Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
JAMA Ophthalmol. 2021 Nov 1;139(11):1218-1226. doi: 10.1001/jamaophthalmol.2021.4102.
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.
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.
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.
早发性年龄相关性黄斑变性（EODM）是一种严重的疾病，可导致生命早期出现晚期黄斑变性；然而，患有 EODM 的个体的遗传和表型特征尚未得到很好的研究。
确定患有 EODM 的个体的基因型和表型特征。
设计、设置和参与者：这项病例对照研究从 2004 年 9 月至 2019 年 10 月从欧洲遗传数据库中收集数据。共纳入 89 名 55 岁或以下确诊为 EODM 的患者和 91 名 65 岁或以上确诊为年龄相关性黄斑变性（AMD）的患者。
对 CFH、CFI、C3、C9、CFB、ABCA4、PRPH2、TIMP3 和 CTNNA1 基因的编码区进行测序，基于 52 个与 AMD 相关的变异计算遗传风险评分（GRS），并比较 EODM 和 AMD 患者的眼底彩色照片的表型特征。
GRS、罕见遗传补体变异的频率和表型特征。
这项病例对照研究纳入了 89 名 EODM 患者（平均[标准差]年龄 51.8[8.7]岁；58[65.2%]为女性）和 91 名 AMD 患者（平均[标准差]年龄 77.6[6.1]岁；45[49.5%]为女性）。在平均（标准差）年龄为 56.4（7.3）岁时，89 名 EODM 患者中有 40 名（44.9%）患有地图样萎缩或脉络膜新生血管。与 AMD 患者相比，EODM 患者的 GRS 较低（1.03 与 1.60；P=0.002），89 名 EODM 患者中有 27 名（30.3%）携带 CFH 基因的罕见变异，而 91 名 AMD 患者中有 7 名（7.7%）携带罕见变异（优势比，7.2；95%CI，2.7-19.6；P<0.001）。携带罕见 CFH 变异与 EODM 相关（比值比，7.2；95%CI，2.7-19.6；P<0.001）。与 AMD 患者相比（9 眼[5.5%]），EODM 患者的大黄斑区（有 162 眼中有超过 50%的区域被大斑状）（24 眼[14.8%]）更为常见（比值比，4.57；95%CI，1.5-14.1；P=0.008）。
在这项研究中，很大一部分 EODM 患者携带罕见的 CFH 变异，大多数确定的 CFH 变异聚集在影响因子 H 和因子 H 样 1 的前 7 个补体控制蛋白结构域中。由于 EODM 经常导致生命早期的晚期黄斑变性，并且可能导致多年的视力丧失，因此这项研究支持针对补体系统并对 EODM 患者进行 CFH 基因测序，以改善遗传咨询和未来 AMD 的治疗。
