Integration of Genetic Testing and Pathology for the Diagnosis of Adults with FSGS

Clin J Am Soc Nephrol. 2019 Feb 7;14(2):213-223. doi: 10.2215/CJN.08750718. Epub 2019 Jan 15.


Background and objectives: FSGS and nephrotic syndrome studies have shown that single gene causes are more likely to be found in pediatric cases than adults. Consequently, many studies have examined limited gene panels in largely pediatric cohorts.

Design, setting, participants, & measurements: Whole-exome sequencing was performed in adults with FSGS diagnosed between 1976 and 2017 in the Toronto GN Registry. An expanded panel of 109 genes linked to FSGS, glomerular basement membrane abnormalities, as well as causes of pediatric ESKD including congenital abnormalities of the kidney and urinary tract (CAKUT) and nephronophthisis, were examined.

Results: The cohort was composed of 193 individuals from 179 families. Nearly half (49%) developed ESKD at a mean age of 47±17 years. The genetic diagnostic rate was 11%. Of definitely pathogenic variants, 55% were in COL4A (A3/A4/A5), 40% were in podocyte genes, and 5% were in CAKUT genes. Many, but not all individuals with COL4A definitely pathogenic variants had some evidence of glomerular basement membrane abnormalities. The estimated mean survival/age of kidney failure for individuals with COL4A definitely pathogenic variants was 58 years (95% confidence interval, 49 to 69), far later than what has been reported in the literature. Likely pathogenic variants were identified in an additional 9% of the cohort, with most in COL4A. Correlation with glomerular basement membrane morphology suggested a causal role for at least some of these likely pathogenic variants.

Conclusions: Even with an expanded gene panel, we find that COL4A disorders are the leading monogenic cause in adults diagnosed with FSGS.

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Keywords: Cohort Studies; FSGS; Genetic Testing; Glomerular Basement Membrane; Kidney Failure, Chronic; Podocytes; Registries; Renal Insufficiency; Urogenital Abnormalities; Whole Exome Sequencing; glomerulonephritis; human genetics; idiopathic nephrotic syndrome; kidney; nephrotic syndrome; renal development; type 4A collagen; vesico-ureteral reflux.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantigens / genetics
  • Collagen Type IV / genetics
  • Congenital Abnormalities / genetics
  • Exome Sequencing
  • Female
  • Genetic Testing
  • Glomerular Basement Membrane / pathology*
  • Glomerulosclerosis, Focal Segmental / diagnosis
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glomerulosclerosis, Focal Segmental / pathology*
  • Humans
  • Kidney Failure, Chronic / etiology*
  • Male
  • Middle Aged
  • Podocytes
  • Survival Rate
  • Urinary Tract / abnormalities
  • Young Adult


  • Autoantigens
  • COL4A4 protein, human
  • COL4A5 protein, human
  • Collagen Type IV
  • type IV collagen alpha3 chain