Familial Variability of Disease Severity in Adult Patients With ADPKD

Abstract

IntroductionAutosomal dominant polycystic kidney disease (ADPKD) is the commonest monogenic nephropathy and has striking familial variability of disease severity.MethodsTo 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 of onset of kidney failure (KF), the decline in estimated glomerular filtration rate, the predicting renal outcome in PKD (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.ResultsMarked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-NT variants. In families with ≥2 members affected by KF, the average interfamilial 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].ConclusionUsing 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.