Elhassan Elhussein A E, Collins Kane E, Heneghan Sophia, Gilbert Edmund, Yang Hana, Senum Sarah R, Schauer Rachel S, Elbarougy Doaa E, Madden Stephen F, Murray Susan L, Sadeghi-Alavijeh Omid, Carmichael Joshua, Gale Daniel, Osman Shohdan M, Kennedy Claire, Griffin Matthew D, Casserly Liam, Moloney Brona, O'Hara Paul, Mallawaarachchi Amali, Ciurli Francesca, Graziano Claudio, Wolff Constantin A, Schönauer Ria, LaManna Gaetano, Durand Axelle, Limou Sophie, Halbritter Jan, Capelli Irene, McCann Emma, Harris Peter C, Cavalleri Gianpiero L, Benson Katherine A, Conlon Peter J
Department of Nephrology, Beaumont Hospital, Dublin, Ireland.
Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
J Nephrol. 2025 Jan 30. doi: 10.1007/s40620-025-02211-x.
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.
常染色体显性多囊肾病（ADPKD）主要由PKD1和PKD2基因的致病变异引起。虽然ADPKD变异类型可影响疾病严重程度，但也有报道称罕见的、低表达的PKD1变异可改变疾病严重程度或导致双等位基因ADPKD。本研究旨在探讨罕见的、额外的、可能改变蛋白质的非致病变异的PKD1是否会影响ADPKD的表型结果。
我们调查了PKD1相关ADPKD患者中罕见的、额外的、可能改变蛋白质的PKD1变异的发生率。研究了罕见的、额外的、可能改变蛋白质的变异与表型结果之间的关联，包括进展至肾衰竭、高血压发病年龄和泌尿系统事件、身高校正后的总肾体积，以及PKD（PROPKD）评分预测的肾脏结局。
在该研究的932例ADPKD患者中，6%检测到罕见的、额外的、可能改变蛋白质的变异。罕见的、额外的、可能改变蛋白质的变异的存在与肾衰竭进展提前4年相关（风险比（HR）：1.66；95%置信区间（CI）：1.18-2.34；P = 0.003），其中反式罕见的、额外的、可能改变蛋白质的变异（n = 13/894）显示出更高的肾衰竭风险（HR：1.83；95% CI 1.00-3.33；P = 0.049）。与没有罕见的、额外的、可能改变蛋白质的变异的患者相比，我们未检测到罕见的、额外的、可能改变蛋白质的变异与其他表型结果之间存在统计学显著差异。
在PKD1相关ADPKD患者中，我们的研究结果表明PKD1中罕见的、额外的、可能改变蛋白质的变异可能影响疾病严重程度。这些发现对咨询和治疗有罕见的、额外的、可能改变蛋白质的变异的患者具有潜在的临床意义，但需要在更大的、具有详细标准化表型数据的纵向队列中对这些变异进行进一步研究。
