Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disorder. Between 85% and 90% of cases result from variations in the PKD1 and PKD2 genes. Over 30 genes have been associated with ADPKD, contributing to its heterogeneity. This study aimed to investigate novel variations in the PKD1, PKD2, and ADPKD-related genes through whole-exome sequencing (WES) and combine the genotype and phenotype data of the patients. WES was performed on peripheral blood samples from 44 ADPKD patients, and variations were evaluated and classified based on ACMG criteria. A heterozygous pathogenic/likely pathogenic (P/LP) PKD1 variant was identified in 33 patients (75%). Seven patients had a heterozygous P/LP PKD2 variant (15.9%). No heterozygous P/LP PKD1 or PKD2 variant was found in 4 patients (9.1%), and one of them (2.3%) had a heterozygous pathogenic PKHD1 variant. Thirteen novel PKD1 variations were identified, with nine associated with fast estimated glomerular filtration rate (eGFR) decline. Potentially pathogenic Variants of Uncertain Significance in ALG9, CEP290, NPHP4, WDR19, and TTC21B were identified in three patients lacking PKD1/PKD2 variants. Survival analysis indicated that patients with PKD1 or PKD2 or without any PKD1/PKD2 mutations experienced a similar age of onset for end-stage kidney disease. The annual decline in eGFR was significantly higher in patients with a PKD1 mutation than in those with a PKD2 mutation, along with a higher Mayo Class. Genetic studies evaluating novel variants in the PKD1, PKD2, and ADPKD-related genes alongside patients' clinical data are essential for a deeper understanding of ADPKD diagnosis, prognosis, and pathology.