title: Analysis of rare variants in the CFH gene in patients with the cuticular drusen subtype of age-related macular degeneration.
abstract: OBJECTIVE
  Age-related macular degeneration (AMD) and cuticular drusen (CD), a clinical subtype of AMD, have been linked to genetic variants in the complement factor H (CFH) gene. In this study, we aimed to investigate the frequency of rare variants in the CFH gene in 180 cases with CD. In addition, we aimed to determine the frequency of a previously reported rare, highly penetrant CFH variant (p.Arg1210Cys) in a Dutch-German non-CD-type AMD case-control cohort, and to describe the phenotype of patients carrying the p.Arg1210Cys variant.
  
  
  METHODS
  Study subjects were selected from the European Genetic Database (EUGENDA), a joint AMD database of the Radboud University Medical Centre and the University Hospital of Cologne, and graded at the Cologne Image Reading Centre and Laboratory (CIRCL). Additionally, two CD cases were recruited from the VU Medical Centre in Amsterdam. The CFH gene was analyzed in 180 CD cases with Sanger sequencing. All identified variants were analyzed for potential damaging effects with prediction software tools Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen). In addition, we genotyped the p.Arg1210Cys variant in 813 non-CD type AMD cases and 1175 controls.
  
  
  RESULTS
  Sequencing identified 11 rare, heterozygous missense variants, one frameshift variant, and one splice acceptor site variant in 16 CD cases. The p.Arg1210Cys variant was identified in two CD cases but was not identified in our Dutch-German non-CD-type AMD case-control cohort.
  
  
  CONCLUSIONS
  The present study identified the presence of rare variants in the CFH gene in 16 (8.8%) of 180 patients with the CD subtype of AMD. The carriers of rare CFH variants displayed a significantly earlier age at onset than non-carriers (p=0.016). The rare missense variant p.Arg1210Cys was identified in two CD cases, but was not detected in 813 non-CD type AMD cases or in the 1,175 controls of our Dutch-German cohort. The current study suggests that the p.Arg1210Cys variant may be restricted to a subset of patients with the CD subtype of AMD. Detailed clinical phenotyping, including fluorescein angiography, of patients with AMD carrying the p.Arg1210Cys variant in other cohorts is required to confirm this finding.
authors: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands ; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors: Maheswara R
authors: MR
authors: Duvvari
authors: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors: Nicole T M
authors: NT
authors: Saksens
authors: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors: Johannes P H
authors: JP
authors: van de Ven
authors: Department of Ophthalmology, VU Medical Centre, Amsterdam, the Netherlands.
authors: Yvonne
authors: Y
authors: de Jong-Hesse
authors: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors: Tina
authors: T
authors: Schick
authors: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors: Willy M
authors: WM
authors: Nillesen
authors: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors: Sascha
authors: S
authors: Fauser
authors: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands ; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors: Lies H
authors: LH
authors: Hoefsloot
authors: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors: Carel B
authors: CB
authors: Hoyng
authors: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands ; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors: Eiko K
authors: EK
authors: de Jong
authors: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands ; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors: Anneke I
authors: AI
authors: den Hollander
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016570:Bruch Membrane / Q000473:pathology*; D016022:Case-Control Studies; D015331:Cohort Studies; D017242:Complement Factor H / Q000235:genetics*; D004252:DNA Mutational Analysis; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D020641:Polymorphism, Single Nucleotide; D015593:Retinal Drusen / Q000235:genetics* / Q000473:pathology
chemical_list: D017242:Complement Factor H