Autosomal Dominant Polycystic Kidney Disease (ADPKD) via the GANAB Gene

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited kidney disease with multisystem involvement. ADPKD is characterized by bilateral renal cysts accompanied by cysts in other organs including the liver, seminal vesicles, pancreas, and arachnoid membrane (Harris et al. 2011. PubMed ID: 20301424; Cornec-Le Gall et al. 2019. PubMed ID: 30819518). Renal symptoms include hypertension, renal pain, and renal insufficiency. Nearly half of ADPKD patients have end-stage renal disease (ESRD) by age 60 years. The progressive growth of liver cysts is the most common extrarenal manifestation of ADPKD. The most important non-cystic manifestations of ADPKD are vascular and cardiac abnormalities including intracranial aneurysms, mitral valve prolapse, dilatation of the aortic root, dissection of the thoracic aorta, and abdominal wall hernias. The clinical spectrum of ADPKD is wide and substantial variability of disease severity can occur even within the same family. The prevalence of ADPKD is estimated to be between one in 1,000 and one in 2,500 individuals (Cornec-Le Gall et al. 2019. PubMed ID: 30819518).

GANAB-related ADPKD represents an atypical presentation of ADPKD (Cornec-Le Gall et al. 2019. PubMed ID: 30819518). These patients typically have bilateral renal cysts, but kidney size can be normal and kidney function can be preserved. Some patients have predominant liver cysts with few bilateral renal cysts. Onset is usually in mid to late-adulthood. Genetic testing can benefit differential diagnosis of PKD-related phenotypes.

PKD1 and PKD2 are the two major causative genes for classical ADPKD (Rossetti et al. 2007. PubMed ID: 17582161; Audrézet et al. 2012. PubMed ID: 22508176). Representing atypical presentations of ADPKD, defects in GANAB and DNAJB11 account for only a small fraction of ADPKD cases (Porath et al. 2016. PubMed ID: 27259053; Cornec-Le Gall et al. 2018. PubMed ID: 29706351).

Loss-of-function is the underlying mechanism of the causative genes for ADPKD. The GANAB gene (25 coding exons) encodes glucosidase II subunit alpha, an enzyme of the endoplasmic reticulum functioning in N-linked glycosylation. Defects in GANAB result in disruption of the folding, maturation and trafficking of polycystin-1 (the PKD1-encoded protein). Documented pathogenic variants in GANAB include truncating changes (nonsense, canonical splicing variants and frame-shifting small deletion/insertions) and missense substitutions (Human Gene Mutation Database). No large deletions or duplications have been reported. De novo variants have been reported, but are expected to be uncommon. GANAB is relatively intolerant to loss of function variants (Genome Aggregation Database).

GANAB has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). Ganab haploinsufficiency has been reported to not cause polycystic kidney disease or polycystic liver disease in mice. This is the first animal model study of the GANAB gene; further studies are required (Geng et al. 2020. PubMed ID: 32550232). 

Defects in GANAB account for ~0.3% of total autosomal dominant polycystic kidney disease (ADPKD) (~3% of genetically ADPKD-affected families unexplained by PKD1 and PKD2 pathogenic variants) (Porath et al. 2016. PubMed ID: 27259053).

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

This test provides full coverage of all coding exons of the GANAB gene 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 full 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).