Whole exome sequencing reveals novel COL4A3 and COL4A4 mutations and resolves diagnosis in Chinese families with kidney disease

BMC Nephrol. 2014 Nov 7:15:175. doi: 10.1186/1471-2369-15-175.


Background: Collagen IV-related nephropathies, including thin basement membrane nephropathy and Alport Syndrome (AS), are caused by defects in the genes COL4A3, COL4A4 and COL4A5. Diagnosis of these conditions can be hindered by variable penetrance and the presence of non-specific clinical or pathological features.

Methods: Three families with unexplained inherited kidney disease were recruited from Shanghai, China. Whole exome sequencing (WES) was performed in the index case from each family and co-segregation of candidate pathogenic mutations was tested by Sanger sequencing.

Results: We identified COL4A4 missense variants [c.G2636A (p.Gly879Glu) and c.C4715T (p.Pro1572Leu)] in the 21-year-old male proband from family 1, who had been diagnosed with mesangial proliferative nephropathy at age 14. COL4A4 c.G2636A, a novel variant, co-segregated with renal disease among maternal relatives. COL4A4 c.C4715T has previously been associated with autosomal recessive AS and was inherited from his clinically unaffected father. In family 2, a novel COL4A3 missense mutation c.G2290A (p.Gly997Glu) was identified in a 45-year-old male diagnosed with focal segmental glomerulosclerosis and was present in all his affected family members, who exhibited disease ranging from isolated microscopic hematuria to end stage renal disease (ESRD). In family 3, ESRD occurred in both male and females who were found to harbor a known AS-causing COL4A5 donor splice site mutation (c.687+1G>A). None of these variants were detected among 100 healthy Chinese individuals.

Conclusion: WES identified 2 novel and 2 known pathogenic COL4A3/COL4A4/COL4A5 mutations in 3 families with previously unexplained inherited kidney disease. These findings highlight the clinical range of collagen IV-related nephropathies and resolved diagnostic confusion arising from atypical or incomplete clinical/histological findings, allowing appropriate counselling and treatment advice to be given.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Substitution
  • Asian People / genetics*
  • Autoantigens / genetics*
  • China / epidemiology
  • Chromosomes, Human, Pair 2 / genetics
  • Chromosomes, Human, X / genetics
  • Collagen Type IV / genetics*
  • Collagen Type VI / genetics*
  • DNA Mutational Analysis
  • Exome / genetics*
  • Female
  • Genes, X-Linked
  • Genetic Diseases, X-Linked / ethnology
  • Genetic Diseases, X-Linked / genetics
  • Glomerulonephritis, Membranoproliferative / genetics
  • Glomerulosclerosis, Focal Segmental / genetics
  • Humans
  • Kidney Diseases / ethnology
  • Kidney Diseases / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Nephrotic Syndrome / genetics
  • Pedigree
  • Point Mutation*
  • Pseudogenes / genetics*
  • Sequence Alignment
  • Sequence Analysis, DNA / methods*
  • Sequence Homology, Amino Acid
  • Young Adult


  • Autoantigens
  • COL6A4P1 protein, human
  • COL6A5 protein, human
  • Collagen Type IV
  • Collagen Type VI
  • type IV collagen alpha3 chain