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<i>Background:</i> Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either <i>PKD1</i> or <i>PKD2</i> gene mutations. The majority (85%) of the mutations are in the <i>PKD1</i> gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. <i>Materials and Methods:</i> In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. <i>Results:</i> Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the <i>PKD1</i> gene was exon15: (c.4264G > A). Two missense mutations were identified with a <i>PKD1</i> (c.1758A > C and c.9774T > G), and one patient had a <i>PKD2</i> mutation (c.1445T > G). Three detected variants were novel, identified at <i>PKD1</i> (c.1758A > C), <i>PKD2L2</i> (c.1364A > T), and <i>TSC2</i> (deletion of a’a at the 3’UTR, R1680C) genes. Other variants in <i>PKD1L1</i> (c.3813_381 4delinsTG) and <i>PKD1L2</i> (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. <i>Conclusion:</i> This study reported a common variant in the <i>PKD1</i> gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in <i>PKD1 and PKD2L2</i> genes and one indel mutation at the 3’UTR of the <i>TSC2</i> gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein–protein interaction studies to investigate the influence of these mutations on <i>PKD1</i> and <i>PKD2</i> functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.