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.

重要性 早发性玻璃膜疣 (EODM) 是一种严重的疾病，可导致生命早期的晚期黄斑变性；然而，EODM 个体的遗传和表型特征尚未得到很好的研究。

目的 确定EODM个体的基因型和表型特征。

设计、设置和参与者 本病例对照研究从 2004 年 9 月至 2019 年 10 月从欧洲遗传数据库收集数据。共有 89 名 55 岁或以下诊断的 EODM 患者和 91 名年龄相关性黄斑变性 (AMD) 患者被诊断为 65 岁或以上的患者被包括在内。

对CFH、CFI、C3、C9、CFB、ABCA4、PRPH2、TIMP3和CTNNA1基因的编码区域进行测序，根据 52 个 AMD 相关变异计算遗传风险评分 (GRS)，并对彩色眼底照片上的表型特征进行分析。分析比较患有 EODM 和 AMD 的患者。

主要结果和测量 GRS、罕见遗传补体变异的频率和表型特征。

结果 该病例对照研究包括 89 名 EODM 患者（平均 [SD] 年龄，51.8 [8.7] 岁；58 [65.2%] 为女性）和 91 名 AMD 患者（平均 [SD] 年龄，77.6 [6.1] 岁； 45 [49.5%] 女性）。在平均 (SD) 年龄 56.4 (7.3) 岁时，89 名 EODM 患者中有 40 名 (44.9%) 受到地理萎缩或脉络膜新生血管的影响。与 AMD 患者相比，EODM 患者的 GRS 较低（1.03 对 1.60；P  = .002），89 名 EODM 患者中有 27 名（30.3%）携带CFH基因罕见变异，而 91 名患有 CFH 基因的患者中有 7 名携带罕见变异。 AMD (7.7%)。携带罕见CFH变异与 EODM 相关（优势比，7.2；95% CI，2.7-19.6；P < .001)。EODM 患者（162 只眼中的 24 只眼 [14.8%]）与 AMD 患者（164 只眼中的 9 只眼 [5.5%]）相比，观察到大的黄斑玻璃疣区域（超过 50% 覆盖玻璃疣）（优势比，4.57 ；95% CI，1.5-14.1；P  = .008）。

结 _ _ _ _ _早期黄斑变性并可能导致多年视力丧失，这项研究支持针对EODM 患者的补体系统和CFH基因测序，以改善 AMD 的遗传咨询和未来治疗。