Clinical utility of ultra-rapid whole-genome sequencing in an infant with atypical presentation of WT1-associated nephrotic syndrome type 4

Cold Spring Harb Mol Case Stud. 2020 Aug 25;6(4):a005470. doi: 10.1101/mcs.a005470. Print 2020 Aug.


Relatively little is known about phenotypic variability in nonsyndromic nephropathy associated with the gene encoding the WT1 transcription factor. We report a 12-mo-old female who presented with vomiting, diarrhea, and fatigue in the setting of renal failure and malignant hypertension. Trio ultra-rapid whole-genome sequencing identified a novel, likely pathogenic, de novo missense variant (c.485T > A, p.Val162Asp) in WT1 in 46 h, consistent with a diagnosis of nephrotic syndrome type 4 (NPHS4; OMIM 256370). This disorder typically presents with nephrotic syndrome (gross proteinuria, hypoalbuminemia, and edema). Rapid diagnosis had an immediate impact on her clinical management in the pediatric intensive care unit. Diagnostic renal biopsy was avoided, and placement of permanent dialysis access, a gastrostomy tube, and bilateral nephrectomy were accelerated. This report expands the presenting phenotype of nonsyndromic nephrotic syndrome and/or renal failure due to heterozygous variants in WT1 (NPHS4). It also highlights the relationship between time to genomic diagnosis and clinical utility in critically ill infants.

Keywords: abnormal renal physiology; abnormality of urine homeostasis; anuria; chronic metabolic acidosis; episodic vomiting; global glomerulosclerosis; hypertensive crisis; hyponatremia; intermittent diarrhea; nephrotic range proteinuria.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exons
  • Female
  • Genomics
  • Heterozygote
  • Humans
  • Infant
  • Mutation, Missense / genetics
  • Nephrotic Syndrome / diagnosis*
  • Nephrotic Syndrome / genetics*
  • Phenotype
  • WT1 Proteins / genetics*
  • WT1 Proteins / metabolism
  • Whole Genome Sequencing


  • WT1 Proteins
  • WT1 protein, human