Genetics behind the Phenotypic Spectrum of Polycystic Kidney Disease

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Background: Polycystic kidney disease (PKD) is an inherited disorder with a broad range of clinical presentations. The most common form is autosomal dominant PKD (ADPKD), caused by mutations in PKD1 or PKD2 genes. ADPKD typically manifests in adulthood, leading to bilateral kidney cysts, kidney enlargement, and end-stage chronic kidney disease (ESKD). Autosomal recessive PKD (ARPKD), caused by PKHD1 gene mutations, is more severe and usually appears in childhood or adolescence. Atypical presentations exist, characterized by variations in family history, renal imaging patterns, and phenotypic variability. Here, we want to analyse the genetics behind the cases in our cohort of atypical PKD. Methods: A retrospective cohort study was performed. Inclusion criteria were 1) having a request for genetic analysis specifying the condition of atypical polycystic disease or mentioning the presence of multiple cysts among its clinical manifestations, 2) having a pathogenic variant in one of the less common cystic genes after genetic analysis, regardless of clinical suspicion. Results: In our preliminary cohort of 142 patients, 60.68% have received a genetic diagnosis. In 36.75% of cases, no mutation was detected (NMD), and 2.56% remain inconclusive pending further testing. Preliminary data suggest that 14.53% of atypical polycystic disease cases result from PKHD1 gene mutations. COL4A3 and COL4A4 mutations account for 15.38% of cases, presenting with bilateral renal cysts and microhematuria. The next gene that explains more atypical cases is HNF1B, which shows great phenotypic heterogeneity. Other mutated genes in our cohort include ALG8, GANAB, IFT140, DNAJB11, PKD1, SEC63, and TSC1. Conclusion: Our preliminary atypical PKD cohort has a mutation detection rate of 60,68% The gene responsible for 14% of cases is PKHD1 in heterozygosity COL4A3 and COL4A4 are responsible for approx. 14% of cases. In general, the inheritance pattern is dominant When analyzing genetic results in an atypical PKD case, it’s crucial to consider multiple polycystic disease-associated genes. Additionally, we shouldn’t overlook different modes of inheritance and the variable impact of genetic variants. Funding: Government Support – Non-U.S.

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