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

dc.contributor.author

Malone, Andrew F

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Phelan, Paul J

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Hall, Gentzon

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Cetincelik, Umran

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Homstad, Alison

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Alonso, Andrea S

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Jiang, Ruiji

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Lindsey, Thomas B

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Wu, Guanghong

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Sparks, Matthew A

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Smith, Stephen R

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Webb, Nicholas JA

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Kalra, Philip A

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Adeyemo, Adebowale A

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Shaw, Andrey S

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Conlon, Peter J

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Jennette, J Charles

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Howell, David N

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Winn, Michelle P

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Gbadegesin, Rasheed A

dc.coverage.spatial

United States

dc.date.accessioned

2016-02-21T17:22:23Z

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2014-12

dc.description.abstract

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 (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS 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 finding at diagnosis was 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 GBM, 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.

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/25229338

dc.identifier

S0085-2538(15)30471-3

dc.identifier.eissn

1523-1755

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https://hdl.handle.net/10161/11616

dc.language

eng

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Nature Publishing Group

dc.relation.ispartof

Kidney Int

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10.1038/ki.2014.305

dc.subject

Adolescent

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Adult

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Autoantigens

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Child

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Collagen Type IV

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DNA Mutational Analysis

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Exome

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Female

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Genetic Testing

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Genotype

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Glomerular Basement Membrane

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Glomerulosclerosis, Focal Segmental

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Hearing Loss

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Hematuria

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Humans

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Male

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Middle Aged

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Mutation, Missense

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Phenotype

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Podocytes

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Proteinuria

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Young Adult

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Sparks, Matthew A|0000-0003-2075-2691

duke.contributor.orcid

Gbadegesin, Rasheed A|0000-0001-5641-6644

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/25229338

pubs.begin-page

1253

pubs.end-page

1259

pubs.issue

6

pubs.organisational-group

Clinical Science Departments

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Duke

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Duke Molecular Physiology Institute

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Institutes and Centers

pubs.organisational-group

Medicine

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Medicine, Nephrology

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Pathology

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Pediatrics

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Pediatrics, Nephrology

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

86

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