A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome

Pediatr Nephrol. 2013 Nov;28(11):2221-5. doi: 10.1007/s00467-013-2560-2. Epub 2013 Jul 24.


Background: Mutations in complement factor H (CFH) are associated with complement dysregulation and the development of an aggressive form of atypical hemolytic uremic syndrome (aHUS) that progresses to end-stage renal disease (ESRD) and in most patients has a high rate of recurrence following transplantation. Sequence analysis of CFH and its downstream complement factor H-related genes (CFHR1-5) reveals several macrohomologous blocks caused by large genomic duplications. This high degree of sequence identity renders this area susceptible to nonallelic homologous recombination (NAHR) events, resulting in large-scale deletions, duplications, and the generation of hybrid CFH genes.

Case-diagnosis: Here, we report the finding of a novel CFHR1/CFH hybrid gene created by a de novo NAHR event in a 14-year-old girl with aHUS. The resulting fusion protein contains the first three short consensus repeats (SCRs) of CFHR1 and the terminal two SCRs of CFH.

Conclusions: This finding demonstrates a novel pathogenic mechanism for the development of aHUS. Additionally, since standard Sanger sequencing is unable to detect such rearrangements, all aHUS patients should receive comprehensive genetic screening that includes analysis of copy number variation in order to identify patients with poor clinical prognoses.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Autoantibodies / analysis
  • Blotting, Western
  • Child
  • Complement C3b Inactivator Proteins / genetics*
  • Complement Factor H / genetics*
  • Creatinine / blood
  • DNA / genetics
  • Female
  • Gene Amplification
  • Hemolytic-Uremic Syndrome / genetics*
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Kidney Transplantation
  • Polymerase Chain Reaction
  • Renal Dialysis


  • Antibodies, Monoclonal, Humanized
  • Autoantibodies
  • CFHR1 protein, human
  • Complement C3b Inactivator Proteins
  • Immunosuppressive Agents
  • Complement Factor H
  • DNA
  • eculizumab
  • Creatinine