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

Tony Yao, Khalil Udwan, Rohan John, Akanchaya Rana, Amirreza Haghighi, Lizhen Xu, Saidah Hack, Heather N. Reich, Michelle Adrienne Hladunewich, Daniel C. Cattran, Andrew D. Paterson, York Pei and Moumita Barua
CJASN January 2019, CJN.08750718; DOI: https://doi.org/10.2215/CJN.08750718
Tony Yao
Division of Nephrology andToronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada;
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Khalil Udwan
Division of Nephrology andToronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada;
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Rohan John
Department of Pathology, University Health Network, Toronto, Canada;
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Akanchaya Rana
Division of Nephrology andToronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada;Institute of Medical Sciences,
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Amirreza Haghighi
Division of Nephrology and
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Lizhen Xu
The Centre for Applied Genomics and
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Saidah Hack
Division of Nephrology andToronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada;
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Heather N. Reich
Division of Nephrology andToronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada;Institute of Medical Sciences,Department of Medicine, and
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Michelle Adrienne Hladunewich
Division of Nephrology, Sunnybrook Health Sciences Center, Toronto, Canada
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Daniel C. Cattran
Division of Nephrology andToronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada;Institute of Medical Sciences,Department of Medicine, and
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Andrew D. Paterson
Institute of Medical Sciences,Department of Medicine, andGenetics and Genome Biology, Research Institute at Hospital for Sick Children, Toronto, Canada; and Division of Epidemiology and Biostatistics, Dalla Lana School of Public Health, Toronto, Ontario, Canada;
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York Pei
Division of Nephrology andToronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada;Institute of Medical Sciences,Department of Medicine, and
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Moumita Barua
Division of Nephrology andToronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada;Institute of Medical Sciences,Department of Medicine, and
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Abstract

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.

Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_01_15_CJASNPodcast_19_02_.mp3

  • FSGS
  • idiopathic nephrotic syndrome
  • human genetics
  • type 4A collagen
  • renal development
  • Glomerular Basement Membrane
  • Podocytes
  • nephrotic syndrome
  • Whole Exome Sequencing
  • Urogenital Abnormalities
  • vesico-ureteral reflux
  • kidney
  • glomerulonephritis
  • Kidney Failure, Chronic
  • Renal Insufficiency
  • Genetic Testing
  • Registries
  • Cohort Studies
  • Received July 20, 2018.
  • Accepted November 16, 2018.
  • Copyright © 2019 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 14 (12)
Clinical Journal of the American Society of Nephrology
Vol. 14, Issue 12
December 06, 2019
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Integration of Genetic Testing and Pathology for the Diagnosis of Adults with FSGS
Tony Yao, Khalil Udwan, Rohan John, Akanchaya Rana, Amirreza Haghighi, Lizhen Xu, Saidah Hack, Heather N. Reich, Michelle Adrienne Hladunewich, Daniel C. Cattran, Andrew D. Paterson, York Pei, Moumita Barua
CJASN Jan 2019, CJN.08750718; DOI: 10.2215/CJN.08750718

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Integration of Genetic Testing and Pathology for the Diagnosis of Adults with FSGS
Tony Yao, Khalil Udwan, Rohan John, Akanchaya Rana, Amirreza Haghighi, Lizhen Xu, Saidah Hack, Heather N. Reich, Michelle Adrienne Hladunewich, Daniel C. Cattran, Andrew D. Paterson, York Pei, Moumita Barua
CJASN Jan 2019, CJN.08750718; DOI: 10.2215/CJN.08750718
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Keywords

  • FSGS
  • idiopathic nephrotic syndrome
  • human genetics
  • type 4A collagen
  • renal development
  • Glomerular Basement Membrane
  • Podocytes
  • nephrotic syndrome
  • Whole Exome Sequencing
  • Urogenital Abnormalities
  • vesico-ureteral reflux
  • kidney
  • glomerulonephritis
  • Kidney Failure, Chronic
  • renal insufficiency
  • genetic testing
  • Registries
  • cohort studies

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