The Site and Type of CLCN5 Genetic Variation Impact the Resulting Dent Disease-1 Phenotype

Abstract

Introduction: Dent disease is an X-linked recessive disorder associated with low molecular weight proteinuria (LMWP), nephrocalcinosis, kidney stones, and kidney failure in the third to fifth decade of life. It consists of Dent disease 1 (DD1) (60% of patients) because of pathogenic variants in the CLCN5 gene and Dent disease 2 (DD2) with changes in OCRL.

Methods: Retrospective review of 162 patients from 121 different families with genetically confirmed DD1 (82 different pathogenic variants validated using American College of Medical Genetics [ACMG] guidelines). Clinical and genetic factors were compared using observational statistics.

Results: A total of 110 patients had 51 different truncating (nonsense, frameshifting, large deletions, and canonical splicing) variants, whereas 52 patients had 31 different nontruncating (missense, in-frame, noncanonical splicing, and stop-loss) changes. Sixteen newly described pathogenic variants were found in our cohort. Among patients with truncating variants, lifetime stone events positively correlated with chronic kidney disease (CKD) evolution. Patients with truncating changes also experienced stone events earlier in life and manifested a higher albumin excretion rate than the nontruncating group. Nevertheless, neither age of nephrocalcinosis nor CKD progression varied between the truncating versus nontruncating patients. A large majority of nontruncating changes (26/31; 84%) were clustered in the middle exons that encode the voltage ClC domain whereas truncating changes were spread across the protein. Variants associated with kidney failure were restricted to truncating (11/13 cases), plus a single missense variant previously shown to markedly reduce ClC-5 functional activity that was found in the other 2 individuals.

Conclusion: DD1 manifestations, including the risk of kidney stones and progression to kidney failure, may relate to the degree of residual ClC-5 function.

Keywords: CKD; Dent disease; hypercalciuria; nephrocalcinosis; proteinuria.

Graphical abstract

Figure 1

Prevalence of 82 unique pathogenic variant types (a) and mutation groups (b) among the 121 families in the study. Missense mutations (n = 27), frameshift mutations (n = 23) and nonsense mutations (n = 17) were most frequent followed by canonical splice site mutations (n = 6), copy number variants (CNV; n = 5), in-frame dup/ins (n = 2), noncanonical splicing (n = 1), and stop-loss (n = 1).

Figure 2

Comparison of the number of families with recurrent versus unique pathogenic variants in the truncating and nontruncating groups. Recurrent indicates more than 1 family within our cohort and/or with variants previously described in the literature; Unique indicates the variant present just in 1 family in our cohort.

Figure 3

Location of truncating pathogenic variants (frameshift, nonsense, noncanonical splicing, and CNV) along the entire length of CLCN5 and its known functional domains. ∗Novel variants are in red color

Figure 4

Location of nontruncating pathogenic variants (missense, in-frame [deletions, insertions], stop-loss, and noncanonical splicing) along ClC-5 and its functional domains. The majority fall within middle exons encoding the voltage ClC domain of the protein. ∗Novel variants are in red color

Figure 5

Prevalence of clinical phenotypes at last follow-up in the truncating and nontruncating groups.

Figure 6

Kaplan–Meier survival analysis of clinical phenotypes by variant type (truncating vs. nontruncating). Age at CKD stage 3a (eGFR < 60ml/min/1.73m²) (a), kidney failure (eGFR < 15ml/min/1.73 m²) (b), and nephrocalcinosis (c) are shown. eGFR, estimated glomerular filtration rate.