Next-Generation Sequencing in Early Diagnosis of Dent Disease 1: Two Case Reports

Abstract

Dent disease 1 is a rare X-linked recessive inherited disease, caused by pathogenic variants in the chloride voltage-gated channel 5 (CLCN5) gene. Dent disease 1 is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, and chronic kidney disease. Infants may manifest only asymptomatic LMW proteinuria, which increases the difficulty of early diagnosis. We describe two male infants presenting only with nephrotic-range LMW proteinuria observed on examination using urine protein electrophoresis. Hereditary renal tubular diseases were highly suspected based on early onset age and LMW proteinuria. Thus, next-generation sequencing (NGS) was performed and pathogenic mutations in CLCN5 were identified in both patients. A diagnosis of Dent disease 1 was established based on the above informations. The two patients developed hypercalciuria during late follow-up, which verified the diagnosis. These two cases highlight the importance of next-generation sequencing in the early diagnosis of Dent disease 1 with only LMW proteinuria.

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

“…More than 220 CLCN5 pathogenic mutations have been reported so far. Mutations were found scattered along all exons of the gene and in different protein domains [9,[34][35][36][37][38][39][40][41][42][43][44][45]. Mansour-Hendili et al [9] reported that the majority were missense and frameshift mutations (33.33% and 29.05% respectively) followed by nonsense mutations (17.52%), splicing mutations (12.39%), and large deletions (4.70%).…”

Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition

“…The proximal tubule represents the site of greatest calcium reabsorption within the renal tubule, and it is mutations in the ClC-5 chloride transporter in this region, encoded by CLCN5, that give rise to Dent disease type 1 [12]. This condition demonstrates an X-linked recessive pattern of inheritance; affected males usually display a triad of low molecular weight (LMW) proteinuria, hypercalciuria and nephrocalcinosis, although the triad may be incomplete at initial presentation [11]. Female carriers are usually asymptomatic, but may occasionally have LMW proteinuria, hypercalciuria or nephrolithiasis [12].…”

“…OCRL mutations, which may result in a spectrum of phenotypes ranging from Dent disease 2 to the more severe Lowe oculocerebrorenal syndrome, account for a further 15% of cases, whilst the underlying genetic mutation remains unascertained in 25% of cases [12]. The varied phenotypes of Dent disease may also include a partial Fanconi syndrome as the initial clue indicating proximal tubular dysfunction [13], whilst nephrolithiasis or haematuria can also feature alongside the cardinal LMW proteinuria [11]. Although genetic conditions with a Fanconi syndrome, including Lowe oculocerebrorenal syndrome (OCRL mutations) and cystinosis (CTNS mutations) may also feature nephrocalcinosis [14,15], it remains more commonly associated with Dent disease 1 (CLCN5 mutations) [16].…”

“…Treatment options for Dent disease are limited. Early diagnosis is crucial in order to prioritise preservation of renal function for as long as possible and offer accurate prognostic information [11]. Patients should undergo careful CKD monitoring with control of variables such as blood pressure.…”

“…Commonly used medications may easily inadvertently worsen the condition of patients with other inherited tubulopathies: loop diuretic use can potentiate hypercalciuria and worsen nephrolithiasis/nephrocalcinosis burden, whereas use of potassium-sparing diuretics should be avoided in patients with distal renal tubular acidosis [10]. Furthermore, in cases where a proactive approach to personalised genetic medicine has been taken, next generation sequencing has identified CLCN5 mutations (Dent disease 1) in patients for whom only low-molecular weight proteinuria was present at diagnosis, i.e., before the full phenotype had emerged [11]. Finally, given the current paucity of treatment options for nephrocalcinosis, it is potentially from the study of these rare monogenic causes that key future therapeutic targets may emerge which could revolutionise our management of the condition (Table A1).…”