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Background <p>Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by pathogenic variants in the <i>PKD1</i> and <i>PKD2</i> genes. Although the type of ADPKD variant can influence disease severity, rare, hypomorphic <i>PKD1</i> variants have also been reported to modify disease severity or cause biallelic ADPKD. This study examines whether rare, additional, potentially protein-altering, non-pathogenic <i>PKD1</i> variants contribute to ADPKD phenotypic outcomes.</p> Methods <p>We investigated the prevalence of rare, additional, potentially protein-altering <i>PKD1</i> variants in patients with <i>PKD1</i>-associated ADPKD<i>.</i> 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.</p> Results <p>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&#xa0;years earlier progression to kidney failure (hazard ratio (HR): 1.66; 95% confidence interval (CI): 1.18–2.34; <i>P</i> = 0.003), with in-<i>trans</i> rare, additional, potentially protein-altering variants (<i>n</i> = 13/894) showing a greater risk of kidney failure (HR: 1.83; 95% CI 1.00–3.33; <i>P</i> = 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.</p> Conclusions <p>In patients with <i>PKD1</i>-associated ADPKD, our findings suggest that rare, additional, potentially protein-altering variants in <i>PKD1</i> 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.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月30日

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  • Elhussein A. E. Elhassan,
  • Kane E. Collins,
  • Sophia Heneghan,
  • Edmund Gilbert,
  • Hana Yang,
  • Sarah R. Senum,
  • Rachel S. Schauer,
  • Doaa E. Elbarougy,
  • Stephen F. Madden,
  • Susan L. Murray,
  • Omid Sadeghi-Alavijeh,
  • Joshua Carmichael,
  • Daniel Gale,
  • Shohdan M. Osman,
  • Claire Kennedy,
  • Matthew D. Griffin,
  • Liam Casserly,
  • Brona Moloney,
  • Paul O’Hara,
  • Amali Mallawaarachchi,
  • Francesca Ciurli,
  • 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,
  • Claudio Graziano,
  • Constantin A. Wolff,
  • Ria Schönauer,
  • Gaetano LaManna,
  • Axelle Durand,
  • Sophie Limou,
  • Jan Halbritter,
  • Irene Capelli,
  • Emma McCann,
  • Peter C. Harris,
  • Gianpiero L. Cavalleri,
  • Katherine A. Benson,
  • Peter J. Conlon

摘要

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.

Graphical abstract