. 2025 Jun;38(5):1457-1467.

doi: 10.1007/s40620-025-02211-x. Epub 2025 Jan 30.

The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease

Elhussein A E Elhassan^#^{1

2}, Kane E Collins^#^{3

4

5}, Sophia Heneghan^{3

4

5}, Edmund Gilbert³, Hana Yang⁶, Sarah R Senum⁶, Rachel S Schauer⁶, Doaa E Elbarougy⁶, Stephen F Madden⁷, Susan L Murray¹, Omid Sadeghi-Alavijeh⁸, Joshua Carmichael⁸, Daniel Gale^{8

9}, Shohdan M Osman^{1

2}, Claire Kennedy¹⁰, Matthew D Griffin^{11

12}, Liam Casserly¹³, Brona Moloney¹, Paul O'Hara¹, Amali Mallawaarachchi^{14

15}, Francesca Ciurli¹⁶; Genomics England Consortium; Claudio Graziano¹⁷, Constantin A Wolff¹⁸, Ria Schönauer^{18

19}, Gaetano LaManna^{16

20}, Axelle Durand²¹, Sophie Limou²¹, Jan Halbritter^{18

19}, Irene Capelli¹⁶, Emma McCann²², Peter C Harris⁶, Gianpiero L Cavalleri², Katherine A Benson^#³, Peter J Conlon^#^{23

24}

Collaborators, Affiliations

Collaborators

Genomics England Consortium:
John C Ambrose, Prabhu Arumugam, Marta Bleda, Freya Boardman-Pretty, Christopher R Boustred, Helen Brittain, Mark J Caulfield, Georgia C Chan, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim J P Hubbard, Rob Jackson, Louise J Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Sarah E A Leigh, Ivonne U S Leong, Javier F Lopez, Fiona Maleady-Crowe, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C Need, Peter O'Donovan, Chris A Odhams, Christine Patch, Daniel Perez-Gil, Mariana B Pereira, John Pullinger, Tahrima Rahim, Augusto Rendon, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H Scott, Afshan Siddiq, Alexander Sieghart, Samuel C Smith, Alona Sosinsky, Alexander Stuckey, Melanie Tanguy, Ellen R A Thomas, Simon R Thompson, Arianna Tucci, Emma Walsh, Matthew J Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M Wood

Affiliations

¹ Department of Nephrology, Beaumont Hospital, Dublin, Ireland.
² Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
³ School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁴ The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland.
⁵ SFI Research Ireland Centre for Research Training in Genomics Data Science, University of Galway, Galway, Ireland.
⁶ Division of Nephrology & Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
⁷ Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁸ Department of Renal Medicine, University College London, London, UK.
⁹ Genomics England, Queen Mary University of London, London, UK.
¹⁰ Kingston General Hospital & Queen's University, Kingston, ON, Canada.
¹¹ Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, University of Galway, Galway, Ireland.
¹² Nephrology Department, Galway University Hospitals, Saolta University Healthcare Group, Galway, Ireland.
¹³ Department of Renal Medicine, University Hospital Limerick, Limerick, Ireland.
¹⁴ Rare Disease Program, Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁵ Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
¹⁶ Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy.
¹⁷ Medical Genetics Unit, AUSL Romagna, 47522, Cesena, Italy.
¹⁸ Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁹ Division of Nephrology, Department of Endocrinology, Nephrology, and Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
²⁰ Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40138, Bologna, Italy.
²¹ Ecole Centrale Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR1064, Nantes University, Nantes, France.
²² The Department of Clinical Genetics, Children's Health Ireland at Crumlin, Dublin, Ireland.
²³ Department of Nephrology, Beaumont Hospital, Dublin, Ireland. peterconlon@beaumont.ie.
²⁴ Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland. peterconlon@beaumont.ie.

^# Contributed equally.

PMID: 39883360
PMCID: PMC12289752
DOI: 10.1007/s40620-025-02211-x

The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease

Elhussein A E Elhassan et al. J Nephrol. 2025 Jun.

. 2025 Jun;38(5):1457-1467.

doi: 10.1007/s40620-025-02211-x. Epub 2025 Jan 30.

