title: Genotype/phenotype correlations in complement factor H deficiency arising from uniparental isodisomy.
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.
authors.affiliation: Northern Molecular Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
authors.forename: Valerie
authors.initials: V
authors.lastname: Wilson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Darlay
authors.forename: William
authors.initials: W
authors.lastname: Wong
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Wood
authors.forename: Jeannette
authors.initials: J
authors.lastname: McFarlane
authors.forename: Lone
authors.initials: L
authors.lastname: Schejbel
authors.forename: Ida M
authors.initials: IM
authors.lastname: Schmidt
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
authors.forename: James
authors.initials: J
authors.lastname: Tellez
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Hunze
authors.forename: Kevin
authors.initials: K
authors.lastname: Marchbank
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
mesh_terms: D065766:Atypical Hemolytic Uremic Syndrome; D017242:Complement Factor H / Q000172:deficiency* / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D000081208:Hereditary Complement Deficiency Diseases; D006720:Homozygote; D006801:Humans; D007223:Infant; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D024182:Uniparental Disomy / Q000235:genetics*; D015432:Glomerulonephritis, Membranoproliferative
chemical_list: D051916:Membrane Cofactor Protein; D017242:Complement Factor H
keywords: Complement; glomerulonephritis; hemolytic uremic syndrome