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

BackgroundFamilial 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.Case presentationWe 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.ConclusionsThis 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.

Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation

“…The A of the ATG initiator codon is denoted as nucleotide 1. Patients 1 and 2 have been described by Blanchard et al; patient 5 has been described by Yamaguti et al…”

“…He is from a consanguineous family; accordingly, he is homozygous for a known missense mutation with in vitro confirmed pathogenicity . Patient 5 is a Brazilian patient diagnosed with FHHNC, stage 3 CKD, and AI at the age of 20 years . At 25 years, she reached end‐stage renal disease and started dialysis.…”

“…(24) Patient 2 had seizures at the age of 8 years, leading to the discovery of severe hypocalcemia, hypomagnesemia, HC, and NC; AI was diagnosed at the age of 26 years. In patient 3, NC was discovered at the age of 8 years during the workup of abdominal pain; (24) patient 5 has been described by Yamaguti et al (34) b Supplemental Table S1. c Konrad et al; (58) Hou et al (22) hypomagnesemia and HC were first noticed at the age of 20 years.…”

“…(22) Patient 5 is a Brazilian patient diagnosed with FHHNC, stage 3 CKD, and AI at the age of 20 years. (34) At 25 years, she reached end-stage renal disease and started dialysis. Her parents are first-degree cousins and she harbors a homozygous CLDN16 deletion of exons 2 to 5 detected by multiplex ligation-dependent probe amplification (MLPA).…”

Novel compound heterozygous mutations of CLDN16 in a patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis

“…regions. Only one large deletion has been identified in the CLDN16 gene of a patient with FHHNC (Yamaguti et al, 2015).…”