Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome

Abstract

Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype–phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation.

Bartter Syndrome-Related Variants Distribution: Brazilian Data and Its Comparison with Worldwide Cohorts

“…These authors also detected CKD ≥ stage 2 in 5/12 patients (41.7%) with a molecular diagnosis of BS type 1, while smaller percentage of 2/12 (16.7%), 1/12 (8.3%), and 4/12 (33.3%) showed causative variants in genes responsible for BS types 3, 4a, and GS, respectively. However, there is no mention about the type of the variants in each group [45]. In this Brazilian cohort, we were able to demonstrate that the presence of homozygous 1–20 del in CLCNKB was related to CKD progression characterized by decreasing in eGFR, changing in CKD status and higher proteinuria levels.…”

“…Furthermore, unexpectedly, we identified a novel likely pathogenic variant in SLC12A3 diagnosing GS in two siblings with antenatal/neonatal disease onset. Early GS manifestation has been rarely reported in literature [44, 45]; however, to the best of our knowledge, an antenatal clinical picture is described for the 1st time in this current Brazilian cohort.…”

“…Studies on the CKD progression of these patients have been scarce in the literature. CKD stages 2-5 have been reported in patients with BS with extremely variable rates (0-27%), but some studies did not perform genetic testing confirmation or did not include BS type 3 patients [45]. Palazzo et al [45], by studying BS and GS patients, reported a significantly higher frequency of CKD ≥stage 2 (defined as eGFR <90 mL/min/1.73 m 2 ) in patients with BS than in those affected by GS.…”

“…CKD stages 2–5 have been reported in patients with BS with extremely variable rates (0–27%), but some studies did not perform genetic testing confirmation or did not include BS type 3 patients [45]. Palazzo et al [45], by studying BS and GS patients, reported a significantly higher frequency of CKD ≥stage 2 (defined as eGFR <90 mL/min/1.73 m 2 ) in patients with BS than in those affected by GS. These authors also detected CKD ≥ stage 2 in 5/12 patients (41.7%) with a molecular diagnosis of BS type 1, while smaller percentage of 2/12 (16.7%), 1/12 (8.3%), and 4/12 (33.3%) showed causative variants in genes responsible for BS types 3, 4a, and GS, respectively.…”

A Clinical Workflow for Cost-Saving High-Rate Diagnosis of Genetic Kidney Diseases

“…Selection criteria were usually stringent and phenotype-centered. 15,[19][20][21][22][23][24][25][26][27] However, genetic testing can provide diagnostic certainty also in less well-defined settings such as in advanced CKD where biopsy is usually no longer performed or only reveals nonspecific features of kidney atrophy (CKD of unknown origin [CKDu]). 3,28 Recently, testing with WES in a large cross-section cohort of unselected patients with kidney diseases across all age groups showed an overall diagnostic yield of approximately 10%, 29 questioning cost-effectiveness for health care systems and hence a broader implementation into daily clinical practice in unselected cohorts of patients.…”