Autosomal Dominant Polycystic Kidney Disease (ADPKD) via the DNAJB11 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). 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.

Defects in the DNAJB11 gene cause atypical ADPKD, in which patients present with non-enlarged cystic kidneys, progressive interstitial fibrosis and late-onset ESRD (Cornec-Le Gall et al. 2018. PubMed ID: 29706351). The normal-sized cystic kidneys and interstitial fibrosis in non-cystic parenchyma suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD).

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

DNAJB11 (10 coding exons) encodes a co-factor of BiP, a key chaperone in the endoplasmic reticulum (ER) that controls folding, trafficking and degradation of secreted and membrane proteins. Documented pathogenic variants in DNAJB11 include truncating changes (nonsense and frame-shifting small deletion/insertions) and missense substitutions (Cornec-Le Gall et al. 2018. PubMed ID: 29706351). No large deletions or duplications have been reported yet.

After the identification of DNAJB11 as a new causative gene for autosomal dominant polycystic kidney disease (ADPKD) in two index families, analysis of an additional 591 genetically unresolved ADPKD families found five (~1%) families with pathogenic variants in DNAJB11 (Cornec-Le Gall et al. 2018. PubMed ID: 29706351).

This test provides full coverage of all coding exons of the DNAJB11 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).