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Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephr...

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Autores principales: Malone, Andrew F, Phelan, Paul J, Hall, Gentzon, Cetincelik, Umran, Homstad, Alison, Alonso, Andrea, Jiang, Ruiji, Lindsey, Thomas, Wu, Guanghong, Sparks, Matthew A, Smith, Stephen R, Webb, Nicholas J A, Kalra, Philip, Adeyemo, Adebowale, Shaw, Andrey S, Conlon, Peter J, Jennette, J Charles, Howell, David N, Winn, Michelle P, Gbadegesin, Rasheed A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245465/
https://www.ncbi.nlm.nih.gov/pubmed/25229338
http://dx.doi.org/10.1038/ki.2014.305
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author Malone, Andrew F
Phelan, Paul J
Hall, Gentzon
Cetincelik, Umran
Homstad, Alison
Alonso, Andrea
Jiang, Ruiji
Lindsey, Thomas
Wu, Guanghong
Sparks, Matthew A
Smith, Stephen R
Webb, Nicholas J A
Kalra, Philip
Adeyemo, Adebowale
Shaw, Andrey S
Conlon, Peter J
Jennette, J Charles
Howell, David N
Winn, Michelle P
Gbadegesin, Rasheed A
author_facet Malone, Andrew F
Phelan, Paul J
Hall, Gentzon
Cetincelik, Umran
Homstad, Alison
Alonso, Andrea
Jiang, Ruiji
Lindsey, Thomas
Wu, Guanghong
Sparks, Matthew A
Smith, Stephen R
Webb, Nicholas J A
Kalra, Philip
Adeyemo, Adebowale
Shaw, Andrey S
Conlon, Peter J
Jennette, J Charles
Howell, David N
Winn, Michelle P
Gbadegesin, Rasheed A
author_sort Malone, Andrew F
collection PubMed
description Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical findings at diagnosis were proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin glomerular basement membrane, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.
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spelling pubmed-42454652015-06-01 Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis Malone, Andrew F Phelan, Paul J Hall, Gentzon Cetincelik, Umran Homstad, Alison Alonso, Andrea Jiang, Ruiji Lindsey, Thomas Wu, Guanghong Sparks, Matthew A Smith, Stephen R Webb, Nicholas J A Kalra, Philip Adeyemo, Adebowale Shaw, Andrey S Conlon, Peter J Jennette, J Charles Howell, David N Winn, Michelle P Gbadegesin, Rasheed A Kidney Int Article Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical findings at diagnosis were proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin glomerular basement membrane, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes. 2014-09-17 2014-12 /pmc/articles/PMC4245465/ /pubmed/25229338 http://dx.doi.org/10.1038/ki.2014.305 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Malone, Andrew F
Phelan, Paul J
Hall, Gentzon
Cetincelik, Umran
Homstad, Alison
Alonso, Andrea
Jiang, Ruiji
Lindsey, Thomas
Wu, Guanghong
Sparks, Matthew A
Smith, Stephen R
Webb, Nicholas J A
Kalra, Philip
Adeyemo, Adebowale
Shaw, Andrey S
Conlon, Peter J
Jennette, J Charles
Howell, David N
Winn, Michelle P
Gbadegesin, Rasheed A
Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis
title Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis
title_full Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis
title_fullStr Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis
title_full_unstemmed Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis
title_short Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis
title_sort rare hereditary col4a3/col4a4 variants may be mistaken for familial focal segmental glomerulosclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245465/
https://www.ncbi.nlm.nih.gov/pubmed/25229338
http://dx.doi.org/10.1038/ki.2014.305
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