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Abstract: TH-PO359

A Cohort of Patients With Autosomal Dominant Polycystic Kidney (ADPKD) With the Same Germline Mutation: The Contribution of Other Genetic Variants Can Determine the Extreme Phenotypic Variability

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Caprara, Carlotta, Ospedale San Bortolo di Vicenza, Vicenza, Veneto, Italy
  • Corradi, Valentina, Ospedale San Bortolo di Vicenza, Vicenza, Veneto, Italy
  • Rigato, Matteo, Ospedale San Bortolo di Vicenza, Vicenza, Veneto, Italy
  • Mancini, Barbara, Ospedale San Bortolo di Vicenza, Vicenza, Veneto, Italy
  • Proglio, Marta, Ospedale San Bortolo di Vicenza, Vicenza, Veneto, Italy
  • Gastaldon, Fiorella, Ospedale San Bortolo di Vicenza, Vicenza, Veneto, Italy
  • Ronco, Claudio, Ospedale San Bortolo di Vicenza, Vicenza, Veneto, Italy
  • Zanella, Monica, Ospedale San Bortolo di Vicenza, Vicenza, Veneto, Italy
Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major genetic disorder affecting up to 12.5 million individuals worldwide and it is the fourth most common global cause for renal replacement therapy.
ADPKD is a chronic, progressive condition characterized by the development and growth of cysts in the kidneys and other organs and by additional systemic manifestations. Two principle causative genes have been identified: PKD1 and PKD2. ADPKD phenotype is highly variable intra and inter-family.
The aim of the study was to describe a cohort of ADPKD patients with the same PKD2 genetic mutation and try to find a genetic contribution to the extreme phenotypic variability of the subjects.

Methods

We performed linkage analysis to define disease haplotype. We performed NGS with Sophia Genetic “Nephropathies Solution” Panel. This panel analyzed 44 genes (target region 105.8kb) involved in different types of nephropathies.
We considered variants with autosomal dominant transmission, that are categorized as Vous or likely pathogenic (Class 3 and 4 of ACMG).

Results

We enrolled 29 patients (17 M, 12F) from 12 different families (same geographical area) characterized by the same PKD2 (NM_000297.4) disease haplotype and the same germinal mutation c.2533C>T (p.Arg845Ter). 4 patients out of 29 (13,8%) reported a variant in collagen’s genes:
2 patients share COL4A3 NM_000091.5:c.4421T>C (p.Leu1474Pro) variant and 2 patients share COL4A4 NM_000092.5:c.2996G>A (p.Gly999Glu) variant.
These variants are associated to Thin Basement Membrane Nephropathy (TBMN) and patients with these variants express worst renal clinical phenotype (2pt microhematuria and proteinuria; 1 pt early ESRD).

Conclusion

The analysis did not find out a single “extra” variant that was common among patients with the same clinical course, but highlight variants that may be associated with some phenotypic manifestations not only associated with ADPKD. Study different variants in genes other than “classic” PKD1 and PKD2 can help to better interpret the phenotypic difference, especially in patients that share causative mutation where we expect a “similar genetic impact”.