Next generation sequencing identifies WNT signalling as a significant pathway in Autosomal Recessive Polycystic Kidney Disease (ARPKD) manifestation and may be linked to disease severity

Background: Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by mutations in PKHD1. ARPKD presents with considerable clinical variability relating to the type of PKHD1 mutation, but not its position. Animal models of Polycystic Kidney Disease (PKD) suggest that there is a complex genetic landscape, with genetic modifiers as a potential cause of disease variability.

Methods: To assess this relationship, a Whole Exome Sequencing (WES) and RNA-Sequencing (RNA-Seq) approach was employed on human ARPKD kidneys and age-matched healthy controls, to investigate in an unbiased manner the molecular mechanisms of ARPKD and identify potential markers of disease severity.

Results: WES confirmed the clinical diagnosis of ARPKD in our patient cohort. Mutation type, nor position of PKHD1 mutations, were linked to disease severity. Mutations in genes associated with other ciliopathies were detected in the ARPKD cohort, but only PKD1 could be linked to disease severity. Transcriptomic analysis identified a significant number of genes relating to WNT signalling, cellular metabolism and development. Amongst these genes, increased expression of WNT signalling-related genes was validated by RT-qPCR. In addition, two individuals in our cohort had the same PKHD1 mutations but different rates of kidney disease progression. Amongst the transcriptomic differences of these two individuals were differences in the expression of WNT signalling genes.

Conclusion: ARPKD kidney transcriptomics highlights changes in WNT signalling as potentially significant in ARPKD manifestation and severity and could provide a future therapeutic target for slowing down the progression of ARPKD.