Familial Variability of Disease Severity in Adult Patients With ADPKD

Elhussein A E Elhassan; Patrick O'Kelly; Kane E Collins; Omri Teltsh; Francesca Ciurli; Susan L Murray; Claire Kennedy; Stephen F Madden; Katherine A Benson; Gianpiero L Cavalleri; Peter J Conlon

doi:10.1016/j.ekir.2023.12.002

Familial Variability of Disease Severity in Adult Patients With ADPKD

Kidney Int Rep. 2023 Dec 12;9(3):649-660. doi: 10.1016/j.ekir.2023.12.002. eCollection 2024 Mar.

Authors

Affiliations

¹ Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.
² Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
³ School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons, Dublin, Ireland.
⁴ SFI Centre for Research Training in Genomics Data Science, Ireland.
⁵ Data Science Centre, School of Population Heath Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.

Abstract

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity.

Methods: To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity.

Results: Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = <0.001).

Conclusion: Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.

Keywords: ADPKD; CKD; PKD1; intrafamilial variability; kinship; polygenic score.