Experimental Nephrology and Genetics: Research Article
Nephron
DOI: 10.1159/000528557
Bartter Syndrome-Related Variants
Distribution: Brazilian Data and Its
Comparison with Worldwide Cohorts
Maria Helena Vaisbich Ana Carola Hebbia Lobo Messa
Andréia Cristiane Rangel-Santos Juliana Caires de Oliveira Achili Ferreira
Fernanda Andrade Macaferri da Fonseca Nunes Andreia Watanabe
Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, Brazil
Keywords
Bartter syndrome · Gitelman syndrome · Pseudo-Bartter
syndrome · Brazilian cohort · CLCNKB mutation
Abstract
Background: Genetic testing is recommended for accurate
diagnosis of Bartter syndrome (BS) and serves as a basis for
implementing specific target therapies. However, popula-
tions other than Europeans and North Americans are under-
represented in most databases and there are uncertainties
in the genotype-phenotype correlation. We studied Brazilian
BS patients, an admixed population with diverse ancestry.
Methods: We evaluated the clinical and mutational profile of
this cohort and performed a systematic review of BS muta-
tions from worldwide cohorts. Results: Twenty-two patients
were included; Gitelman syndrome was diagnosed in 2 sib-
lings with antenatal BS and congenital chloride diarrhea in 1
girl. BS was confirmed in 19 patients: BS type 1 in 1 boy (an-
tenatal BS); BS type 4a in 1 girl and BS type 4b in 1 girl, both
of them with antenatal BS and neurosensorial deafness; BS
type 3 (CLCNKB mutations): 16 cases. The deletion of the en-
tire CLCNKB (1–20 del) was the most frequent variant. Pa-
tients carrying the 1–20 del presented earlier manifestations
Karger@karger.com © 2023 S. Karger AG, Basel
www.karger.com/nef
Received: May 7, 2022
Accepted: November 28, 2022
Published online: March 7, 2023
   
than those with other CLCNKB-mutations and the presence
of homozygous 1–20 del was correlated with progressive
chronic kidney disease. The prevalence of the 1–20 del in this
BS Brazilian cohort was similar to that of Chinese cohorts and
individuals of African and Middle Eastern descent from other
cohorts. Conclusion: This study expands the genetic spec-
trum of BS patients with different ethnics, reveals some ge-
notype/phenotype correlations, compares the findings with
other cohorts, and provides a systematic review of the litera-
ture on the distribution of BS-related variants worldwide.
© 2023 S. Karger AG, Basel
Introduction
Bartter syndrome (BS) encompasses a group of genet-
ic tubular renal diseases characterized by hypokalemia,
hypochloremia, hyponatremia, metabolic alkalosis, in-
creased blood levels of renin, and aldosterone in patients
with normal to low blood pressure [1]. Clinically, these
tubulopathies can be classified into two types, antenatal
BS and classic BS.
Antenatal BS is the most severe form, characterized by
polyhydramnios, premature birth, failure to thrive, hy-
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Correspondence to:
Maria Helena Vaisbich, mhvaisbich @ gmail.com
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 Color version available online
TAL DCT
Tubular Blood Tubular Blood
Lumen - Lumen +
+ Na+/K+-ATPase -

2K+ Bar�n
2K+ NCCT
K+
3Na+
Na+ Na+ Cl-
Cl- ClC-Ka Cl-
ClC-Kb
Cl-
NKCC2
TRPV5
Bar�n Ca++
ROMK Na+/K+-ATPase

K+ Cl- Mg++ 2K+

2K+
ClC-Kb TRPM6
3Na+

CaSR
Ca++
Mg++

Subtypes of BS Affected gene / Location Molecule implicated

Antenatal type 1 (OMIN 601678) SLC12A1 /15q21.1 Na+K+2Cl- cotransporter NKCC2
Antenatal type 2 (OMIN 241200) KCNJ1 /11q24 Luminal K+ channel ROMK
Classic Bar�er Type 3 (OMIN 607364) CLCNKB /1p36 ClC-Kb channel
Type 4a with neurosensorial deafness (OMIN 602522) BSND /1p31 Barttin, an essential ß subunit for chloride channels
Type 4b with neurosensorial deafness (OMIN 613090) ClCNKA-ClCNKB / 1p36 ClC-Ka and ClC-Kb (chloride channels)
Antenatal Transient BS type 5 (OMIM 300971) MAGED2 / chromosome X MAGE-D2 protein

Fig. 1. Schematic model of sodium, chloride, and potassium transport pathways in the thick ascending limb of
Henle’s Loop and in the distal convoluted tubule, and classification of inherited salt-losing tubulopathies, Bartter
syndrome, and Gitelman syndrome, according to the affected gene and implicated molecule. Transport pathways
in the thick ascending limb of Henle’s loop depicting the four (1–4) types of Bartter syndrome (a). Transport
pathways in the distal convoluted tubule depicting abnormality of Gitelman syndrome (b).

