Abstract
Early-onset drusen maculopathy (EODM) is a severe disease and can lead to advanced macular degeneration early in life; however, genetic and phenotypic characteristics of individuals with EODM are not well studied. To identify genotypic and phenotypic characteristics of individuals with EODM. This case-control study collected data from the European Genetic Database from September 2004 to October 2019. A total of 89 patients with EODM diagnosed at 55 years or younger and 91 patients with age-related macular degeneration (AMD) diagnosed at 65 years or older were included. Coding regions of CFH, CFI, C3, C9, CFB, ABCA4, PRPH2, TIMP3, and CTNNA1 genes were sequenced, genetic risk scores (GRS) were calculated based on 52 AMD-associated variants, and phenotypic characteristics on color fundus photographs were analyzed comparing patients with EODM and AMD. GRS, frequency of rare genetic complement variants, and phenotypic characteristics. This case-control study included 89 patients with EODM (mean [SD] age, 51.8 [8.7] years; 58 [65.2%] were female) and 91 patients with AMD (mean [SD] age, 77.6 [6.1] years; 45 [49.5%] female). At a mean (SD) age of 56.4 (7.3) years, 40 of 89 patients with EODM (44.9%) were affected by geographic atrophy or choroidal neovascularization. A lower GRS was observed in patients with EODM compared with patients with AMD (1.03 vs 1.60; P = .002), and 27 of 89 patients with EODM (30.3%) carried rare variants in the CFH gene compared with 7 of 91 patients with AMD (7.7%). Carriership of a rare CFH variant was associated with EODM (odds ratio, 7.2; 95% CI, 2.7-19.6; P < .001). A large macular drusen area (more than 50% covered with drusen) was observed in patients with EODM (24 of 162 eyes [14.8%]) compared with patients with AMD (9 of 164 eyes [5.5%]) (odds ratio, 4.57; 95% CI, 1.5-14.1; P = .008). A large proportion of patients with EODM in this study carried rare CFH variants, with most of the identified CFH variants clustered in the first 7 complement control protein domains affecting factor H and factor H-like 1. Because EODM frequently leads to advanced macular degeneration at an early age and can result in many years of vision loss, this study supports targeting the complement system and sequencing the CFH gene in patients with EODM to improve genetic counseling and future treatments for AMD.
Highlights
We aimed to describe phenotypic characteristics, determine the contribution of 52 age-related macular degeneration (AMD)-associated variants using genetic risk score (GRS), and perform a comprehensive analysis of the coding and splice-site regions of complement factor H (CFH), complement factor I (CFI), complement 3 (C3), complement 9 (C9), CFB, ABCA4, PRPH2, TIMP3, and CTNNA1 in a cohort of 89 patients with Early-onset drusen maculopathy (EODM) and compare these characteristics with characteristics of patients with AMD
Description of the EODM Cohort The EODM cohort consisted of individuals with a heterogenous spectrum of drusen phenotypes, including 7 individuals with extensive extramacular drusen (EMD), 6 individuals with large colloid drusen, 3 individuals with temporal drusen, and multiple individuals with cuticular drusen (Figure 1; eFigure 1 in the Supplement)
Analysis of 52 Single-Nucleotide Variations in Individuals With EODM The median (IQR) genetic risk scores (GRS) in individuals with EODM (1.03 [0.16 to 1.94]) was lower compared with that of individuals with AMD (1.60 [0.84 to 2.64]) (P = .002), and there was a positive correlation between disease stage and GRS (ρ, 197; P = .01)
Summary
Study Population We collected data on patients diagnosed with EODM from the European Genetic Database (EUGENDA). Patient recruitment took place from September 2004 to October 2019. This study was approved by the medical ethics committee of the Radboud University Medical Center, Nijmegen, the Netherlands, and all study participants provided written informed consent. No compensation or incentive was offered to patients for participation in this study. This research adhered to the tenets of the Declaration of Helsinki. EODM was defined as any sign of age-related maculopathy (eTable 1 in the Supplement) diagnosed at 55 years or
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