Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of PKD1 Hypomorphic Alleles

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic PKD1 variants are often identified in early onset ADPKD, with one main pathogenic variant and a modifier hypomorphic variant showing an in trans configuration. We describe two unrelated individuals with early onset cystic kidney disease and unaffected parents, where a combination of next-generation sequencing of cystic genes including PKHD1, HNF1B and PKD1 allowed the identification of biallelic PKD1 variants. Furthermore, we review the medical literature in order to report likely PKD1 hypomorphic variants reported to date and estimate a minimal allele frequency of 1/130 for this category of variants taken as a group. This figure could help to orient genetic counseling, although the interpretation and the real clinical impact of rare PKD1 missense variants, especially if previously unreported, remain challenging.

Automated summary

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic cause of kidney failure, and rare severe presentations are associated with reduced gene dosage. We identified biallelic PKD1 variants using next-generation sequencing in two unrelated individuals with early onset cystic kidney disease. Our analysis of literature estimated a minimal allele frequency of 1/130 for PKD1 hypomorphic variants. This information could guide genetic counseling, but the clinical impact of rare and previously unreported PKD1 missense variants remains challenging.