percalciuria, early onset life-threatening salt and water
loss episodes, and nephrocalcinosis [2]. Classic BS occurs
in infancy or early childhood, and it is characterized by
remarkable waste of salt and potassium clinically mani-
fested as polyuria, polydipsia, volume contraction, failure
to thrive, muscle weakness, growth retardation, and, oc-
casionally, nephrocalcinosis [3]. However, before the es-
tablishment of BS clinical hypothesis, acquired or genetic
pseudo-Bartter conditions (PBS), renal or extrarenal,
should be ruled out [4–7]. Among them, Gitelman syn-
drome (GS; OMIN 263800) is an important differential
diagnosis. GS is classically described as a milder BS-like
renal tubular disease frequently associated with hypo-
magnesemia and hypocalciuria that often manifests in
teenagers and young adults with cramps, muscle weak-
ness, salt craving, paresthesia, and tetany [8]. It is also
important to mention the autosomal dominant hypocal-
cemia (OMIN 601198) which can cause BS-like clinical
picture. It is a consequence of gain-of-function mutation
in CASR which encodes the calcium receptor sensor
(CaSR) located in the thick ascending Henle’s loop lead-
ing to secondary disturbances in NKCC2 and ROMK
channels and in Na-K-ATPase pump [9].
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2 Nephron Vaisbich/Messa/Rangel-Santos/Ferreira/
DOI: 10.1159/000528557 Nunes/Watanabe
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 The current classification of BS is based on mutations
in genes encoding specific transporters in renal tubular
membranes (Fig.  1). These mutations lead to dysfunc-
tional proteins determining the clinical and biochemical
abnormalities [10].
Currently, the BS treatment is symptomatic, based on
potassium, chloride and sodium supplementation, and
cyclooxygenase (COX) inhibitors, either nonselective
(ex.: indomethacin) or COX2 selective (ex.: celecoxib)
[11, 12]. A potassium-sparing drug such as spironolac-
tone can be associated. These patients can also be treated
with renin-angiotensin-aldosterone system blockers re-
placing the COX inhibitors. However, these drugs can be
associated with significant and symptomatic hypotension
[12].
Although these treatments can promote complete or
partial electrolyte and metabolic recovery leading to
growth improvement, they are associated with significant
side effects [11]. Furthermore, the patient would always
be prone to severe metabolic and electrolyte imbalance
during common and even mild pediatric illness. There-
fore, there is a need for novel treatments and genetic test-
ing of these patients is essential to serve as a basis for im-
plementing specific target therapies in the near future
[13].
The clinical and genetic profiles of BS have been poor-
ly characterized in developing countries, in non-Cauca-
sian populations and, particularly, in highly admixed
populations. Moreover, the underrepresentation of those
populations represents a limitation in the use of the cur-
rent genomic databases as reference for the analysis of
new variants [14]. Brazilian population is unique owing
to its diverse ancestry and high rate of miscegenation
[15]. We sequenced Brazilian patients with clinical hy-
pothesis of BS to seek the distribution of mutations in this
singular population and to compare the genetic findings
with those already described in BS patients from other
parts of the globe. A possible genotype-phenotype corre-
lation was also explored, mainly to verify factors corre-
lated with chronic kidney disease (CKD) progression.
Patients and Methods
This study has 2 parts: the first one was the clinical and molecu-
lar characterization of Brazilian patients with a clinical diagnosis of
BS, and in part 2, we performed a systematic review of the literature
to explore the genetic spectrum in worldwide cohorts of BS.
Part 1
This is a descriptive part reporting the clinical and genetic
characterization of clinically suspected-BS Brazilian patients up to
Bartter Syndrome: Brazilian and Other
Cohorts’ Genetic Findings
21 years old, followed at University of Sao Paulo Pediatric Ne-
phrology Medical Center. This protocol was approved by the Lo-
cal Ethical Review Board, São Paulo, Brazil (reference number
3.261.257). Patients were enrolled after they and/or their parents
(or guardians) signed the informed consent form. All procedures
were performed in accordance with the International Conference
on Harmonization Good Clinical Practice Guidelines and the
Declaration of Helsinki, in full compliance with Brazilian data
protection law.
Clinical and laboratory data were collected from the patients’
medical records by the same doctors who followed them up. Clin-
ical data surveyed included gestational age at birth, familial his-
tory and consanguinity, age at presentation, presence of polyhy-
dramnios, polyuria, polydipsia, episodes of fever, vomiting, sei-
zures, cramps, neurosensorial deafness (NS), and failure to thrive.
The main laboratory data comprised venous gas analysis, serum
potassium, chloride, sodium, ionic calcium, phosphate, and mag-
nesium; the urinary exams included excretion fraction of potassi-
um, chloride, and sodium as well as morning urinary calcium/cre-
atinine ratio, microalbuminuria, and urinary protein/creatinine
ratio. Estimated Glomerular filtration rate (eGFR) was calculated
using the Modified Schwartz Formula [16]. Renal ultrasound was
also evaluated.
DNA Analysis
Genomic DNA was extracted from peripheral blood leukocytes
using QIAamp DNA Blood Mini kit protocol (Qiagen, Hilden,
Germany) and storage at −20°C until analysis. Libraries were pre-
pared according to Nextera Rapid Capture Custom Panel (Illu-
mina, San Diego, CA, USA) that included GLA, CLCNKA,
CLCNKB, BSND, KCNJ1, SLC12A1, CTNS, AQP2, AVPR2, SL-
C12A3, CLDN19, CNNM2, CLDN16, TRPM6, SCNN1G, SCNN1B,
ATP6V1B1, ATP6V0A4, and SLC4A4 genes, followed by next gen-
eration sequencing (NGS) using Illumina HiSeq protocol (Illumi-
na). Alignment and identification of variants using bioinformatic
protocols were performed with reference to the GRCh37 version
of the human genome. All causative variants were confirmed by
Sanger sequencing.
In addition, copy number variations in CLCNKA and CLCNKB
were verified by multiplex ligation-dependent probe amplification
(MLPA) according to the protocol supplied by the manufacturer
of the SALSA- MLPA Kit P266 (MRC-Holland, Amsterdam, The
Netherlands) containing 14 specific probes for the CLCNKB gene
(exon 1, 2, 3, 5, 6, 8, 10, 11, 13, 14, 15, 17, 18, and 19) and 2 probes
for the CLCNKA (exon 5 and 10).
All variants detected were classified according to the ACMG
classification [17]. Segregation analysis was performed according
to parental availability. The original data of some patients have al-
ready been published in ad hoc publications.
Part 2
In the current study, we also performed a literature systematic
review seeking studies reporting genetic testing results in other BS
cohorts around the world. The search strategy was as follows:
(“Bartter Syndrome”) AND (genetics OR mutations) and the fil-
ters applied were humans, English, Portuguese, Spanish and full-
text. The search was carried out at the PubMed, Cochrane Central
Register of Controlled Trials (Cochrane Library) and LILACS,
(Literatura Latino-Americana e do Caribe em Ciências da Saúde),
a research site of Latin-American Scientific Literature, up to Janu-
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DOI: 10.1159/000528557
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 4
Table 1. Initial clinical diagnosis, final genetic diagnosis (type of BS, GS, or pseudo-Bartter), variants detected in this Brazilian cohort of suspected BS, characteristics of the
variants, level of pathogenicity, and references in what the variant was described or if it is a novel mutation [18–30]

Case Skin color Clinical Final Gene Position Protein Level of pathogenicity Ref.
No. Ancestry diagnosis diagnosis

1 White Antenatal BS Pseudo- SLC26A3 c.1487 T>G p.(Leu496Arg) - LIKELY pathogenic 18

Portuguese Bartter (homozygosis) - The position of this variant is highly conserved among species
- CCD - “In silico” predictors consider this a deleterious variant
- This mutation has already been reported and is absent in
138,000 subjects of the world population

Nephron
2 White Antenatal BS BS type 1 SLC12A1 c.1103A>G p.(Glu368Gly); Variant 1 19
Portuguese/Spanish c.905G>A p.(Arg302Gln) - Pathogenic 20
(compound - c.1103A>G was described in a Caucasian female child from a
heterozygosis) French cohort and was found in heterozygosis in 1: 141,000
subjects of the world population

DOI: 10.1159/000528557
Variant 2
- Pathogenic
- c.905G>A was reported in a patient with Germany ethnic origin
and is present in heterozygosis in 6:141,000 subjects of the world
population

3 White Antenatal BS/ BS type 3 CLCNKB c.(?_-1)_(*1_?)del del exons 1 a 20 - Pathogenic 21

Portuguese/Gallic ND (homozygosis) - Deletion of the entire gene 22

4 Brown Classic BS BS type 3 CLCNKB c. (?_-1)_(*1_?)del del exons 1 a 20 - Pathogenic 21

Portuguese (homozygosis) - Deletion of the entire gene 22

5 Brown Classic BS BS type 3 CLCNKB c. (?_-1)_(*1_?)del del exons 1 a 20 - Pathogenic 21

Afro-American (Nigerian)/ (homozygosis) - Deletion of the entire gene 22
Portuguese/Spanish

6 White Classic BS BS type 3 CLCNKB c. (?_-1)_(*1_?)del del exons 1 a 20 - Pathogenic 21

Spanish/Portuguese (homozygosis) - Deletion of the entire gene 22

7 White Antenatal BS BS type 3 CLCNKB c. (?_-1)_(*1_?)del del exons 1 a 20 - Pathogenic 21

Portuguese (homozygosis) - Deletion of the entire gene 22

8 White Classic BS BS type 3 CLCNKB c.610G>A p.(Ala204Thr) - Pathogenic 21

Arabian/Lebanese (homozygosis) - Spanish founder mutation 23

9 White Antenatal BS BS type 3 CLCNKB c.610G>A p.(Ala204Thr) - Pathogenic 21

Italian/Portuguese (homozygosis) - Spanish founder mutation 23

Nunes/Watanabe
10 White Classic BS BS type 3 CLCNKB c.673G>T p.(Glu225*) - Pathogenic novel
Portuguese (homozygosis) - This variant was not previously reported, but it was not found mutation
in 123,000 subjects of the world population, and the molecular
mechanism, characteristics of the region and clinical correlation
make it definitively pathogenic

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 Table 1 (continued)

Case Skin color Clinical Final Gene Position Protein Level of pathogenicity Ref.
No. Ancestry diagnosis diagnosis

11 White Antenatal BS BS type 3 CLCNKB c.610G>A p.(Ala204Thr) Variant 1 23

Italian/Portuguese/Spanish c.(?_-1)_(*1_?)del del exons 1–20 - Pathogenic 21
(compound - Spanish founder mutation
heterozygosis) Variant 2
- Pathogenic

Cohorts’ Genetic Findings

- Deletion of the entire gene

12 Brown Classic BS BS type 3 CLCNKB c.610G>A p.(Ala204Thr) Variant 1 23

Spanish c. (?_-1)_(*1_?)del del exons 1–20 - Pathogenic 21
(compound - Spanish founder mutation

