Dent Disease via the CLCN5 Gene

Dent disease is a progressive proximal renal tubulopathy with hypercalciuria, low-molecular-weight proteinuria, and nephrocalcinosis (Devuyst and Thakker 2010). Signs and symptoms of this condition appear in early childhood and progress to end-stage renal disease (ESRD) in early to mid-adulthood. Some patients may develop rickets or osteomalacia. The severity of the disease in affected individuals may vary greatly within the same family.

Dent disease is inherited in an X-linked recessive pattern. Defects in the CLCN5 and OCRL genes account for about 50-60% and 15% of all cases of Dent disease, respectively (Devuyst and Thakker 2010). Dent disease occurs de novo in approximately 10% of patients. The milder features of low-molecular-weight (LMW) proteinuria proteinuria and hypercalciuria present in approximately 70% and 50% of females carriers, respectively. The CLCN5 gene encodes the ClC-5 chloride channel expressed in tubular epithelial cells. So far, genetic defects of CLCN5 found in Dent disease include missense, nonsense, splicing variants, small deletion/insertions and large deletions (Human Gene Mutation Database).

Defects in the CLCN5 gene account for about 50-60% of all cases of Dent disease (Devuyst and Thakker 2010). Given that large deletions are not detectable by Sanger sequencing, the overall CLCN5 mutation detection rate via current Sanger sequencing will be lower than 50-60% for Dent disease.

This test provides full coverage of all coding exons of the CLCN5 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).