Genetic Characteristics of Autosomal Dominant Polycystic Kidney Disease in a Greek Population

Background: Autosomal Dominant Polycystic Kidney Disease is the predominant monogenic renal genetic disorder. Confirmatory genetic testing defines the disease, provides prognostic information and may support therapeutic management. This study aims to investigate the genetic characteristics of a cohort of ADPKD patients from a single Greek center. Methods: Ninety-three patients ( 46 females, 47 males, mean age: 34±15 years ) were enrolled from 59 distinct families attending our outpatient ADPKD clinic. Genetic analysis included Targeted next-generation sequencing of over 600 genes, Sanger sequencing, and Multiplex ligation-dependent probe amplification. MRI was performed in 74 patients, revealing more than 10 renal cysts in all but one patient. Children with positive family history (FH) displayed at least one cyst, while two without FH had multiple renal cysts. Results: Genetic diagnosis was established in 88 of 93 patients (94.5%). Seventy patients (75%), had single nucleotide variants (SNVs) and large deletions (4 patients) in the PKD1 gene, whereas SNVs and large deletions (5 patients) in the PKD2 gene were identified in 15 (16%) cases. Other gene mutations were found in 3 patients (3.5%). Two cases, involving a father and son, revealed a SEC61B variant; the father displayed more than 10 renal and liver cysts in the MRI, while the son had only liver cysts. Another patient with nephrolithiasis and over 10 renal cysts, had a SLC3A1 variant. Five patients (5.5%) had negative genetic analyses. Truncating mutations in PKD1 were observed in 43 cases, (61%), while the rest (39%) had non-truncating mutations. Variants were classified as Pathogenic (45.5%), Likely Pathogenic (36%), and Variants of Uncertain Significance (VUS 13.5%), according to the guidelines of the American College of Medical Genetics. Reclassification to Likely Pathogenic could be proposed for 6 VUS cases with noted family segregation. Finally, 52% and 82% of the detected variants have not been previously reported in ClinVar and gnomAD databases, respectively. Conclusion: In this ethnically homogenous population, truncating mutations in PKD1 gene were the predominant genetic cause of ADPKD, followed by PKD1 non-truncating mutations, PKD2 gene variants and other rare or undefined genetic etiologies.