Bartter Syndrome: Brazilian and Other

heterozygosis) Variant 2
- Pathogenic
- Deletion of the entire gene

13 Brown Classic BS BS type 3 CLCNKB c.18dupG p.(Leu7Alafs*3) Variant 1 24

Portuguese c. (?_-1)_(*1_?)del del exons 1–20 - Pathogenic 21
(compound - c.18dupG is present in heterozygosis in 3:123,000 subjects of
heterozygosis) the world population and has been previously reported in a
patient with Brazilian origin from an Italian cohort
Variant 2
- Pathogenic
- Deletion of the entire gene

14 Brown Classic BS BS type 3 CLCNKB c.18dupG p.(Leu7Alafs*3) Variant 1 24

Portuguese c. (?_-1)_(*1_?)del del exons 1–20 - Pathogenic 21

Nephron
(compound - c.18dupG was found in heterozygosis in 3:123,000 subjects of
heterozygosis) the world population and has been previously reported in a
patient with Brazilian origin from an Italian cohort
Variant 2
- Pathogenic

DOI: 10.1159/000528557
- Deletion of the entire gene

15 White Antenatal BS BS type 3 CLCNKB c.910C>T p.(Arg304*) Variant 1 novel

Portuguese c. (?_-1)_(*1_?)del del exons 1 a 20 - Pathogenic mutation
(compound - c.910C>T;p.Arg304* is a novel mutation present in 20
heterozygosis) heterozygosis in 10:123,000 subjects of the world population.
Variants leading to abnormal protein transcription are
pathogenic
Variant 2
- Pathogenic
- Deletion of the entire gene

5
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 6
Table 1 (continued)

Case Skin color Clinical Final Gene Position Protein Level of pathogenicity Ref.
No. Ancestry diagnosis diagnosis

16 Brown Antenatal BS BS type 3 CLCNKB c.1400C>T p.(Ala467Val) Variant 1 novel

Portuguese c. (?_-1)_(*1_?)del del exons 1 a 20 - Likely pathogenic mutation
(compound - This is a novel mutation, 20
heterozygosis) - Absent in 123,000 subjects of the world population
- The position is highly conserved among species
- “In silico” predictors consider this variant to be deleterious

Nephron
Variant 2
- Pathogenic
- Deletion of the entire gene

17 White Classic BS BS type 3 CLCNKB c.1783C>T p.(Arg595*); p. Variant 1 23

Portuguese c.1560T>G (Tyr520*) - Pathogenic novel

DOI: 10.1159/000528557
(compound - This variant is present in heterozygosis in 26:123,000 subjects of mutation
heterozygosis) the world population
- It has been previously described in a patient with Italian origin
-It leads to an early interruption of the protein translation
Variant 2
- Pathogenic
- This variant was not previously described, but the molecular
mechanism, the characteristics of the region and the clinical
correlation are criteria to classify this variant as pathogenic

18 Brown Antenatal BS BS type 3 CLCNKB c.1309G>A p.(Gly437Arg) Variant 1 25

Portuguese/Spanish del 6–19 del exons 6–19 - Pathogenic 21, 22
[Chr1:6.374.838– this variant was detected in heterozygosis in 7: 123,000 subjects
16.383.003] of the world population and was previously described in a
(compound Korean patient
heterozygosis) Variant 2
- Pathogenic
- This is a copy number variation mutation and big deletions in
CLCNKB are associated with BS.

19 Brown Antenatal BS/ BS type 4A BSND c.139G>A p.(Gly47Arg) - Pathogenic 26–28

Portuguese/Spanish ND (homozygosis) - This mutation was previously reported in a patient from Japan
and is present in heterozygosis in 25:138,000 subjects of the
world population
- Functional studies have demonstrated this mutation leads to a
decrease in membrane expression of the protein. The severity of

Nunes/Watanabe
the renal phenotype is variable

20 White Antenatal BS/ BS type 4b CLCNKB/ del 1–20 del exons 1–20/ Digenic inheritance: 29
Portuguese/Spanish ND CLCNKA del exons 5 and 10 del exons 5 and - CLCNKB- pathogenic (deletion of the entire gene)
(digenic 10 - CLCNKA)- pathogenic
inheritance) (del exons 5 and 10)

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 ary 7, 2022. We use the new 2020 format for the PRISMA flow

mutation

mutation
diagram to report on systematic reviews available at https://pris-

Novel

Novel
ma-statement.org/PRISMASStatement/FlowDiagram [18].
Ref.

30

30
Statistical Analysis
subjects of the world population. A related variant p.Thr649Arg

subjects of the world population. A related variant p.Thr649Arg

has been previously reported in homozygosis related to GS in a

has been previously reported in homozygosis related to GS in a

Data with homogeneous distribution were shown as mean and
- This novel mutation is found in heterozygosis in 10: 123,000

- This novel mutation is found in heterozygosis in 10: 123,000

standard deviation. All others were shown as median and range.
T test for paired samples was employed to compare variables with
normal distribution, and Wilcoxon test was used to compare
paired samples with non-normal distribution variables. The inde-
pendent samples t test was employed to compare variables among
the three groups of BS type 3 patients according to the presence of
homozygous or heterozygous 1–20 del or its absence. Statistical
significance was defined as p < 0.05.
patient from Netherlands

patient from Netherlands

Results
Level of pathogenicity

- Likely pathogenic

- Likely pathogenic

Part 1
This descriptive study enrolled 22 patients (12 fe-
males) from 21 families. Table 1 shows the clinical type of
BS, Bartter syndrome; GS, Gitelman syndrome; CCD, chronic chloride diarrhea; ND, neurosensorial deafness. 1 Siblings.

BS (antenatal/neonatal BS, classic BS), the final genetic

diagnosis and the characteristics of the variant found for
each patient. Pathogenic or likely pathogenic variants in
p.(Thr648Met)

p.(Thr648Met)

BS-related genes were detected in 19/22 patients. Three

patients were diagnosed with a PBS condition.
Protein

Pathogenic/Likely Pathogenic Variants Found in BS-

Related Genes in the Current Study
(homozygosis)

(homozygosis)

BS type 1 (OMIM #600839): BS type 1 was diagnosed

c.1943C>T

c.1943C>T

in a boy born to non-consanguineous healthy parents at

Position

28 weeks of gestation. Severe polyhydramnios required

amniocenteses during the last weeks of pregnancy. He
evolved with hypokalemic hypochloremic metabolic al-
SLC12A3

SLC12A3
Gene

kalosis, severe polyuria, and failure to thrive. The genetic

analysis revealed a loss of function compound heterozy-
diagnosis

gous mutation in SLC12A1 gene [variant 1: c.1103A>G,

p.(Glu368Gly); variant 2: c.905G>A, p.(Arg302Gln)]. Af-
Final

GS

GS

ter 32 months of follow-up, the patient reached CKD

stage 2 (eGFR = 85 mL/min/1.73 m2) and presents high
Antenatal BS

Antenatal BS

serum levels of 1.25 (OH)2 vitamin D and difficult to con-

diagnosis
Clinical

trol hypercalciuria.
BS type 4a (OMIM #602522): A homozygous patho-
genic BSND variant [c.139G>A, p.(Gly47Arg)] was found
in a preterm neonate born to consanguineous (first-de-
gree cousins) healthy parents. After 6 months of age, she
Italian/Spanish

Italian/Spanish

presented polyuria, polydipsia, failure to thrive, and de-

Table 1 (continued)

hydration episodes, associated with NS deafness. She also

Skin color
Ancestry

presented hypocalciuria, an unexpected finding. Nephro-

Brown

Brown

calcinosis was not observed. During the 185-month fol-

low-up, she progressed from CKD stage 1 to 2 (initial and
Case
No.

221

final eGFR: 103 and 86 mL/min/1.73 m2).

