Genetic analysis of autosomal dominant polycystic kidney disease in Iranian families: a combined Sanger and next-generation sequencing study.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder, primarily caused by mutations in the PKD1 and PKD2. Genetic testing is valuable for the diagnosis, prognosis, and clinical management of ADPKD. Next-generation sequencing (NGS) techniques can overcome the limitations of traditional Sanger sequencing for the genetic diagnosis of ADPKD. This study included 18 Iranian ADPKD families. Long-range PCR and Sanger sequencing were used to analyze PKD1 and PKD2. Subsequently, NGS-based gene panel testing and whole-exome sequencing (WES) were also performed in selected families. Pathogenic/likely pathogenic variants were identified in 13/18 families (72.2%), including 9 in PKD1 and 4 in PKD2. Five novel variants were discovered (c.10016C > A, c.2096_2097 + 4del, c.12138 + 5G > C in PKD1; c.2359-8_2373del, c.180_181delGC in PKD2). Additionally, WES revealed a pathogenic PKD1 frameshift deletion (c.11376delG) in one genetically unresolved family, likely missed by initial Sanger sequencing due to allelic dropout. This study expands the mutational spectrum of PKD1/PKD2 with five novel variants. The findings demonstrate the advantages of NGS over conventional Sanger sequencing methods. The genetically unresolved cases suggest the potential involvement of variants within non-coding regions, large copy number variations, or novel genes in ADPKD pathogenesis. Whole-genome sequencing is warranted to investigate these unresolved cases further.