Familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by CLDN16/CLDN19 mutations in four Chinese families

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. 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. Clinical manifestations included polydipsia, polyuria, sterile leukocyturia or urinary tract infections. Meanwhile, hypomagnesemia was observed in the entire cohort on laboratory analyses. One patient presented with hemorrhagic ovarian cyst and proteinuria, and the renal biopsy revealed tubulointerstitial injury accompanied by glomerular sclerosis. Whole-exome sequencing identified four patients with compound heterozygosity in the CLDN16 gene, [c.217+5G>A]; [ c.218_382del], [c.130C>T]; [c.158delA] and [c.436C>T]; [c.158delA], and one patient with compound heterozygosity in the CLDN19 gene for the c.223G > S (p.G75S) variant and a novel frameshift pathogenic variant c.2;20delG (p.D74Tfs*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 c.218_382del). For the first time, we identified a novel CLDN19 pathogenic variant 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. Integrated clinical and genetic analyses of our patients might help to offer preliminary insights that contribute to refining the phenotypic and genotypic spectrum of this rare renal disorder.