Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Caused by CLDN16/CLDN19 Mutations in Four Chinese Families

Abstract Background Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubulopathy caused by mutations in the CLDN16 or CLDN19 genes, patients usually develop hypomagnesemia, hypercalciuria, nephrocalcinosis and renal failure early in life, and those with CLDN19 gene mutations have ocular findings in addition. Methods Five children from four non-consanguineous Chinese Han families presenting with nephrocalcinosis and renal insufficiency were enrolled in our study. Metabolic profiling and radiology examinations were performed, in addition to whole exome sequencing (WES) used for detection of the causative variant. Results Clinical manifestations included polydipsia, polyuria, sterile leukocyturia, and urinary tract infections, with one patient exhibiting hemorrhagic ovarian cyst and proteinuria. Laboratory analyses revealed hypomagnesemia. Renal biopsy demonstrated renal tubulointerstitial injury accompanied by glomerular sclerosis. Whole-exome sequencing identified five CLDN16 variants: c.217 + 5 (IVS2) G > A with exon 3 deletion, compound heterozygous c.130C > T/c.158delA, and compound heterozygous c.436C > T/c.158delA, and two CLDN19 variants: c.223G > A (p.Gly75Arg) and a novel frameshift mutation c.220delG (p.Gly74Valfs*10), which has not been previously reported in PubMed or ClinVar. Importantly, an unusual phenotype of hemorrhagic ovarian cyst was observed in one patient carrying CLDN16 mutations (c.217 + 5 (IVS2) G > A and exon 3 deletion). Conclusions For the first time, we identified a novel CLDN19 mutation and documented hemorrhagic ovarian cyst in a patient with CLDN16 mutations. This study represents the largest multi-family analysis of FHHNC in a Chinese population cohort. The integrated clinical and genetic findings from our patients provide critical insights to expand the phenotypic and genotypic spectrum of this rare renal disorder.