Abstract
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 describedADPKD-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 analysesexamined 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 (-1.4mL/min/1.73m2/year vs. -3.2; p < 0.001), smaller ht-TKV (449.7mL/m vs. 1769; p 0.002) and a delayed progression towards kidney failure (73 vs. 52years; 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. 49years 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.
Published Version
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