Genotype/phenotype correlations in complement factor H deficiency arising from uniparental isodisomy

Am J Kidney Dis. 2013 Nov;62(5):978-83. doi: 10.1053/j.ajkd.2013.05.020. Epub 2013 Jul 16.

Abstract

We report a male infant who presented at 8 months of age with atypical hemolytic uremic syndrome (aHUS) responsive to plasma therapy. Investigation showed him to have complement factor H (CFH) deficiency associated with a homozygous CFH mutation (c.2880delT [p.Phe960fs]). Mutation screening of the child's parents revealed that the father was heterozygous for this change but that it was not present in his mother. Chromosome 1 uniparental isodisomy of paternal origin was confirmed by genotyping chromosome 1 SNPs. CD46 SNP genotyping was undertaken in this individual and another patient with CFH deficiency associated with chromosome 1 uniparental isodisomy. This showed a homozygous aHUS risk haplotype (CD46GGAAC) in the patient with aHUS and a homozygous glomerulonephritis risk haplotype (CD46AAGGT) in the patient with endocapillary glomerulonephritis. We also showed that FHL-1 (factor H-like protein 1) was present in the patient with aHUS and absent in the patient with glomerulonephritis. This study emphasizes that modifiers such as CD46 and FHL-1 may determine the kidney phenotype of patients who present with homozygous CFH deficiency.

Keywords: Complement; glomerulonephritis; hemolytic uremic syndrome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atypical Hemolytic Uremic Syndrome
  • Complement Factor H / deficiency*
  • Complement Factor H / genetics
  • Genotype*
  • Haplotypes / genetics
  • Hemolytic-Uremic Syndrome / genetics*
  • Hereditary Complement Deficiency Diseases
  • Homozygote
  • Humans
  • Infant
  • Kidney Diseases / genetics*
  • Male
  • Membrane Cofactor Protein / genetics
  • Mutation / genetics
  • Phenotype*
  • Polymorphism, Single Nucleotide / genetics
  • Uniparental Disomy / genetics*

Substances

  • Membrane Cofactor Protein
  • Complement Factor H

Supplementary concepts

  • Complement Factor H Deficiency