Autosomal Recessive Polycystic Kidney Disease (ARPKD) via the PKHD1 Gene

Autosomal recessive polycystic kidney disease (ARPKD) is a hepatorenal fibrocystic disorder characterized by enlarged kidneys with collecting duct cysts and congenital hepatic fibrosis due to ductal plate malformation (DPM) during development (Bergmann. 2017. PubMed ID: 29479522; Sweeney et al. 1993. PubMed ID: 20301501). Arterial hypertension often develops during the first months of life and affects up to 80% of children with ARPKD. Severity varies widely; and the most severe cases are often neonatal lethal, accounting for approximately 30% of ARPKD patients with pathogenic variants in PKHD1. Diagnosis is often made pre- or neonatally although some cases are diagnosed in childhood or adult life. Many who survive the newborn period progress to end stage renal disease (ESRD).

PKHD1 is the primary causative gene for ARPKD (Bergmann. 2017. PubMed ID: 29479522; Ward et al. 2002. PubMed ID: 11919560). Accounting for a small fraction of genetically positive cases, DZIP1L was newly identified as the second causative gene for ARPKD (Lu et al. 2017. PubMed ID: 28530676; Hartung and Guay-Woodford. 2017. PubMed ID: 28736432).

The PKHD1 gene (67 coding exons) encodes fibrocystin, a ciliary-localized membrane protein involved in a wide range of cellular functions including cell-to-cell adhesion and proliferation, acting as a membrane-bound receptor, and microtubule organization and/or in mechano- or chemosensation (Bergmann. 2017. PubMed ID: 29479522). Documented pathogenic variants in PKHD1 include truncating changes (nonsense, typical splicing variants and frame-shifting small deletion/insertions) and missense substitutions throughout the length of the gene (Human Gene Mutation Database). Multi-exon deletions and duplications occur, but are relatively rare (probably <5% of all pathogenic variants) (Bergmann et al. 2005. PubMed ID: 16199545). No obvious genotype-phenotype correlations have been established to date, but patients with two protein-truncating variants usually have the most severe disease with perinatal or neonatal mortality.

Patients with a heterozygous pathogenic variant in autosomal dominant polycystic kidney disease (ADPKD) genes such as PKD1 and PKD2 typically have onset of symptoms in adulthood. In some rare cases, however, patients with bi-allelic PKD1 variants may have clinical features similar to those of patients with ARPKD (Rossetti et al. 2009. PubMed ID: 19165178; Vujic et al. 2010. PubMed ID: 20558538; Audrézet et al. 2016. PubMed ID: 26139440). In these rare cases, symptoms may appear in early childhood or even in utero. Therefore, testing for ADPKD genes have been recommended for early onset PKD patients, especially when testing of PKHD1 or DZIP1L returns negative.

Homozygous or compound heterozygous pathogenic variants in PKHD1 can be found in ~80% of autosomal recessive polycystic kidney disease (ARPKD) patients regardless of disease severity. Approximately 95% of affected individuals were found to have at least one pathogenic variant in PKHD1 (Bergmann. 2017. PubMed ID: 29479522). Multi-exon deletions and duplications occur, but are relatively rare (probably <5% of all pathogenic variants) (Bergmann et al. 2005. PubMed ID: 16199545).

This test provides full coverage of all coding exons of the PKHD1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.