21

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Bartter Syndrome: Brazilian and Other Nephron 7

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Table 2. Clinical and laboratory characteristics of Brazilian BS type 3 patients – patients with homozygous del 1–20 in CLCNKB, compound
heterozygous - 1 allele with del 1–20, and those with other biallelic variants in CLCNKB

Characteristics Homozygous del 1–20, Compound heterozygous, Biallelic mutations,

n = 5 patients 1 allele: del 1–20, other variants,
n = 6 patients n=5

Consanguinity, n (%) 4 (80) 1 (16.7) 3 (60)

Polyhydramnios, n (%) 3 (60) 5 (83.5) 2 (40)
Prematurity, n (%) 3 (60) 2 (33.5) 1 (20)
Age at initial manifestations*, months
Mean/SD 2.8/2.3 4.1/2.1 15.6/13.6
Median (range) 2.0 (0–6) 4.5 (1–6) 18 (2–36)
Hypercalciuria, n (%) 2 (40) 5 (83.5) 3 (60)
Nephrocalcinosis, n (%) 2 (40) 1/6 (16.7) 2 (40)
Duration of follow-up
Mean/SD 132.4/80.9 112.3/37.3 145.6/51.3
Median (range) 123 (29–219) 112 (59–157) 157 (90–210)
Initial eGFR
Mean/SD 97.2/52.3 109.1/43.5 118.6/24.7
Median (range) 109 (21–165) 102.5 (62–177) 116 (92–152)
Final eGFR *
Mean/SD 64/46.9 116.1/34.6 98.4/6.1
Median (range) 47 (13–136) 122 (62–155) 99 (89–106)
Final proteinuria
Median (range) 0.53 (0.15–9.2) 0.19 (0.07–0.35) 0.13 (0.04–0.58)
Final microalbuminuria
Median (range) 210 (26–555) 25.5 (9.4–96) 18 (13.6–58)

N/A, not applicable; del 1–20, deletion of the entire gene CLCNKB. * p < 0.05.

BS type 4b (OMIM #613090): We detected homozy-
gous digenic deletion encompassing the genes CLCNKA
and CLCNKB in a girl, diagnosing BS type 4b [19]. NS
deafness was later uncovered. This patient has been fol-
lowed for 6 months, and eGFR has remained >90 mL/
min/1.73 m2.
BS type 3 (OMIM #607364): Pathogenic or likely
pathogenic variants in CLCNKB were identified in 16 pa-
tients with long-term follow-up of 10.1 years (±4.4).
Among them, the deletion of the entire gene (1–20 del)
was the most frequent variant, which was observed in ho-
mozygosis in 5 cases and compound heterozygosis in 6.
Therefore, the allelic frequency of this variant among all
BS-related alleles (19 patients) was 42.1% (16/38 alleles).
A premature girl with homozygous 1–20 del in
CLCNKB had NS deafness, and, therefore, an additional
mutation in CLCNKA gene was investigated, as, if pres-
ent, it could set up the diagnosis of BS type 4b (Table 1)
[19]. However, as no pathogenic variant in CLCNKA was
detected by neither NGS nor MLPA, the final diagnosis
was BS type 3. In this case, NS deafness could be inter-
preted as a consequence of prematurity [20].
The other CLCNKB variants found in this cohort are
described in Table 1. In this study, 5 novel related-disease
variants were identified in CLCNKB, and a novel likely
pathogenic variant in SLC12A3 was identified in 2 sib-
lings with antenatal presentation of GS.
Table 2 shows the main clinical and laboratory data of
BS type 3 patients. Patients carrying one or both 1–20 del
alleles presented BS in younger age than patients carrying
other CLCNKB causative mutations, median age (range)
= 3 (0–6) months versus median age (range) = 18 (2–36)
months, respectively (p = 0.01). In addition, patients with
homozygous 1–20 del evolved with significant reduction
of renal function (initial eGFR: 97.2 ± 52.3 vs. final eGFR:
64.0 ± 46.9, p = 0.02) and a tendency to present higher
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 Color version available online
1st step is to rule out
Clinical suspicion of BS
pseudoBar�er condi�ons

confirming
Na+, K+ and Cl-
urinary losses

MLPA: MLPA detected no CNVs

Screening for in CLCNKA and CLCNKB
1-20 del as well as other CNVs in CLCNKB
and co-muta�on CLCNKA/CLCNKB

without neurosensorial deafness with neurosensorial deafness

Fig. 2. Algorithm for the investigation of
clinically suspected Bartter syndrome Bra- Other CLCNKB variants?
zilian patients. BS, Bartter syndrome; SLC12A1, KCNJ1 or SLC12A3 variants? BSND variants?
MLPA, multiplex ligation-dependent
probe amplification; del 1–20, deletion of
the entire gene CLCNKB; CNVs, copy NGS - custom panel analyzing the following genes
number variations; NGS, next generation CLCNKB, KCNJ1, SLC12A1, BSND and SLC12A3
sequencing.

urinary protein/creatinine ratio at the last evaluation than
patients with other mutations, including those with het-
erozygous 1–20 del (p = 0.05). Therefore, the presence of
1–20 del in both alleles was correlated with CKD progres-
sion.
There was no significant difference between initial and
final eGFR in BS type 3 patients with nephrocalcinosis
(105.0 ± 32.6 vs. 81.8 ± 20.6 mL/min/1.73 m2, p = 0.23),
but 2/5 patients reached CKD stage 2 at the last follow-up
visit. When comparing BS type 3 patients born prema-
turely or at term, no significant differences in renal out-
comes related to eGFR and proteinuria were found.
In addition, arterial hypertension was not observed in
any patient during the long-term follow-up. Finally, no
patient was diagnosed with BS type 2 (ROMK mutations),
type 5, or BS-like due to gain-of-function mutation in
CASR.
Patients with No BS-Related Genes Mutations
Observed in the Current Study (Pseudo-Bartter
Conditions)
Case 1: We diagnosed 1 patient with congenital chlo-
ride diarrhea (CCD) (OMIM #214700), and this case has
been previously reported [6]. During the pregnancy,
polyhydramnios was observed and delivery was prema-
ture. She evolved with polyuria, BS typical electrolyte and
metabolic disturbances and failure to thrive. Although
CCD was suspected, the diagnosis was not confirmed by
fecal and urinary electrolytes measurements. Reviewing
the medical records, we concluded that the samples were
collected at inappropriate time. Fecal sample was collect-
ed during dehydration status resulting in false low fecal
chloride. Likewise, the urinary sample was collected im-
mediately after physiologic solution and potassium intra-
venous infusion, resulting in high urinary chloride con-
tent. These data led to misdiagnosis BS. During patient
follow-up, liquid stools were probably misinterpreted as
polyuria.
As no variant was identified by the gene panel NGS
used in this study, whole-exome sequencing (WES) was
performed and a homozygous likely pathogenic variant
[c.1487 T>G; p.(Leu496Arg)] in SLC26A3 on chromo-
some 7q31 was identified. This mutation had already
been reported in a family with CCD from Hong Kong
[21].
Cases 21 and 22: Two male siblings born to non-con-
sanguineous healthy parents presented a novel homozy-
gous SLC12A3 likely pathogenic variant, c.1943C>T
p.(Thr648Met), diagnosing GS. They were preterm neo-
nates and after 1 month of age they evolved with vomit-
ing, polyuria, polydipsia, failure to thrive and seizures.
Hypocalciuria was observed in both patients, but hypo-
magnesemia in one. Therefore, they presented a different
clinical picture than what would be expected in patients
with classic GS.
Based on these results, the authors suggest a pathway
to investigate Brazilian patients with BS suspicion (Fig. 2).
The first step is to rule out PBS conditions, acquired or
genetic that require proper anamnesis and exams to lo-
cate the exact site of sodium, potassium and chloride
waste. Further, as the deletion of the entire CLCNKB was
present in 42.1% of all BS-related alleles, genetic investi-
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Bartter Syndrome: Brazilian and Other Nephron 9

Cohorts’ Genetic Findings DOI: 10.1159/000528557
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 Color version available online
Identification of studies via databases and registers Identification of studies via other methods

Records removed before screening:

Records identified from
Identification

Duplicate records removed (n =4 ) Records identified from:

3 Databases
Records marked as ineligible by Websites (n = 0 )
PubMed (n=453), LILACS (11)
automation tools (n = ) Organisations (n = 0)
and Cochrane (3):
Records removed for other reasons Citation searching (n = 0)
Registers (n = 0)
(n = ) etc.

