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.

Keywords: Bartter syndrome; Gitelman syndrome; chronic kidney disease; genetics; salt-losing tubulopathies; whole-exome sequencing.

Figure 1

Diagnostic yield and disease reclassification. Patients are initially classified based on the clinical suspicion raised by referring physicians (left node). The clinical diagnosis was reframed during pre-WES consultation (middle node). All the patients underwent genetic testing with WES that allowed us to confirm or reclassify the clinical diagnosis (right node). GS, Gitelman syndrome; BS, Bartter syndrome; Other: genetic diagnosis outside BS and GS; Negative: patients without pathogenic variants.

Figure 2

Clinical features of patients according to genetic diagnosis. (A) Age at onset and age at referral for genetic testing in patients with a molecular diagnosis of BS and GS. (B) Birth weight in patients with a molecular diagnosis of BS and GS. (C) Gestational age at birth in patients with a molecular diagnosis of BS and GS. Individual scores are shown as ◆. ** p value < 0.001. GS, Gitelman syndrome; BS, Bartter syndrome.

Figure 3

Clinical and laboratory features in patients with nephrocalcinosis. (A) Frequency of nephrocalcinosis in patients with a molecular diagnosis of BS and GS. (B) Frequency of hypercalciuria in patients with a molecular diagnosis of BS and GS. (C) Frequency of hypercalciuria in patients with and without nephrocalcinosis, irrespective of the molecular diagnosis. (D) Frequency of alkaline venous blood pH (venous blood pH ≥ 7.45) in patients with and without nephrocalcinosis, irrespective of the molecular diagnosis. (E) Frequency of hypomagnesemia (serum magnesium < 1.7 mg/dL) in patients with and without nephrocalcinosis, irrespective of the molecular diagnosis. (F) Frequency of alkaline urinary pH (urinary pH ≥ 7.5) in patients with nephrocalcinosis, irrespective of the molecular diagnosis. (G) Distribution of urinary specific gravity in patients with and without nephrocalcinosis, irrespective of the molecular diagnosis. (H) Distribution of eGFR in patients with and without nephrocalcinosis, irrespective of the molecular diagnosis. eGFR was calculated with Schwartz revised formula in children and CKD-EPI in adults. Individual scores are shown as ◆. * p value < 0.05, ** p value < 0.001. GS, Gitelman syndrome; BS, Bartter syndrome; NC, nephrocalcinosis; NO NC, absence of nephrocalcinosis; eGFR, estimated glomerular filtration rate.

Figure 4

Long-term outcome of patients with BS and GS. (A) Box and whiskers plot of eGFR at last follow up in patients with a molecular diagnosis of BS and GS. Individual scores are shown as ◆. (B). Plot of eGFR over time in patients with a molecular diagnosis of BS (white dots) and GS (black dots). Each dot represents a measurement in one patient. (C) Plot of the eGFR over time in patients with a molecular diagnosis of BS with at least three measurements during follow up. (D) Plot of the estimated glomerular filtration rate over time in a subset of patients with a molecular diagnosis of GS with at least three measurements during follow up. eGFR was calculated with Schwartz revised formula in children and CKD-EPI in adults. ** p value < 0.001. GS, Gitelman syndrome; BS, Bartter syndrome; eGFR, estimated glomerular filtration rate.