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

<p><em>Background: </em>Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by mutations in <em>PKHD1</em>. ARPKD presents with considerable clinical variability relating to the type of <em>PKHD1 </em>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.</p> <p><em>Methods: </em>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.</p> <p><em>Results: </em>WES confirmed the clinical diagnosis of ARPKD in our patient cohort. Mutation type, nor position of <em>PKHD1 </em>mutations, were linked to disease severity. Mutations in genes associated with other ciliopathies were detected in the ARPKD cohort, but only <em>PKD1</em> 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 <em>PKHD1</em> 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.</p> <p><em>Conclusion: </em>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.</p>