Records screened Records excluded**

(n = 463) (n = 405)

Reports sought for retrieval Reports not retrieved Reports sought for retrieval Reports not retrieved
Screening

(n = 58) (n =0 ) (n = 0) (n = 0)

Reports excluded:
Case report (including up to 5 Reports assessed for eligibility
Reports assessed for eligibility cases) (n = 16 )
(n = 38) (n = 0) Reports excluded: 0
No genetic evaluation report (n =
1)
Other diseases than BS (n = 1)

Studies included in review

Included

(n = 20)

Fig. 3. Workflow of systematic review of publications reporting the genetic profile in patients with diagnosis of
Bartter syndrome type 3 in different parts of the globe.

gation could start by performing MLPA for CLCNKB
which makes it possible to also investigate CLCNKA as
well.
Part 2
Genetic Findings of BS Patients from Other
Worldwide Cohorts
The literature search yielded 467 results, and 462 pa-
pers were left after removing duplicates. In order to avoid
missing data, all abstracts were read. Then, 58 selected
papers were fully read and 20 studies were finally includ-
ed. Figure 3 shows the methodology of the review.
The characteristics of each included study are listed in
Table 3. Most studies from Europe and North America
have reported higher prevalence of BS type 3 than other
types [3, 22–24] as well as the current Brazilian study. A
higher prevalence of 1–20 del has been found in different
cohorts which included specially individuals with Afri-
can, Middle East, and Chinese ethnic origin [3, 4, 23, 24,
34, 36–38]. A founder effect has been observed in Spanish
cohorts [p.(Ala204Thr)] [25, 32, 35] as well as in Korean
[31, 33] and Japanese [26, 28, 29] cohorts (p.Trp610*), in
which the 1–20 del is rare. CLCNKB disease-related mu-
tations have been found in most cases of classic BS but
also in some antenatal/neonatal BS cohorts (specially the
1–20 del) [22]. Classic clinically GS has been detected in
patients with CLCNKB variants as well as SLC12A3 muta-
tions have been found in classic BS phenotypes but rarely
with earlier manifestation [33]. In the current study, to
the best of our knowledge, we detected an antenatal man-
ifestation of a novel SLC12A3 mutation for the first time.
Discussion
The estimated incidence of BS is 1/1million of the pop-
ulation with a prevalence of approximately 1 in 100,000
[39–41]. Although the diagnosis is mainly based on clin-
ical and biochemical parameters, there is an overlap
among the different types of BS and also with renal or
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10 Nephron Vaisbich/Messa/Rangel-Santos/Ferreira/
DOI: 10.1159/000528557 Nunes/Watanabe
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 Table 3. Results of the main genetic studies in suspected BS patients in different populations. Ethnic origin and ancestry are mentioned when available

1st author - Country of the study Genetic type of BS Number of patients or del 1–20 Other CLCNKB variants Conclusion Ref.
(year) - Study group (number of patients or families with CLCNKB - Number of patients or families with Ancestry
according to the type families) mutations homozygous del 1–20 (number of all patients - Variant (number of patients)
of BS (number of (All genetic diagnosed or families with BS type 3) %
patients or families) BS patients or families - Ancestry
included in the study) - Number of alleles with del 1–20 (total
number of alleles with an identified mutation
in CLCNKB from different families) %

Simon et al., - USA, Portugal, Spain, - BS type 1 or 2 (22 17 families (39 - 10 families (17 families) 58,8% Spain Among 17 families with BS type 3, the 21

Cohorts’ Genetic Findings

(1997) Saudi Arabia, UK, kindreds) families) - Ancestry: - c.610G>A, p.Ala204Thr homozygosis (2) homozygous deletion of the entire
Turkey - BS type 3 (17 kindreds) African American (5) Turkey (2) gene (del 1–20) was detected in 59%, in
- Suspected BS patients - No mutation found (27 Portugal (3) - c.405C>G, p.(Pro124Leu) homozygosis (2) 5 patients with African American
(66 families) families) Saudi Arabia (1) ancestry, in 3 with Portuguese origin
Yemen (1) and 2 from Middle East
- 20 (34) 58.8%

Bartter Syndrome: Brazilian and Other

Konrad et al., - Germany, France, USA, BS type 3 (36 patients 36 patients from 30 - 9 families (30 families) 30% Caucasian American Homozygous del 1–20 was the most 3
(2000) Netherlands from 30 families) families (45 patients - Ancestry: - c.1044C>T, p.(Ser337Phe) (1) frequent mutation found (30% of the
- Non-BS type 1 or 2 with Non-BS types 1 African American (1) - c.1647G>C, p.(Arg538Pro) (1) studied families)
(45 patients from 39 and 2) West Indian (1) - c.263G>A, p.(Arg77Thr) (1)
families) Dutch (1) - c.1752T>A, p.Ser573Tyr (1)
Turkish (4) - c.1347G>A, p.(Arg438His)
German (2) - c.264–2A>C, splice donor (1)
- 18 (60) 30% German
- c.816–2A>G, splice acceptor (1)
- c.1423delA, fs463>X478 (1)
- c.901-1G>T, splice acceptor (1)
- Unequal cross [CLCNKA/CLCNKB]; LOF (1)
- c. 1924ins4bp, p.fs630>X644
- c.450T>C, p.Leu139Pro (1)
Italy
- c.405C>T, p.(Pro124Leu) (1)
North African
- c.925C>A, p.(Ser297Arg) (1)
- c.611del78bp (1)
Dutch
- c.816–2A>G, splice acceptor (1)

Nephron
- c.901-1G>A, splice acceptor (1)
- c.1423delA, fs463>X478 (1)
French
- c.1588ins4bp; p.fs518>X522 (1)
Saudi Arabian
- c.1713A>T, p.(Lys560Met) (1)
Hispanic
- c.1713A>T, p.(Lys560Met) (1)

DOI: 10.1159/000528557
French Canadian
- c.1105T>A, p.(His357Gln) (1)
Turkish
- c.405C>T, p.(Pro124Leu) (1)

Schurman et al., USA BS type 3 5 patients from 5 5 patients (5) No other mutation was identified in this series of patients del 1–20 in homozygosis was detected 31
(2001) 5 BS patients; 2 patients (5 patients from 5 families (N/A) - Ancestry: in all 5 African Americans BS type 3
were previously families) African Americans (5) patients; 2 patients from this series
reported by Simon et - 10 (10) 100% were previously reported by Simon et
al., 1997 al., 1997

Rodríguez- 10 BS patients (from 8 BS type 3 (10 patients 10 patients from 8 - 0 patients (10 patients) 0% Spain c.610G>A, p.A204T was present in 23
Soriano families; 2 sisters) from 8 families) families (N/A) - 0 (20) 0% - c.610G>A, p.(Arg204Thr) (homozygous in 10 patients) 100% of the patients including in this
et al., (2005) Spanish series. The authors concluded
this variant is a founder mutation

Tajima et al., - Japan BS type 3 (7 patients) 7 patients (N/A) - 2 patients (7 patients) 28.5% Japanese The findings support other studies 32
(2006) - BS type 3 (7 patients) - Ancestry - c.1830G>A, p.(Trp610*) (homozygous 1 + heterozygous - W610X is important in Japanese
Japan (7) in 2) population
- 4 (14) 28.5% - c.del exon 3; p.Leu130* heterozygosis (1)
- c. del exons 1 and 2 heterozygosis (1)

11
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 12
Table 3 (continued)

1st author - Country of the study Genetic type of BS Number of patients or del 1–20 Other CLCNKB variants Conclusion Ref.
(year) - Study group (number of patients or families with CLCNKB - Number of patients or families with Ancestry
according to the type families) mutations homozygous del 1–20 (number of all patients - Variant (number of patients)
of BS (number of (All genetic diagnosed or families with BS type 3) %
patients or families) BS patients or families - Ancestry
included in the study) - Number of alleles with del 1–20 (total
number of alleles with an identified mutation
in CLCNKB from different families) %

