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Abstract: SA-PO1008

A Novel Frameshift Mutation in CLCN5 in a Family with Podocytopathy Phenotype

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology


  • Moore, Adolya M., Duke University, Durham, North Carolina, United States
  • Lane, Brandon M., Duke University School of Medicine, Durham, North Carolina, United States
  • Chryst-Stangl, Megan, Duke University School of Medicine, Durham, North Carolina, United States
  • Wu, Guanghong, Duke University School of Medicine, Durham, North Carolina, United States
  • Gbadegesin, Rasheed A., Duke University School of Medicine, Durham, North Carolina, United States

Steroid resistant nephrotic syndrome (SRNS) is a common cause of pediatric chronic kidney disease (CKD). However, the cause of approximately 80% of familial SRNS cases remain unknown. We hypothesized that additional genetic causes of disease can be discovered through next generation sequencing analysis of a large cohort of families with NS.


To identify the genetic cause of podocytopathy we performed whole genome sequencing, followed by direct sequencing and segregation analysis in over 300 patients from ~200 families.


We identified a novel segregating hemizygote truncating mutation (c.1199del, p.Gly400ValfsTer29) in the gene encoding Chloride Voltage Gated Channel 5 (CLCN5) in a family with four affected boys with NS phenotypes including nephrotic range proteinuria and biopsy proven focal segmental glomerulosclerosis (FSGS). Segregation analysis revealed that the mother is heterozygous for the same variant, while the variant is absent in the father. Chloride Voltage Gated Channel 5 encodes a member of the chloride ion channels and ion transporters that regulate endosomal acidification and receptor mediated endocytosis in tubules. Mutations in CLCN5 is a major cause of Dent Disease, a proximal tubulopathy characterized by hypercalciuria, nephrocalcinosis and nephrolithiasis. However, CLCN5 is enriched in the podocyte at the mRNA and protein level. We also analyzed whole exome sequencing data from additional 200 patients with nephrotic syndrome and identified another family with a hemizygote variant of unknown significance (VUS).


Pathogenic variants in CLCN5 represent a rare cause of secondary podocytopathy and should be included in the gene panel for SRNS. Analysis of iPSC-derived podocytes from this family will unravel the mechanisms by which CLCN5 deficiency in podocyte can cause a podocytopathy-like phenotype.


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