title: Poor phenotype-genotype association in a large series of patients with Type III Bartter syndrome.
abstract: BACKGROUND
  Type III Bartter syndrome (BS) is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKB gene, which encodes the chloride channel protein ClC-Kb. In this study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS.
  
  
  METHODS
  Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR) followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses.
  
  
  RESULTS
  Polyuria, polydipsia and dehydration were the main common symptoms. Metabolic alkalosis and hypokalemia of renal origin were detected in all patients at diagnosis. Calciuria levels were variable: hypercalciuria was detected in 31% of patients, while 23% had hypocalciuria. Nephrocalcinosis was diagnosed in 20% of the cohort. Two novel CLCNKB mutations were identified: a small homozygous deletion (c.753delG) in one patient and a small deletion (c.1026delC) in another. The latter was present in compound heterozygosis with the already previously described p.Glu442Gly mutation. No phenotypic association was obtained regarding the genotype.
  
  
  CONCLUSIONS
  A poor correlation was found between a specific type of mutation in the CLCNKB gene and type III BS phenotype. Importantly, two CLCNKB mutations not previously described were found in our cohort.
authors.affiliation: BioCruces Health Research Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain.
authors.forename: Alejandro
authors.identifier: http://orcid.org/0000-0002-9734-6600
authors.initials: A
authors.lastname: García Castaño
authors.affiliation: BioCruces Health Research Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pérez de Nanclares
authors.affiliation: Pediatric Nephrology, Cruces University Hospital, Bizkaia, Spain.|Department of Pediatrics, School of Medicine and Odontology, University of Basque Country UPV/EHU, Bizkaia, Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Madariaga
authors.affiliation: Pediatric Nephrology, Cruces University Hospital, Bizkaia, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Aguirre
authors.affiliation: Pediatric Nephrology, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Madrid
authors.affiliation: Pediatric Nephrology, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Chocrón
authors.affiliation: Pediatric Nephrology, Virgen del Camino Hospital, Pamplona, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Nadal
authors.affiliation: Pediatric Nephrology, La Paz University Hospital, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Pediatrics, Manises Hospital, Valencia, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Lucas
authors.affiliation: Pediatric Nephrology, Virgen del Rocío Hospital, Sevilla, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Fijo
authors.affiliation: Pediatric Nephrology, Fundación Alcorcón University Hospital, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Espino
authors.affiliation: San Ignacio University Hospital, Bogotá, Colombia.
authors.forename: Zilac
authors.initials: Z
authors.lastname: Espitaletta
authors.affiliation: Pediatric Nephrology, Nuestra Señora de Candelaria University Hospital, Tenerife, Canarias, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: García Nieto
authors.affiliation: Pediatric Nephrology, Virgen de las Nieves Hospital, Granada, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Barajas de Frutos
authors.affiliation: Nephrology Unit, Cayetano Heredia University, Cayetano Heredia Hospital, Lima, Peru.
authors.forename: Reyner
authors.initials: R
authors.lastname: Loza
authors.affiliation: Germans Trias i Pujol University Hospital, Badalona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Pintos
authors.affiliation: BioCruces Health Research Institute, Ciberer, Cruces University Hospital, Bizkaia, Spain.|Department of Pediatrics, School of Medicine and Odontology, University of Basque Country UPV/EHU, Bizkaia, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
authors.affiliation: Pediatric Nephrology, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Ariceta
mesh_terms: D001477:Bartter Syndrome / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype