Dent disease (DD) is a rare X-linked genetic cause of Fanconi syndrome. The DD phenotype is defined as a clinical picture characterized by LMWP associated with hypercalciuria and/or at least one of the following: nephrocalcinosis, nephrolithiasis, phosphaturic tubulopathy, bone disorders, chronic kidney disease, and family history of nephropathy.
From 2008 to 2014 DNA samples from 130 unrelated pediatric (71%) and adult (29%) patients with a clinical suspicion of DD were analyzed. We defined as a probable DD phenotype when patients presented with LMWP and hypercalciuria in association with at least one of the other signs indicated above and “possible” when patients presented with LMWP with at least one of the other signs also in the absence of hypercalciuria.
Among these patients, we detected 23 CLCN5 mutations, of which 14 are novel, giving a detection rate 18%. Of the 107 patients with no CLCN5 mutation, we selected 34 for mutational screening of OCRL gene. The selection was based on the presence of a probable DD phenotype with or without extra-renal symptoms. We detected 15 OCRL mutations, of which 2 are novel, giving a detection rate of 44%. Twelve patients who were six pairs of brothers in pediatric age were all positive. The remaining CLCN5 and OCRL negative patients represent a selected sample where conduct whole exome sequencing for discovering further DD gene/s.
Our results suggest that a well assessed clinical suspicion is determinant for the success of molecular diagnosis of DD. We think that the CLCN5 negative patients not investigated for the presence of OCRL mutations due to the lack of a clear DD may represent a heterogeneous pool of patients with phenotypic variants of already known hereditary renal disease. Targeted sequencing using a panel of disease genes for renal tubulopathies and nephrolithiasis should be more appropriated as molecular diagnostic procedure.
