Determinants of renal disease variability in ADPKD

Abstract

In common with other Mendelian diseases, the presentation and progression of autosomal dominant polycystic kidney disease (ADPKD) vary widely in the population. The typical course is of adult-onset disease with ESRD in the 6th decade. However, a small proportion has adequate renal function into the 9th decade, whereas others present with enlarged kidneys as neonates. ADPKD is genetically heterogeneous, and the disease gene is a major determinant of severity; PKD1 on average is associated with ESRD 20 years earlier than PKD2. The majority of PKD1 and PKD2 mutations are likely fully inactivating although recent studies indicate that some alleles retain partial activity (hypomorphic alleles). Homozygotes for such alleles are viable and in combination with an inactivating allele can result in early-onset disease. Hypomorphic alleles and mosaicism may also account for some cases with unusually mild disease. The degree of phenotypic variation detected in families indicates that genetic background influences disease severity. Genome-wide association studies are planned to map common variants associated with severity. Although ADPKD is a simple genetic disease, fully understanding the phenotypic variability requires consideration of influences at the genic, allelic, and genetic background level, and so, ultimately, it is complex.

Figure 1

Illustration showing the variability in severity of renal disease in ADPKD. Kaplan-Meier data, of percent of cases with ESRD (up to 80 years) in total PKD1 (black), PKD2 male (red) and PKD2 female (green) populations. Values from 0–50% ESRD are shown ascending (left scale) and values from 50–100% are shown descending (right scale). PKD1 is significantly more severe than PKD2, and PKD2 males have more severe disease than females. The broad spread of age at ESRD for all three groups indicate that other genetic modifiers and environmental factors influence the phenotype. The milder extremes of the PKD1 (and possibly PKD2) range may partially reflect the presence of hypomorphic alleles and mosaicism. The severe extremes of the ranges may be influenced by in trans inherited PKD1/PKD2 modifying alleles, as is the disease in very early onset cases (not shown).