Phenotypic outcomes of PKD1 compared with non-PKD1 genetically confirmed autosomal dominant polycystic kidney disease

<p dir="ltr"><b>Background: </b>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 <i>PKD1</i> and non-<i>PKD1 </i>variants.</p><p dir="ltr"><b>Methods: </b>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.</p><p dir="ltr"><b>Results:</b> 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) <i>PKD1</i> families and 23.2% (46/198) non-<i>PKD1</i> families, which include <i>PKD2</i> (<i>n</i> = 29 families), <i>IFT140</i> variants (<i>n</i> = 4), <i>ALG5</i>, <i>DNAJB11</i> and <i>NEK8 </i>(<i>n</i> = 3 each),<i> ALG8 </i>and <i>ALG9 </i>variants (<i>n</i> = 2 each). The remaining 2.6% (5/198) accounted for non-ADPKD variants. </p><p dir="ltr">Compared to<i> PKD1</i>, non-<i>PKD1 </i>families were characterized by a milder phenotype; milder eGFR decline (- 1.4 mL/min/1.73m²/year vs. - 3.2; <i>p</i> < 0.001), smaller ht-TKV (449.7 mL/m vs. 1769;<i> p</i> 0.002) and a delayed progression towards kidney failure (73 vs. 52 years; HR: 0.12, <i>p</i> < 0.001 [95% CI: 0.07-0.19]). ADPKD-<i>NEK8</i> heterozygotes demonstrated earlier progression to kidney failure (average age 8 vs. 49 years for<i> PKD1</i>; Bonferroni-corrected p 0.017).</p><p dir="ltr"><b>Conclusion: </b>Non-<i>PKD1</i> variants have heterogeneous phenotypic and genotypic attributes resulting in milder disease, although ADPKD-<i>NEK8</i> is an important exception with early progression.</p>