Isolated Polycystic Liver Disease (PCLD) Panel

Isolated polycystic liver disease (PCLD) is one of the three clinical entities of polycystic liver disease (PLD), a collection of disorders characterized by development of multiple hepatic cysts in adulthood due to embryonic ductal plate malformation of the intrahepatic biliary tree (Keimpema et al. 2011; Cnossen et al. 2014). A polycystic liver can be also found in Von Meyenburg complexes (VMC; also termed microhamartomas) characterized by small, nonhereditary nodular cystic lesions; and autosomal dominant polycystic kidney disease (ADPKD) with concurrent hepatic cysts in over 80% of cases as the most frequent extra-renal manifestation.

The presentation of isolated polycystic liver disease (PCLD) is restricted to the liver in the absence of polycystic kidneys. In contrast, ADPKD is a multi-systemic disorder with polycystic kidneys as the major feature.

Isolated polycystic liver disease (PCLD) is an autosomal dominant disorder caused by mutations in PRKCSH, SEC63 or LRP5 (Drenth et al. 2003; Li et al. 2003; Davila et al. 2004; Cnossen et al. 2014).

PRKCSH (16 coding exons) and SEC63 (21 coding exons) encode the beta-subunit of glucosidase II (a protein kinase C substrate) and Sec63p, respectively. Both proteins are located within the endoplasmic reticulum (ER) and are responsible for quality control and translocation of glycoproteins into the ER. Defects in PRKCSH and SEC63 account for about 16-25% of PLCD patients (Keimpema et al. 2011; Cnossen et al. 2014).

The LRP5 gene (23 coding exons) encodes a transmembrane low-density lipoprotein receptor, which plays a key role in skeletal homeostasis. Many bone density related diseases such as autosomal dominant osteopetrosis are caused by mutations in this gene. LRP5 mutations were recently reported to cause hepatic cystogenesis (clinically diagnosed as PCLD) due to deregulation of the canonical wingless signaling pathway (Cnossen et al. 2014).

Defects in PRKCSH and SEC63 can be found in 16-25% of PLCD patients (Keimpema et al. 2011; Cnossen et al. 2014). In a cohort of 150 unrelated PCLD patients without mutations in PRKCSH, SEC63 or PKD2 genes, four families were found to have LRP5 mutations (Cnossen et al. 2014).

No large deletion or duplications have been reported in PRKCSH and SEC63.

Only two large deletions to date have been reported in LRP5 for osteoporosis-pseudoglioma syndrome (Human Gene Mutation Database).

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).