Elhassan Elhussein A E, O'Donoghue Darragh, Heneghan Sophia, Teltsh Omri, Sarihan Sahin, Osman Shohdan M, Clince Michelle, Synnott David, Craig Sophie, Hudson Amy, Doyle Brendan, Lappin David, Sexton Donal J, Casserly Liam, Holian John, Magee Colm, Denton Mark, Sweeney Clodagh, Awan Atif, McCann Emma, Cavalleri Gianpiero L, Benson Katherine A, Conlon Peter J
Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.
Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
J Nephrol. 2025 Jan 30. doi: 10.1007/s40620-024-02184-3.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) represents the most common monogenic cause of kidney failure. While identifying genetic variants predicts disease progression, characterization of recently described ADPKD-like variants is limited. We explored disease progression and genetic spectrum of genetically-confirmed ADPKD families with PKD1 and non-PKD1 variants.
In this observational study, we evaluated the clinical (ADPKD-related complications, estimated glomerular filtration rate (eGFR) decline, and progression to kidney failure), radiological (height-adjusted total kidney volume (ht-TKV)), and genetic characteristics of ADPKD families referred to the Irish Kidney Gene Project. Logistic regression and Kaplan-Meier analyses examined relationships between genetic variants and disease progression.
Genomic sequencing was performed on 261 ADPKD families, and 75.8% (198/261 families, comprising 391 individuals) were identified to harbor pathogenic/likely pathogenic variants; 74.2% (147/198) PKD1 families and 23.2% (46/198) non-PKD1 families, which include PKD2 (n = 29 families), IFT140 variants (n = 4), ALG5, DNAJB11 and NEK8 (n = 3 each), ALG8 and ALG9 variants (n = 2 each). The remaining 2.6% (5/198) accounted for non-ADPKD variants. Compared to PKD1, non-PKD1 families were characterized by a milder phenotype; milder eGFR decline (- 1.4 mL/min/1.73m/year vs. - 3.2; p < 0.001), smaller ht-TKV (449.7 mL/m vs. 1769; p 0.002) and a delayed progression towards kidney failure (73 vs. 52 years; HR: 0.12, p < 0.001 [95% CI: 0.07-0.19]). ADPKD-NEK8 heterozygotes demonstrated earlier progression to kidney failure (average age 8 vs. 49 years for PKD1; Bonferroni-corrected p 0.017).
Non-PKD1 variants have heterogeneous phenotypic and genotypic attributes resulting in milder disease, although ADPKD-NEK8 is an important exception with early progression.
常染色体显性多囊肾病（ADPKD）是肾衰竭最常见的单基因病因。虽然识别基因变异可预测疾病进展，但对最近描述的类似ADPKD变异的特征描述有限。我们探索了具有PKD1和非PKD1变异的基因确诊ADPKD家族的疾病进展和基因谱。
在这项观察性研究中，我们评估了转介至爱尔兰肾脏基因项目的ADPKD家族的临床特征（与ADPKD相关的并发症、估计肾小球滤过率（eGFR）下降以及进展至肾衰竭情况）、影像学特征（身高校正后的总肾体积（ht-TKV））和基因特征。逻辑回归和Kaplan-Meier分析检验了基因变异与疾病进展之间的关系。
对261个ADPKD家族进行了基因组测序，75.8%（198/261个家族，共391人）被确定携带致病/可能致病变异；74.2%（147/198）为PKD1家族，23.2%（46/198）为非PKD1家族，其中包括PKD2（n = 29个家族）、IFT140变异（n = 4）、ALG5、DNAJB11和NEK8（各n = 3）、ALG8和ALG9变异（各n = 2）。其余2.6%（5/198）为非ADPKD变异。与PKD1相比，非PKD1家族的表型较轻；eGFR下降较轻（-1.4 mL/min/1.73m/年 vs. -3.2；p < 0.001），ht-TKV较小（449.7 mL/m vs. 1769；p 0.002），进展至肾衰竭的时间延迟（73岁 vs. 52岁；HR：0.12，p < 0.001 [95% CI：0.07 - 0.19]）。ADPKD-NEK8杂合子进展至肾衰竭的时间较早（平均年龄8岁 vs. PKD1为49岁；Bonferroni校正p 0.017）。
非PKD1变异具有异质性的表型和基因型特征，导致疾病较轻，不过ADPKD-NEK8是一个重要例外，其进展较早。