Authors

Collaborators

Genomics England Consortium:
John C Ambrose, Prabhu Arumugam, Marta Bleda, Freya Boardman-Pretty, Christopher R Boustred, Helen Brittain, Mark J Caulfield, Georgia C Chan, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim J P Hubbard, Rob Jackson, Louise J Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Sarah E A Leigh, Ivonne U S Leong, Javier F Lopez, Fiona Maleady-Crowe, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C Need, Peter O'Donovan, Chris A Odhams, Christine Patch, Daniel Perez-Gil, Mariana B Pereira, John Pullinger, Tahrima Rahim, Augusto Rendon, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H Scott, Afshan Siddiq, Alexander Sieghart, Samuel C Smith, Alona Sosinsky, Alexander Stuckey, Melanie Tanguy, Ellen R A Thomas, Simon R Thompson, Arianna Tucci, Emma Walsh, Matthew J Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M Wood

Affiliations

¹ Department of Nephrology, Beaumont Hospital, Dublin, Ireland.
² Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
³ School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁴ The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland.
⁵ SFI Research Ireland Centre for Research Training in Genomics Data Science, University of Galway, Galway, Ireland.
⁶ Division of Nephrology & Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
⁷ Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁸ Department of Renal Medicine, University College London, London, UK.
⁹ Genomics England, Queen Mary University of London, London, UK.
¹⁰ Kingston General Hospital & Queen's University, Kingston, ON, Canada.
¹¹ Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, University of Galway, Galway, Ireland.
¹² Nephrology Department, Galway University Hospitals, Saolta University Healthcare Group, Galway, Ireland.
¹³ Department of Renal Medicine, University Hospital Limerick, Limerick, Ireland.
¹⁴ Rare Disease Program, Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁵ Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
¹⁶ Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy.
¹⁷ Medical Genetics Unit, AUSL Romagna, 47522, Cesena, Italy.
¹⁸ Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁹ Division of Nephrology, Department of Endocrinology, Nephrology, and Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
²⁰ Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40138, Bologna, Italy.
²¹ Ecole Centrale Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR1064, Nantes University, Nantes, France.
²² The Department of Clinical Genetics, Children's Health Ireland at Crumlin, Dublin, Ireland.
²³ Department of Nephrology, Beaumont Hospital, Dublin, Ireland. peterconlon@beaumont.ie.
²⁴ Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland. peterconlon@beaumont.ie.

^# Contributed equally.

PMID: 39883360
PMCID: PMC12289752
DOI: 10.1007/s40620-025-02211-x

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.

Keywords: ADPKD; Disease severity; Genetic burden; PKD; Prognosis.

Plain language summary

Autosomal dominant polycystic kidney disease (ADPKD) is usually caused by variants in the PKD1 and PKD2 genes. This study found that people with PKD1 ADPKD carrying additional damaging genetic variants in the PKD1 gene, progress to kidney failure at an earlier age.

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Conflict of interest statement

Declarations. Conflict of interest: This work was in part supported by funds received by BioMarin Ltd. Ethical approval: This study, which involved human participants, their data or biological material, was approved (or granted exemption) by the appropriate institutional and/or national research ethics committee which was the Hammersmith and Queen Charlotte’s & Chelsea Research Ethics Committee REC No 08/H0707/1. Informed consent to participate: This study was conducted in accordance with the standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All participants have provided their informed consent to participate and publish this research.

References

1. Benson KA et al (2021) The genetic landscape of polycystic kidney disease in Ireland. Eur J Hum Genet 29(5):827–838. 10.1038/s41431-020-00806-5 - DOI - PMC - PubMed
1. Lemoine H et al (2022) Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis. Am J Hum Genet 109(8):1484–1499. 10.1016/j.ajhg.2022.06.013 - DOI - PMC - PubMed
1. Chebib FT, Torres VE (2016) Autosomal dominant polycystic kidney disease: core curriculum 2016. Am J Kidney Dis Kidney Dis. 10.1053/j.ajkd.2015.07.037 - DOI - PMC - PubMed
1. Gall EC-L et al (2016) The PROPKD score: A new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 27(3):942–951. 10.1681/ASN.2015010016 - DOI - PMC - PubMed
1. Le Gall EC et al (2013) Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 24(6):1006–1013. 10.1681/ASN.2012070650 - DOI - PMC - PubMed

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The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease

Collaborators

Affiliations

The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease

Authors

Collaborators

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Abstract

Plain language summary

Conflict of interest statement

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