Abstract
Importance: 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. Objective: To identify genotypic and phenotypic characteristics of individuals with EODM. Design, Setting, and Participants: 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. Exposures: 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. Main Outcomes and Measures: GRS, frequency of rare genetic complement variants, and phenotypic characteristics. Results: 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). Conclusions and Relevance: 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..
| Original language | English |
|---|---|
| Pages (from-to) | 1218-1226 |
| Number of pages | 9 |
| Journal | JAMA Ophthalmology |
| Volume | 139 |
| Issue number | 11 |
| Early online date | 14 Oct 2021 |
| DOIs | |
| Publication status | Published - Nov 2021 |
Bibliographical note
Funding Information:Conflict of Interest Disclosures: Mr Verzijden reports support from the European Union’s Horizon 2020 during the conduct of the study. Dr Lechanteur reports personal fees from Novartis and Bayer outside the submitted work. Dr den Hollander reports grants from the Dutch Research Council during the conduct of the study and consulting fees paid to her institution from Gemini Therapeutics, Gyroscope Therapeutics, Ionis Pharmaceuticals, and F. Hoffmann-La Roche outside the submitted work. No other disclosures were reported.
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