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Kidney Week

Abstract: SA-PO748

Incompletely Penetrant Variants Underlie the Familial Variability in Disease Progression in Adults with ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Elhassan, Elhussein Aamir Elzein, Beaumont Hospital, Dublin, Ireland
  • Benson, Katherine A., Royal College of Surgeons in Ireland, Dublin, Dublin, Ireland
  • Madden, Stephen, Royal College of Surgeons in Ireland, Dublin, Dublin, Ireland
  • Ciurli, Francesca, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Emilia-Romagna, Italy
  • Aiello, Valeria, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Emilia-Romagna, Italy
  • Vella, Anna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Emilia-Romagna, Italy
  • Montanari, Francesca, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Emilia-Romagna, Italy
  • Cristalli, Carlotta P., IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Emilia-Romagna, Italy
  • La Manna, Gaetano, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Emilia-Romagna, Italy
  • Capelli, Irene, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Emilia-Romagna, Italy
  • Cavalleri, Gianpiero, Royal College of Surgeons in Ireland, Dublin, Dublin, Ireland
  • Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
Background

Although familial variability is one of the most prominent characteristics of autosomal dominant polycystic kidney disease (ADPKD), its molecular causes remain unknown. We hypothesize that co-inheritance of additional PKD1 or PKD2 variants with a pathogenic inactivating variant may contribute to familial disease progression.

Methods

Family members with clinically diagnosed polycystic kidney disease were recruited. Primary disease-causing variants were identified using ADPKD targeted next-generation sequencing panel. Additional variants (AV) were investigated using the criteria listed below: 1) rare (allele frequency <0.01), 2) missense variants in exonic or splicing regions, and 3) SIFT and PolyPhen predicted to be detrimental to protein formation variants were included. All AVs were deemed as variants of uncertain significance. We compared the progression to end-stage kidney failure (ESKF) between families with AV (at least one member with an additional ADPKD variant per family) and families with only primary variants.

Results

A total of 115 families with ADPKD (338 individuals, 55.9% female, 53.8% progressed to ESKF) were included; 60 different truncating PKD1 variants, 37 non-truncating PKD1 changes, and 7 PKD2 variants. 31 (26.9%) families (52 individuals) had at least one patient with AV. Among these families, those with non-truncating PKD1 variants and AV had a lower mean age of ESKF than in families without additional variants (46 ± 10.1 vs. 52.35 ± 11.6, p = 0.041). The mean age of ESKF was not different between families with truncating PKD1 and PKD2 variants based on AV, 47.8 ± 8.4 vs. 47.3 ± 9.2 and 61.5 ± 3.5 vs. 67.3 ± 11.6, respectively. In a multivariate Cox mixed-effects model (adjusted for sex, early-onset of hypertension, early-onset urological events, and primary ADPKD variants), we identified an independent effect of the additional variants on familial disease progression [multivariate shared frailty model p = 0.0015].

Conclusion

Our findings suggest that familial variability in ADPKD may be explained by co-inheritance of additional damaging variants, particularly in families with PKD1 non-truncating variants.