title: Identification of the first large deletion in the CLDN16 gene in a patient with FHHNC and late-onset of chronic kidney disease: case report.
abstract: BACKGROUND
  Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease characterized by tubular disorders at the thick ascending limb of Henle's loop. It is caused by mutations in the tight junction structural proteins claudin-16 or claudin-19, which are encoded by the CLDN16 and CLDN19 genes, respectively. Patients exhibit excessive wasting of calcium and magnesium, nephrocalcinosis, chronic kidney disease, and early progression to end-stage renal failure during infancy.
  
  
  METHODS
  We here report the phenotype and molecular analysis of a female Brazilian patient with a novel large homozygous deletion in the CLDN16 gene. The proband, born from consanguineous parents, presented the first symptoms at age 20. Clinical examination revealed hypocalcemia, hypomagnesemia, nephrocalcinosis, mild myopia, high serum levels of uric acid and intact parathyroid hormone, and moderate chronic kidney disease (stage 3). She and her mother were subjected to CLDN16 and CLDN19 mutational analysis. In addition, the multiplex ligation-dependent probe amplification method was used to confirm a CLDN16 multi-exon deletion. Direct sequencing revealed a normal CLDN19 sequence and suggested a large deletion in the CLDN16 gene. Multiplex ligation-dependent probe amplification showed a homozygous CLDN16 multi-exon deletion (E2_E5del). The patient initiated conventional treatment for familial hypomagnesemia with hypercalciuria and nephrocalcinosis and progressed to end-stage kidney disease after five years.
  
  
  CONCLUSIONS
  This study provides the first report of a large homozygous deletion in the CLDN16 gene causing familial hypomagnesemia with hypercalciuria and nephrocalcinosis with late onset of the first symptoms. This description expands the phenotypic and genotypic characterization of the disease. The late-onset chronic kidney disease in the presence of a homozygous deletion in the CLDN16 gene reinforces the great variability of genotype-phenotype manifestation in patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.
authors.affiliation: University Hospital of Brasilia, University of Brasilia, Brasilia, Brazil. paulomarcioyamaguti@gmail.com.
authors.forename: Paulo Marcio
authors.initials: PM
authors.lastname: Yamaguti
authors.affiliation: Laboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil. pollybaixinha@gmail.com.
authors.forename: Pollyanna Almeida Costa
authors.initials: PA
authors.lastname: dos Santos
authors.affiliation: Faculty of Medicine, University of Brasilia, Brasilia, Brazil. brunohsakamoto@gmail.com.
authors.forename: Bruno Sakamoto
authors.initials: BS
authors.lastname: Leal
authors.affiliation: Nephrology Division, Hospital de Base de Brasilia, Soclimed Nephrology and Dialysis Unit, Brasilia, Brazil. vivianebbmello@yahoo.com.br.
authors.forename: Viviane Brandão Bandeira de Mello
authors.initials: VB
authors.lastname: Santana
authors.affiliation: Laboratory of Genetics, Faculty of Medicine, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil. julianamazzeu@yahoo.com.
authors.forename: Juliana Forte
authors.initials: JF
authors.lastname: Mazzeu
authors.affiliation: Laboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil. acevpoppe@gmail.com.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Acevedo
authors.affiliation: Soclimed Nephrology and Dialysis Unit, Brasilia, Brazil. nevesfar@gmail.com.|Laboratório de Farmacologia Molecular, Faculdade de Ciências da Saúde, Universidade de Brasília, Campus Universitário Darcy Ribeiro, Brasília, Brazil. nevesfar@gmail.com.
authors.forename: Francisco de Assis Rocha
authors.initials: Fde A
authors.lastname: Neves
mesh_terms: D017668:Age of Onset; D001483:Base Sequence; D057167:Claudins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology; D008275:Magnesium Deficiency / Q000235:genetics* / Q000628:therapy; D009397:Nephrocalcinosis / Q000235:genetics* / Q000628:therapy; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000628:therapy; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D057167:Claudins; C502010:claudin 16