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Kidney Week

Abstract: FR-PO709

ADPKD: Rare PKD1 and PKD2 Complex Genotypes May Explain Intrafamilial Phenotypic Variability

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Izzi, Claudia, Spedali Civili di Brescia, Montichiari, Brescia, Italy
  • Delbarba, Elisa, University of Brescia, Montichiari (Brescia), Italy
  • Gnutti, Barbara, Spedali Civili di Brescia, Brescia, Italy
  • Savoldi, Gianfranco, Spedali Civili di Brescia, Brescia, Italy
  • Dallera, Nadia, Spedali Civili di Brescia, Montichiari, Brescia, Italy
  • Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy

Discordant affected relative-pairs are seen in nearly 10% of ADPKD families.
Complex genotypes may result in renal disease variability beyond that predicted by the sole effect of a PKD mutant allele, leading to the discovery of biallelic or digenic disease. Here we illustrate such complexity in 6 ADPKD pedigrees showing a marked intrafamilial phenotypic variability.


Among our single-center ADPKD cohort (186 patients), we selected pedigrees (P) in which marked phenotypic variability was investigated by NGS analysis of PKD1 and PKD2 genes.


In P1 and P2, the index cases (IC), presented with very early onset (VEO) disease. In P1, with neonatal onset, the ADPKD affected father transmitted a PKD1 truncating (T) mutation, whereas the mother, without cystic phenotype, transmitted a PKD1 hypomorphic mutation. In P2, the ADPKD-PKD2 mother’s pregnancy was complicated by Potter sequence. Parent’s PKHD1 gene analysis was negative. Two non truncating (NT) mutations in PKD1/PKD2 genes were detected in the healthy father. Therefore, a complex PKD inheritance was suspected in the fetus. P3: early onset (EO) ADPKD in two monozygous twins was underpinned by a PKD1 NT mutation on their inherited paternal allele and by a de-novo PKD1 T mutation. In P4 a digenic ADPKD was diagnosed in the two most severely affected siblings: a PKD2 T mutation and a PKD1 NT mutation were detected. Elderly parents in P5 and P6 had few kidney cysts and preserved eGFR, whereas IC showed moderate/severe CKD due to ADPKD. In P5 the IC carried a homozygous PKD1 NT mutation; in P6 the IC harbored 2 PKD1 mutations (in trans).


Our study illustrates the genetic complexity in an otherwise “simple” Mendelian disorder, providing insights into the genetic basis of ADPKD intrafamilial disease variability.


  • Government Support - Non-U.S.