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

<p dir="ltr"><b>Background: </b>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 dir="ltr"><b>Methods: </b>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 dir="ltr"><b>Results: </b>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; <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 dir="ltr"><b>Conclusions: </b>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.