Evaluating gene variations in autosomal dominant polycystic kidney disease patients using whole exome sequencing and phenotype to genotype analysis

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