Bettinelli et al., - Italy BS type 3 (13 patients) 13 patients (N/A) - 2 patients (13 patients) 15,4% Italy del 1–20 was detected in 19.2% of the 24
(2006) - BS type 3 (13 patients) - Ancestry: - c.725C > A, p.(Ala242Glu) (2) studied alleles
Italy (1) - del exons 1–6 (2) No predominant variant was found in
Pakistan (1) - c.1347G>A, p.(Arg438His) (1) these population

Nephron
- 5 (26) 19.2% - c.405C>T, p.(Pro124Leu) (1)
- p.(Gly433Glu) (1)
- c.1347G>A, p.(Arg438His)- -c.725C > A, p.(Ala242Glu) (1)
- c.1783C>T, p.(Arg595*)-(del 1–20) (1)
- p.(Met412Ile)-p.(Cys667*) (1)
Brazil
- c.18dupG, p.(Leu7Alafs*3) (1)

DOI: 10.1159/000528557
Nozu et al., - Japan BS type 3 (5 patients 5 patients (N/A) - 0 (5) 0% Japanese - p.(Trp391*) was the most frequent. It 33
(2007) - BS type 3 (5 patients from 4 families) - 1 (10) 10% - c.1830G>A, p.(Trp610*) (homozygosis in 2 + is considered a founder Japanese
from 4 families) heterozygosis in 3) mutation
- 7 (10 alleles) 70% - del 1–20 was detected in just 1 allele

Brochard et al., - France - BS type 1 (13 patients 6 patients from 6 - 3 patients (6 patients) 50% Tunisian In this study group, BS type 3 was 19
(2009) - Antenatal and from 11 families) families (42 patients - Ancestry - c.1107+1G>T diagnosed in 16.2% of patients with
neonatal BS patients - BS type 2 (19 patients from 37 families) Caucasian (1) Caucasian French Antenatal or Neonatal BS and in this
(42 patients from 37 from 15 families) Congolese (1) - c.343A>C, p.(Thr115Pro) homozygosis (1) group homozygous del 1–20 was
families) - BS type 3 (6 patients Moroccan (1) - c.1588ins4bp, p.(518fs*4) homozygosis (1) detected in 50% (3/6 families)
from 6 families) - 6 (12 alleles) 50%
- BS type 4a (4 patients
from 4 families)

Nozu et al., - Japan - BS type I (2), 9 patients from 7 - 0 (9 patients) 0% Japanese - c.1830G>A, (p.Trp610*) was the most 34
(2010) - Non-specified - BS type II (2), families (16 patients) Ancestry - c.1830G>A, p.(Trp610*) (homozygosis in 4 families + frequent. It is considered a founder
suspected BS - BS type III (9 patients Japanese heterozygosis in 2)/(9) Japanese mutation
(16 patients; 14 from 7 families) - 0 (32) 0% - 10 (14) 71.4% alleles from 7 families including 1 patient - del 1–20 was not present in this
families) -GS (3) from each family cohort

Urbanová et al., - 18 patients from - BS type I (2 patients 9 patients from 7 - 0 (9 patients) 0% 3 patients from different parts of the Czech Republic and Several causative sequence variations 35
(2010) different regions of the with antenatal BS)), families, but 6 patients - Ancestry Slovakia were observed. It was possible to prove
Czech Republic and - BS type II (0), from 4 families Czech Republic and Slovakia - c.226C>T, p.(Arg76*) (homozygous? del 1–20 in the other clinical diagnosis in 5/17 cases by
Slovakia; 2 siblings - BS type III (3 patients) presented just - 0 (18) 0% allele; no segregation analysis); novel variant (1) finding two causative mutations. Our
from India - GS (6 patients from 5 polymorphisms (20 - c.908A>C, p.(Gln303Pro) – p.(Ala423Alafs*56) (novel one-allelic mutation detection was
- Antenatal BS (3 families; 2 of them were patients from 14 mutations) (1) rather a result of incomplete gene
patients from different siblings from India) families) - c.1312C>T, p.(Arg438Cys) (1); previously described by screening than dominance since the
families) - No variant in SLC12A1, Simon et al., 1996 phenotype did not occur more often in
- Non- Antenatal/ CLCNKB, KCNJ1 and - several polymorphisms detected in 2 patients, but no different generations in the families. In
Neonatal BS (17 SLC12A31 (1 patient with likely pathogenic or pathogenic mutation) 12 patients/families it was not possible
patients; 11 families) Antenatal BS) - the most frequent polymorphism was c.80T>G, p. to give final confirmation of the
(Leu27Arg), SNP, detected in 8 patients with BS type 3 from proposed diagnosis. MLPA was done
5 families) for SLC12A3

Lee et al., - Korea - BS type I (1) 23 patients (26 - 1 patient (23 patients) 4.3% Korean - p.(Trp610*) was the most frequent 25

Nunes/Watanabe
(2012) - Non-specified - BS type II (1) patients) - 6 (46) 13.0% - c.1830G>A, p.(Trp610*) (homozygosis in 7 + variant and del 1–20 was the second
suspected BS (26 - BS type III (23) heterozygosis in 11) one, corresponding to 54.3 and 17.4%
patients) - BS type IVa (1) - 25 (46) 54,3% total alleles with CLCNKB variants of the 46 CLCNKB alleles

Garcia-Castanho - Spain BS type 3 (26 affected 26 patients from 23 - 0 patients (26 patients from 23 families) 0% Spain These results confirm the founder 36
et al., (2013) - BS type 3 (26 patients patients from 23 families (N/A) - 4 (52) 7,7% ( 3 patients with Spanish - c.610G>A, p.(Ala204Thr) (homozygous in 15 patients + effect of p.A204T and show the low
from 23 families) families) ancestry and 1 with African Spain ancestry) heterozygous in 8) number of alleles with del 1–20 in this
African Spain Spanish cohort
- c.1192_1203del12, p.(Ile398_Thr401del) – c. (?_-1)_(*1_?)
del, del 1–20 (1)
Latin America
- c.610G>A, p.(Ala210Val) -c.1756+1G>A, Splice (1)

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 Table 3 (continued)

1st author - Country of the study Genetic type of BS Number of patients or del 1–20 Other CLCNKB variants Conclusion Ref.
(year) - Study group (number of patients or families with CLCNKB - Number of patients or families with Ancestry
according to the type families) mutations homozygous del 1–20 (number of all patients - Variant (number of patients)
of BS (number of (All genetic diagnosed or families with BS type 3) %
patients or families) BS patients or families - Ancestry
included in the study) - Number of alleles with del 1–20 (total
number of alleles with an identified mutation
in CLCNKB from different families) %

Lee et al., (2016) Korea - GS (23 patients with 2 patients with 0 (3); 0% Korean del 1–20 is not present in this Korean 37

Cohorts’ Genetic Findings

Clinical GS patients (34 biallelic variants and 6 biallelic mutation in - Korean c.1589C > T, p.(Pro530Leu) cohort. In this GS suspected Korean
patients from 31 patients with 1 mutated CLCNKB and 1 patient 0/7; 0% Homozygous cohort, authors observed patients with
families) allele; 1 patient with 1 with just 1 mutated - c.1830G > A, p.(Trp610*) 1 mutated allele in SLC12A3 + 1
mutated allele in allele in CLCNKB (N/A) Homozygous mutated allele in CLCNKB.
SLC12A3 and 1 mutated c.595G > T, p.(Glu199*)
allele in CLCNKB) Homozygous
BS type 3 (2 patients - c.1166G > A, p.(Trp389*)


Bartter Syndrome: Brazilian and Other

with biallelic mutation in - c.2017A>T, p.(Met673Leu)
CLCNKB; 1 patient with
biallelic mutation in
CLCNKB + 1 allele in
SLC12A3; 1 patient with 1
mutated allele)

