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

Andrew F. Malone, Paul J. Phelan, Gentzon Hall, Umran Cetincelik, Alison Homstad, Andrea S. Alonso, Ruiji Jiang, Thomas B. Lindsey, Guanghong Wu, Matthew A. Sparks, Stephen R. Smith, Nicholas J.A. Webb, Philip A. Kalra, Adebowale A. Adeyemo, Andrey S. Shaw, Peter J. Conlon, J. Charles Jennette, David N. Howell, Michelle P. Winn, Rasheed A. Gbadegesin

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


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.

Original languageEnglish
Pages (from-to)1253-1259
Number of pages7
JournalKidney International
Issue number6
StatePublished - Jan 1 2014


  • Alport syndrome
  • Focal segmental glomerulosclerosis
  • Podocyte
  • Proteinuria


Dive into the research topics of 'Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis'. Together they form a unique fingerprint.

Cite this