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

Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by sequence variants in PKHD1. ARPKD presents with considerable clinical variability relating to the type of PKHD1 sequence variant, but not its position. Animal models of Polycystic Kidney Disease (PKD) suggest a complex genetic landscape, with genetic modifiers as a potential cause of disease variability. To investigate in an unbiased manner the molecular mechanisms of ARPKD and identify potential indicators of disease severity, Whole Exome Sequencing (WES) and RNA-Sequencing (RNA-Seq) were employed on human ARPKD kidneys and age-matched healthy controls. WES confirmed the clinical diagnosis of ARPKD in our patient cohort consisting of ten ARPKD kidneys. Sequence variant type, nor position of PKHD1 sequence variants, was linked to disease severity. Sequence variants in genes associated with other ciliopathies were detected in the ARPKD cohort, but only PKD1 could be linked to disease severity. Transcriptomic analysis on a subset of four ARPKD kidneys representing severe and moderate ARPKD, identified a significant number of genes relating to WNT signalling, cellular metabolism and development. Increased expression of WNT signalling-related genes was validated by RT-qPCR in severe and moderate ARPKD kidneys. Two individuals in our cohort with the same PKHD1 sequence variants but different rates of kidney disease progression, with displayed transcriptomic differences in the expression of WNT signalling genes. ARPKD kidney transcriptomics highlights changes in WNT signalling as potentially significant in ARPKD manifestation and severity, providing indicators for slowing down the progression of ARPKD.