Genetic Insights into Pediatric Polycystic Kidney Disease and Overlapping Ciliopathies: A Narrative Review

Pediatric cystic kidney diseases lie at the intersection of autosomal dominant polycystic kidney disease (ADPKD) and a broad spectrum of ciliopathies. The pediatric phenotype often reflects a spectrum that includes ARPKD-like presentations, nephronophthisis-related disease, Joubert syndrome-associated kidney involvement, Bardet-Biedl syndrome, and other ciliopathies that can mimic or overlap with PKD. While ADPKD is traditionally attributed to pathogenic variants in PKD1 and PKD2, the widespread deployment of next-generation sequencing has uncovered causal variants in novel loci, including GANAB (~0.3%), DNAJB11 (~0.1%), ALG5, ALG9, and recently, IFT140 and NEK8. This review outlines the expanding genetic and clinical landscape of ADPKD, integrating recent cohort data and molecular insights. We discuss radiologically atypical presentations, overlapping syndromic ciliopathies, and the mechanisms of metabolic reprogramming and primary ciliary dysregulation in cyst pathogenesis. Recent milestones in clinical trials and emerging therapeutic strategies, including perspectives on early risk stratification before the transition to adulthood, are also evaluated. Ultimately, this review emphasizes the necessity of gene-based classifications and precise genotype-phenotype correlations, aligned with the 2025 KDIGO Clinical Practice Guideline for ADPKD, to optimize risk stratification and advance precision medicine in the clinical management of ADPKD.