Han et al., - China SB type 1 (1) 14 patients (16 - 3 (14) 21.4 c.887G>A, p.(Gly296Asp) 38
(2017) - 16 BS patients (2 SB type 4 a (1) patients) - China (14) c.1052G>T, p.(Arg351Leu); c.1294_1295TA>CT, p.
patients with antenatal SB type 3 (14) - 9 (28) 32.1 (Tyr432Leu); c.1333T>G, p.(Ser445Ala),
BS) c.75T>A, p.(Cys25*),
c.88C>T, p.(Arg30*),
c.849_851delCTT,
c.1000delG, p.(Val334Phefs*15)
c.1150_1157delCCCCAGCA, c.1657_1664delCACAGCAT,
c.1395dupG,
c. (?_-757)_229+?del,
c.230-?_*410_?del; c.499-?_576+?del)
Previously reported:
c.88C>T
c.887G>A
c.499-?_576+?del

Nephron
García Castañho - Spain BS type 3 patients (30 30 patients (N/A) - 1 (30) Spain p. (Ala204Thr) was the most frequent 39
et al., (2017) - BS type 3 patients patients) - 6 (60) 10% - c.610G>A, p.Ala204Thr variant found and it is considered a
clinical classic BS (30 (homozygous mutation in 16 patients [16 families] + Spanish founder mutation
patients) heterozygous in 8): - del 1–20 was detected in 10% of the
- c.610G>A, p.(Ala204Thr) – (del 1–20) (3) study alleles
- c.610G>A, p.(Ala204Thr) – c.1325A>G, p.(Glu442Gly) (4

DOI: 10.1159/000528557
patients [3 siblings])
- c.610G>A, p.(Ala204Thr) – c
0.508G>A, (Val170Met) (1)
- 40 alleles (60) 66.7%
Other variants:
- c.1192_1203del12, p.(Ile398_Thr401del) – (del 1–20) (1)
- c.1026delC, p.(Ser343Alafs*6) – c.1325A>G, p.(Glu442Gly)
(1)
- c.753delG, p.(Leu252fs) – c.753delG, p.(Leu252fs) (1)
- c.1783C>T, p.(Arg595*) – c.1783C>T, (Arg595*) (1)
p.[Ala210Val) - [?] (1)
- c.610G>A, p.(Ala204Thr) – c.508G>A, p.(Val170Met) (1)

Seys et al (2017) - French cohort BS type 3 (115 patients 115 patients from 111 - 26 families (111 families) 23.4% French The presence of large deletions is 22
- BS type 3 (115 from 111 families) families (N/A) Geographic Origin: - 27 novel mutations/60 mutations detected related to an earlier presentation
patients from 111 Caucasian (10) 60 mutations were identified
families) Central Africa (5) del 1–20 was detected in 47.4% of the
North Africa (3) studied alleles
Turkey (3)
Asia (2)
Western Africa (1)
Guadeloupe (1)
Cape Verde (1)
Not Determined (3)
- 105 (222) 47.4% -

13
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 14
Table 3 (continued)

1st author - Country of the study Genetic type of BS Number of patients or del 1–20 Other CLCNKB variants Conclusion Ref.
(year) - Study group (number of patients or families with CLCNKB - Number of patients or families with Ancestry
according to the type families) mutations homozygous del 1–20 (number of all patients - Variant (number of patients)
of BS (number of (All genetic diagnosed or families with BS type 3) %
patients or families) BS patients or families - Ancestry
included in the study) - Number of alleles with del 1–20 (total
number of alleles with an identified mutation
in CLCNKB from different families) %

Najafi et al., - Iran - BS type 3 (12) 12 patients (12 - 12 (12) 100% Iran - BS type 3 was the most frequent type 4
(2019) - Non-specified - Pseudo-BS (4) patients) - 24 (24) 100% - 0/(12) of BS and
suspected BS - No mutation (1) - 0 (24 alleles) del 1–20 was the most frequent variant
(17 patients) detected

Nephron
Li et al., (2019) China BS type 3 (5 patients 5 patients (N/A) Chinese c.1967T>C, p.(Leu656Pro); c.595G>T, p.(Glu199Ter); These data confirm del 1–20 is present 40
BS patients (5 patients) from 5 families) - 0 (5) 0% c.908A>C, p.(Gln303Pro); c.1004T>C, p.(Leu335Pro); in Chinese population more than in
- 3 (10) 30% c.1312C>T, p.(Arg438Cys), c.1334_1335delCT, p. Japanese or Koreans. This deletion was
(Ser445Phefs*5); c.1718C>A, p.(Ser573Tyr) present in 30% of the alleles
c.1967T>C, p.(lso656Pro)

DOI: 10.1159/000528557
Han et al., (2020) - China BS type 3 (42 patients 42 patients from 41 - 11 (42) 26.2% Chinese del 1–20 was the most frequent variant 41
- BS type 3 (42 patients from 41 families) families (N/A) - 36 (84) 42.8% Heterozygosis - 2 Alleles found in this BS type 3 Chinese cohort
from 41 families) - c.849_851delCTT, p.(Phe284del) – 43% of all BS type 3 alleles
- c.1000delG, p.(Val334Phefs*15)
-c.887G>A, p.(Gly296Asp)
Heterozygosis 4
- c.239G>A, p.(Trp80*)
Homozygosis - 1 case
- c.1657_1664delCACAGCAT, p.Ser554Hisfs*50
- c. c.359-?_(*410_?)del [del 4/5–20])
Homozygosis 1, heterozygosis 1
- c.1309G>A, p.Gly437Arg)
- c. (?_-757)_229+?del [del 1-3/4]
Heterozygosis 1 allele/1 person
- c.1150_1157delCCCCAGCA, p.(Gln385Valfs*63)
- c.1298G>A, p.(Gly433Glu)
- c.359G>T, p.Gly120Val)
- c.801C>G, p.(Tyr267*) (
- c.75T>A, p.Cys25*)
- c.88C>T, p.(Arg30*)
- c.1294_1295TA>CT, p.(Tyr432Leu)
- c.1052G>T, p.(Arg351Leu)
- c.1830G>A, p. (Trp610*)
- c.1244T>A, p. (Leu415Gln)
- c.595G>T, p. (Glu199*)
- c. c. (?_757)_(968+1_969-1)del [del exons 1–10]
- c.1228-2a > G, splicing
- c.1051C>T, p.(Arg351Trp)
- c.1054-1G>A, splicing
- c.1979C>A, p.(Ser660*)
- c.1468G>A, p.(Glu490Lys)
- c.1395dupG, p.(Tyr466Valfs*56)
- c.1333T>G, p.(Ser445Ala)
- c. (498+1_499-1)_(576+1_577-1)del
- c.1-?_(100+1_101-1)del [del exon 2]
- c.228A>C, splicing c. (?_757)_(1929+1_1930-1)del [del
1–18]

Nunes/Watanabe
- c.1257delC, p.Met421Cysfs*58)
-c.359-?_781+?del [del exons 4/5–8/9]
- c.359-?_(1408+1_1409-1)del [del 4/5–14]
- c. (?_-757)_ (1297+1_1298-1)del [del 1–13]

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 extrarenal pseudo-BS conditions. Therefore, a rational

study
This
Ref.

investigation is needed, which requires a proper anamne-

del 1–20 was the most common variant

sis and laboratorial tests exams to characterize the exact

- BS type 3 was the most frequent type

– 50% of all BS type 3 alleles, followed

of BS detected in this Brazilian cohort.

mutation. Four novel mutations were

reported for BS type 3 and 1 for GS.
by p.Ala204Thr, a Spanish founder
site of salt waste, which can be accomplished by urinary
chloride measurement in a sample collected when the pa-
tient is hydrated, and stable. High urinary chloride (frac-
tional chloride excretion usually >0.5%) prior electrolyte
supplementation can direct to renal causes of chloride
Conclusion

loss [41], named “Inherited salt-loss tubulopathies,”

which encompasses the types of BS and renal PBS, such
as GS. However, although these tubulopathies have dif-
- c.610G>A, p.(Ala204Thr) (homozygous 2 + heterozygous

ferent genotypic origins, there is still considerable pheno-

-- c.1400C>T, p.(Ala467Val) (heterozygous (1) novel

typic overlap. Therefore, genetic testing has been recom-

-- c.1560T>G, p.(Tyr520*) (heterozygous 1) novel
- c.910C>T, p.(Arg304*) (heterozygous 1) novel
- c.673G>T, p.(Glu225*) (homozygous 1) novel
- c.18dupG, p.(Leu7Alafs*3) (heterozygous 2)

