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

## TL;DR

This study shows that rare, additional genetic variants in the PKD1 gene may speed up kidney failure in people with a type of kidney disease called ADPKD.

## Contribution

The study identifies a new potential modifier of disease severity in ADPKD through rare, non-pathogenic PKD1 variants.

## Key findings

- Rare, additional PKD1 variants were found in 6% of ADPKD patients.
- These variants were linked to kidney failure 4 years earlier than in patients without them.
- In-trans variants showed an even higher risk of kidney failure.

## Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1007/s40620-025-02211-x.

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.

The online version contains supplementary material available at 10.1007/s40620-025-02211-x.