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Original Investigation
August 31, 2017

Phenotype Characteristics of Patients With Age-Related Macular Degeneration Carrying a Rare Variant in the Complement Factor H Gene

Author Affiliations
  • 1Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
  • 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
  • 3Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany
  • 4Centre for Public Health, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Northern Ireland, United Kingdom
JAMA Ophthalmol. Published online August 31, 2017. doi:10.1001/jamaophthalmol.2017.3195
Key Points

Question  Are there distinctive phenotypical characteristics of patients with age-related macular degeneration carrying a rare variant in the complement factor H gene?

Findings  This cross-sectional study found that larger drusen area within the Early Treatment Diabetic Retinopathy Study grid, a crystalline appearance of some drusen, and drusen nasal to the optic disc were associated with patients with age-related macular degeneration carrying a rare pathogenic complement factor H variant.

Meaning  These phenotypical characteristics might aid ophthalmologists in the identification of complement factor H variant carriers, which may be increasingly important if complement-inhibiting therapies are shown to be beneficial.

Abstract

Importance  Rare variants in the complement factor H (CFH) gene and their association with age-related macular degeneration (AMD) have been described. However, there is limited literature on the phenotypes accompanying these rare variants. Phenotypical characteristics could help ophthalmologists select patients for additional genetic testing.

Objective  To describe the phenotypical characteristics of patients with AMD carrying a rare variant in the CFH gene.

Design, Setting, and Participants  In this cross-sectional study, we searched the genetic database of the department of ophthalmology at the Radboudumc (tertiary ophthalmologic referral center) and the European Genetic Database for patients with AMD with a rare genetic variant in the CFH gene. Patient recruitment took place from March 30, 2006, to February 18, 2013, and data were analyzed from November 30, 2015, to May 8, 2017. Phenotypical features on fundus photographs of both eyes of patients were graded by 2 independent reading center graders masked for carrier status.

Main Outcomes and Measures  Differences in phenotypical characteristics between rare variant carriers and noncarriers were analyzed using univariable generalized estimated equations logistic regression models accounting for intereye correlation.

Results  Analyses included 100 eyes of 51 patients with AMD carrying a CFH variant (mean [SD] age, 66.7 [12.1] years; 64.7% female) and 204 eyes of 102 age-matched noncarriers (mean [SD] age, 67.1 [11.8] years; 54.9% female). Carrying a rare pathogenic CFH variant was associated with larger drusen area (odds ratio range, 6.98 [95% CI, 2.04-23.89] to 18.50 [95% CI, 2.19-155.99]; P = .002), presence of drusen with crystalline appearance (odds ratio, 3.24; 95% CI, 1.24-8.50; P = .02), and drusen nasal to the optic disc (odds ratio range, 4.03 [95% CI, 1.70-9.56] to 7.42 [95% CI, 0.65-84.84]; P = .003).

Conclusions and Relevance  Identification of rare CFH variant carriers may be important for upcoming complement-inhibiting therapies. Patients with an extensive drusen area, drusen with crystalline appearance, and drusen nasal to the optic disc are more likely to have a rare variant in the CFH gene. However, it is not likely that carriers can be discriminated from noncarriers based solely on phenotypical characteristics from color fundus images. Therefore, ophthalmologists should consider genetic testing in patients with these phenotypic characteristics in combination with other patient characteristics, such as early onset, cuticular drusen on fluorescein angiography, and family history of AMD.

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