#1049 Genetic characteristics of autosomal dominant polycystic kidney disease in a Greek population

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Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the predominant monogenic renal genetic disorder, and the fourth leading cause of end stage kidney disease. Confirmatory genetic testing defines the disease, provides prognostic information and may support therapeutic management. This study aims to investigate the genetic characteristics of a substantial cohort of ADPKD patients from a single Greek center. Method Ninety-three patients (46 females, 47 males with a mean age of 34 ± 15 years) were enrolled from 59 distinct families attending the outpatient ADPKD clinic at the Nephrology Department of the General Hospital of Athens “G. Gennimatas.” Genetic analysis included targeted next-generation sequencing (tNGS) of over 600 clinically relevant genes, Sanger sequencing, and Multiplex ligation-dependent probe amplification (MLPA). Whole exome and whole genome sequencing (WES and WGS) studies were conducted in 3 patients with negative results. Magnetic Resonance Imaging (MRI) was performed in 74 out of 93 patients, revealing more than 10 renal cysts in all but one patient. Children with a positive family history (FH) displayed at least one cyst in echography, while two without FH had multiple renal cysts. Results Genetic diagnosis was established in 88 of 93 patients (94.5%). Seventy patients (75%), demonstrated 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%) patients. Additionally, mutations in genes other than PKD1 and PKD2 were identified in 3 patients (3.5%). Two cases, involving a father and son, revealed the presence of a SEC61B variant; the father exhibited more than 10 renal cysts and liver cysts in the MRI, while the son displayed only liver cysts. Additionally, a third patient, a woman with nephrolithiasis and over 10 renal cysts in the MRI, exhibited a SLC3A1 variant. Notably, 5 patients (5.5%) with ADPKD phenotype had negative genetic analyses, despite the application of both WES and WGS in three of these patients. Truncating mutations in PKD1 were observed in 43 of 70 cases, (61%), while the rest (39%) had non-truncating mutations. Detected variants were classified as Pathogenic (45.5%), Likely Pathogenic (36%), and Variants of Uncertain Significance (VUS-13.5%, 12 cases), according to the guidelines of the American College of Medical Genetics and Genomics. Reclassification to Likely Pathogenic could be proposed for 6 out of 12 cases with VUS variants for which family segregation was noted. 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 the 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.