication date: 26/09/2025
Acceptance date: 11/09/2025
Date deposited: 13/10/2025
ISSN (print): 1018-4813
ISSN (electronic): 1476-5438
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41431-025-01949-z
DOI: 10.1038/s41431-025-01949-z
Data Access Statement: The individual genomic datasets from the Garvan and KidGen cohorts generated and analysed during the current study are available from the corresponding author on reasonable request. Permission can be sought to access data from the Genomics England cohort through the Genomics England Research Environment. The public datasets analysed during the current study are available in the gnomAD repository, https://gnomad.broadinstitute.org. The variants identified in this study have been submitted to Clinvar (SUB15496204)
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