Autosomal Recessive Polycystic Kidney Disease (ARPKD) Panel

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 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.

The DZIP1L gene encodes DAZ interacting protein 1?like protein, the impairment of which is associated with ciliary trafficking defects and renal cystogenesis. Documented pathogenic variants in DZIP1L include truncating changes (nonsense variants and frame-shifting small deletions/insertions) and missense substitutions (Lu et al. 2017. PubMed ID: 28530676). No large deletions or duplications have been reported yet.

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.

Biallelic variants in CYS1 have been associated with autosomal recessive polycystic kidney disease (ARPKD), but currently the evidence is limited (Yang et al. 2021. PubMed ID: 34521872).

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).

Defects in the DZIP1L gene were found in only two of 743 (~0.3%) unrelated individuals with suspected ARPKD or sporadic PKD (Lu et al. 2017. PubMed ID: 28530676). No large deletions or duplications have been reported yet.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).