Submission Details

PKHD1 was first reported in relation to autosomal recessive polycystic kidney disease in 2002 (Ward et al., PMID: 11919560). Autosomal recessive polycystic kidney disease (ARPKD) is a rare, genetic hepatorenal fibrocystic syndrome characterized by cystic dilatation and ectasia of renal collecting tubules, and a ductal plate malformation of the liver resulting in congenital hepatic fibrosis. Clinical presentation, whilst typically in utero or at birth, is variable and in the most severe cases includes Potter-sequence, oligohydramnios, pulmonary hypoplasia, and massively enlarged echogenic kidneys. Heterozygous carriers of pathogenic variants in PKHD1 have been associated with susceptibility to liver and/or kidney cysts in two publications (PMID: 21945273, 28375157). However, in reviewing the evidence associating PKHD1 with monoallelic late-onset polycystic kidney disease, it was unclear if the relationship represents a monogenic disorder with reduced penetrance or a risk factor. Published family studies and long-term phenotypic data are currently limited so, without clear evidence, it was decided to not curate PKHD1 for a separate monoallelic disorder. Seventeen variants (missense, indel, nonsense, and frameshift) reported in ten probands in two publications (PMIDs: 11919560, 12506140) are included in this biallelic curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by animal models phenocopying the ARPKD liver phenotype, although the kidney disease is milder in rodents than humans, and expression studies including ciliary/basal body localization (PMIDs: 11919560, 12925574, 14983006, 18782757, 15830394, 17519956, 18286309). The pck rat with homozygous Pkhd1 knockout exhibited significantly less immunoreactivity of the ARPKD protein, fibrocystin (FBC), than wild-type rats. Some collecting duct epithelia completely lacked detectable FPC expression at the cellular level and only ~5% of the pck renal cysts retained FPC labelling with most being at the early stage of cystogenesis with no FPC labelling in large cysts of the pck rat kidneys (PMID:14983006). These findings indicate that significant reduction/loss of PKHD1 expression is associated with cystogenesis in ARPKD. Similar results were seen in a mouse model designed with a targeting construct disrupting exon 15 and deleting exon 16, which resulted in a variant allele. Mice heterozygous for the allele were intercrossed to produce homozygous Pkhd1-/- mice. These mice had cystic or dilated-duct phenotypes in the pancreas with mild-severe tubular dilation (PMID: 18235088, 18782757). In summary, PKHD1 is definitively associated with autosomal recessive polycystic kidney disease (ARPKD-PKHD1). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Disorders GCEP on the meeting date 11/11/2020 (SOP Version 8).