Many lessons still to learn about autosomal dominant polycystic kidney disease

Abstract

We are still learning the genetic basis for many rare diseases. Here we provide a commentary on the analysis of the genetic landscape of patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), one of the most common genetic kidney diseases. Approaches including both phenotype first and genotype first allows some interesting and informative observations within this disease population. PKD1 and PKD2 are the most frequent genetic causes of ADPKD accounting for 78% and 15% respectively, whilst around 7-8% of cases have an alternative genetic diagnosis. These rarer forms include IFT140, GANAB, PKHD1, HNF1B, ALG8, and ALG9. Some previously reported likely pathogenic PKD1 and PKD2 alleles may have a reduced penetrance, or indeed may have been misclassified in terms of their pathogenicity. This recent data concerning all forms of ADPKD points to the importance of performing genetics tests in all families with a clinical diagnosis of ADPKD as well as those with more atypical cystic kidney appearances. Following allele identification, performing segregation analysis wherever possible remains vital so that we continue to learn about these important genetic causes of kidney failure.

Keywords: ADPKD; Penetrance; Prevalence; Rare Disease; Whole Exome Sequencing.

Fig. 1

Sunburst plot summarising the reported genetic landscape of ADPKD and the reported disease penetrance of different subtypes of PKD1 andPKD2 variants and of 'Other’ variants. ‘Other’ variants refers to atypical causes of ADPKD such as ALG8, ALG9, and IFT140 which are discussed in the manuscript, highlighting the genetic heterogeneity of this disorder. The penetrance of non-truncating PKD1 variants has been given as ‘Variable’ due to the differences in penetrance of these variants depending on whether they were uncovered via exome sequencing alone, or within clinical populations and confirmed by co-segregation. This summary integrates information from many of the studies discussed in the manuscript and was created using BioRender