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Abstract: SA-PO447

Novel Truncating Mutations in Autosomal Dominant FSGS Genes Cause Childhood Onset Steroid-Resistant Nephrotic Syndrome

Session Information

  • Pediatric Nephrology - II
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1600 Pediatric Nephrology


  • Varner, Jennifer D., Duke University School of Medicine, Durham, North Carolina, United States
  • Chryst-Stangl, Megan, Duke Molecular Physiology Institute, Durham, North Carolina, United States
  • Hunley, Tracy E., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Lane, Brandon M., Duke Molecular Physiology Institute, Durham, North Carolina, United States
  • Wu, Guanghong, Duke Molecular Physiology Institute, Durham, North Carolina, United States
  • Hall, Gentzon, Duke University Medical Center, Durham, North Carolina, United States
  • Gbadegesin, Rasheed A., Duke University Medical Center, Durham, North Carolina, United States

Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end stage kidney disease in children. Most autosomal dominant genes are presumed to be due to gain-of-function mutations. Mutations in transient receptor potential canonical 6 (TRPC6) and inverted formin 2 (INF2) have been described in familial focal segmental glomerulosclerosis (FSGS). Most of the mutations described are missense mutations. Truncating (loss of function) mutations in these genes have not been well described.


We identified 181 families with SRNS in our worldwide cohort. Families were screened for variants in ten known autosomal dominant FSGS genes (INF2, TRPC6, COL4A3, COL4A4, WT1, ACTN4, ANLN, CD2AP, ARHGAP24, and LMX1B) using targeted sequencing of custom amplicons (TSCA). Causative mutations were defined as non-synonymous variants, obligatory splice site variants, or truncating variants that had a minor allele frequency <1% in the normal population. Non-synonymous variants were considered pathogenic if they were also reported to be deleterious by at least 2 in silico software models. Variants were confirmed using Sanger sequencing.


We identified two novel truncating mutations in TRPC6 and INF2, respectively, in two families with onset of disease at age <10 years. Family DUK34462 consists of three affected members with an autosomal dominant pattern of inheritance. We identified a novel stop codon change in INF2 (p.E249X) in a child who presented with disease at the age of eight years. The second family is DUK40015 with one affected individual with onset of disease at the age of ten years. We identified a frameshift mutation in TRPC6 (p.G39fsX41) in this child. Apart from early onset of disease, the phenotype in these two families was not different from individuals with missense mutations in the two genes, in that they both have therapy resistant disease.


In conclusion, truncating mutations in autosomal dominant SRNS/FSGS genes may cause early onset childhood SRNS, likely by haploinsufficiency effect on pathways that are critical for normal development of the glomerular filtration barrier.


  • NIDDK Support