- c.1309G>A, p.(Gly437Arg) (heterozygous 1)

mended for accurate diagnosis and molecular classifica-

- c.1783C>T, p.(Arg595*) (heterozygous 1)

tion of these diseases, directing the investigation of

- del exons 6–19 (heterozygous 1)

possible extrarenal involvement and collaborating for ge-

Brazilian (admixed population)
homozygous del 1–20 (number of all patients - Variant (number of patients)

netic counseling [42, 43]. Our results reinforce this rec-

ommendation and further highlight the importance of
Other CLCNKB variants

genetic testing in different populations to establish a spe-

cific investigation flowchart and future implementation
Ancestry

of target gene therapies. The indication of genetic test

should be driven according to the genetic spectrum vari-
2)

ants for each specific population, which could be timing

number of alleles with an identified mutation

and money saving [42], which was demonstrated in our

- Number of alleles with del 1–20 (total
- Number of patients or families with

in CLCNKB from different families) %

study. Moreover, the lack of sufficient information on ge-

netic basis in non-European non-North American popu-
or families with BS type 3) %

lations has been widely discussed as a limitation to repro-

duce data from genome-wide association studies (GWAS)
for a number of disorders [14], and the current study ex-
- 16 (32) 50.0%
- 5 (16); 29.4%
- Ancestry

panded the genetic spectrum of BS mutations including

del 1–20

data from an admixed population with different ethnic

background.
related variants) 84.2%
(All genetic diagnosed
Number of patients or

BS patients or families
included in the study)
families with CLCNKB

BS type 3 was the most frequent type of BS in this Bra-

patients with BS-
16 patients (19

zilian cohort, similar to what has been reported in other

mutations

cohorts [29, 31, 34, 41]. All patients presented pathogen-

ic or likely pathogenic biallelic mutations in CLCNKB, 5
of them previously described and 5 novel pathogenic or
(number of patients or

likely pathogenic variants were identified (Table 1), rein-

Genetic type of BS

forcing the importance of genetic database from non-Eu-

- Pseudo-BS (1)
- BS type 4b (1)
- BS type 3 (16)
- BS type 4a (1)
- BS type 1 (1)
- BS type 2 (0)

ropean and non-North American populations [15].

families)

- GS (2)

Our patient with final diagnosis of BS type 1 manifests

according to the characteristic description in the litera-
- Suspected BS cohort
- Country of the study

ture, with antenatal/neonatal BS [22]. However, antena-

according to the type

(22 patients from 21

patients or families)
of BS (number of

tal/neonatal BS was also manifested in BS type 3 patients

- Study group

carrying more severe mutations in CLCNKB such as the

Table 3 (continued)

families)

LOF, loss of function.

This study (2020) - Brazil

1–20 del. In our Brazilian cohort, the presence of the 1–20

del, in 1 or both alleles, was associated with earlier mani-
festations compared to patients carrying other CLCNKB
1st author

mutations. This finding was also observed by Brochard et

(year)

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Bartter Syndrome: Brazilian and Other Nephron 15

Cohorts’ Genetic Findings DOI: 10.1159/000528557
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al. [22], who found homozygous 1–20 del in 50% of BS
type 3 patients with antenatal BS.
On the other hand, a characteristic milder GS-like
phenotype has been observed in patients with mutations
in CLCNKB [33, 36], emphasizing the phenotypic vari-
ability of BS type 3 patients. Furthermore, unexpectedly,
we identified a novel likely pathogenic variant in SL-
C12A3 diagnosing GS in two siblings with antenatal/neo-
natal disease onset. Early GS manifestation has been rare-
ly 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.
The presence of neurosensorial deafness may raise the
suspicion of BS types 4a or 4b. Phenotypically, these con-
ditions are indistinguishable. Neonates present with
polyhydramnios, prematurity, polyuria, severe salt wast-
ing, and hypercalciuria may be transient, but if persists it
can cause nephrocalcinosis [19, 43]. However, it is impor-
tant to keep in mind other NS causes in these premature
babies, mainly if BS types 4a or 4b were ruled out [19].
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 test-
ing 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 m2) in patients with
BS than in those affected by GS. These authors also de-
tected CKD ≥ stage 2 in 5/12 patients (41.7%) with a mo-
lecular diagnosis of BS type 1, while smaller percentage of
2/12 (16.7%), 1/12 (8.3%), and 4/12 (33.3%) showed caus-
ative 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, chang-
ing in CKD status and higher proteinuria levels. Seys et
al. [36] studied a large cohort of BS type 3 patients and
found CKD ≥ stage 2 in 19/77 (25%) patients with a me-
dian follow up time of 8 (range, 1–41) years. These au-
thors also observed that patients with CKD ≥stage 2 were
older than patients with preserved GFR, but they did not
differ in terms of birth weight, use of COX inhibitors or
hypokalemia severity, and no mention was made about
the type of mutation [36].
Regarding the prevalence of 1–20 del in CLCNKB, the
genetic spectrum of this BS Brazilian cohort (allelic fre-
quency = 42.1%) was surprisingly similar to that of Chi-
16 Nephron
DOI: 10.1159/000528557
nese cohorts [38] and individuals of African and Middle
Eastern descent from other worldwide cohorts (Table 3)
[3, 22–24, 34, 36]. The explanation for this finding is a
matter for future investigations. All patients of the BS
type 3 Iranian cohort presented homozygous 1–20 del [4];
this country has a high rate of consanguinity, which may
explain the high prevalence of a single variant. Among
populations with BS type 3, founder effects have been re-
ported in Spanish (p.A204T) and Japanese/Korean (p.
W610X) cohorts, in which the 1–20 del is rarely detected
or absent [25, 26, 28, 31–33, 35].
In conclusion, this study characterized the clinical and
molecular profile of BS Brazilian patients, an admixed pop-
ulation with diverse ancestry, contributing to expand the
genetic spectrum of BS patients with different ethnics and
from different geographic regions of the globe. The lack of
sufficient information on genetic basis in non-European
non-North American populations has been widely dis-
cussed as a limitation to reproduce data from genome-wide
association studies (GWAS) for a number of disorders [14].
In this sense, the current study identified 4 novel CLCNKB
and 1 SLC12A3 mutations expanding the genetic back-
ground of BS-related variants around the world. The dele-
tion of the entire CLCNKB was the most frequent variant
found in this cohort, similar to Chinese cohort reported by
Han et al. [38] and to African and Middle Eastern descen-
dants from other cohorts reported in literature [3, 22–24,
36]. Finally, we were able to correlate the presence of homo-
zygous deletion of the entire CLCNKB with loss of glomer-
ular function and proteinuria, concluding that the presence
of homozygous 1–20 del in CLCNKB could be considered
a marker of CKD progression.
Statement of Ethics
This study protocol was reviewed and approved by the Local
Ethical Review Board of Hospital das Clinicas, University of Sao
Paulo, Comissão de Ética para Análise de Projetos de Pesquisa -
CAPPesq, São Paulo, Brazil (reference number 3.261.257). Writ-
ten informed consent was obtained from participants (or their par-
ent/legal guardian/next of kin) to participate in the study.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
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Nunes/Watanabe
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 Author Contributions
Maria Helena Vaisbich: this author designed the study, col-
lected data, collected the informed consent signature, orga-
nized and interpreted data, wrote the main manuscript, cre-
ated tables and figures, and reviewed whole document; Ana
Carola Hebbia Lobo Messa: this author collected data, collect-
ed the informed consent signature, and organized data; Juliana
Caires de Oliveira Achili Ferreira, Andréia Cristiane Rangel-
Santos, and Fernanda Andrade Macaferri da Fonseca Nunes:
this author contributed with laboratory data and data organi-
zation; Andreia Watanabe: this author reviewed the manu-
script.
Data Availability Statement
All data generated or analyzed during this study are included
in this article. Further inquiries can be directed to the correspond-
ing author.

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