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Abstract: SA-PO448

Evidence Against Routine Genetic Testing for SRNS in an Outbred Population

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
  • Esezobor, Chris, College of Medicine, University of Lagos, Akoka, Lagos, Nigeria
  • 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. Recent advances in genomic technology have led to the identification of more than 50 genetic causes of SRNS, most of which code for proteins located within the glomerular filtration barrier. Despite these advances, there are no clear clinical guidelines for genetic screening in patients with SRNS.


Our worldwide multi-ethnic cohort consisted of 492 individuals from 181 families with SRNS, of whom 86 families had familial disease and 95 individuals had sporadic disease. Initial genetic screening was performed by direct sequencing of candidate genes and whole exome sequencing. Analysis in recent years was performed using targeted high-throughput sequencing of 42 known SRNS genes and risk loci. Causative mutations were defined as missense variants, truncating variants, and obligatory splice site variants with a minor allele frequency <1% in the normal population. Non-synonymous variants were considered pathogenic if determined to be deleterious by at least two in silico software models. In order to provide clinical guidelines, we evaluated for differences in age at disease onset, sex, race, family history of SRNS or chronic kidney disease (CKD), extra-renal manifestations, and renal biopsy findings.


We identified disease causing variants in 34/81 (39.5%) families with familial SRNS and 6/95 (6.3%) individuals with sporadic disease. Amongst families with hereditary disease, causative variants were identified in 44.6% of families with presumed autosomal dominant inheritance and 23.8% of families with presumed autosomal recessive inheritance. Variants in INF2, COL4A3, and WT1 accounted for over half of all causative mutations. Family history of SRNS or CKD was the only significant clinical factor predictive of identifying a causative mutation (χ2 p<0.00001).


In this worldwide cohort, we identified causative mutations in almost 40% of all families with hereditary SRNS, compared to only 6% of individuals with sporadic disease, making family history the single most important clinical predictor of monogenic causes of disease. These data support the use of genetic testing in patients with a positive family history of SRNS, and selective testing in those with sporadic disease.


  • NIDDK Support