Duvvari Maheswara R, Saksens Nicole T M, van de Ven Johannes P H, de Jong-Hesse Yvonne, Schick Tina, Nillesen Willy M, Fauser Sascha, Hoefsloot Lies H, Hoyng Carel B, de Jong Eiko K, den Hollander Anneke I
Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands ; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.
Mol Vis. 2015 Mar 15;21:285-92. eCollection 2015.
Age-related macular degeneration (AMD) and cuticular drusen (CD), a clinical subtype of AMD, have been linked to genetic variants in the complement factor H (CFH) gene. In this study, we aimed to investigate the frequency of rare variants in the CFH gene in 180 cases with CD. In addition, we aimed to determine the frequency of a previously reported rare, highly penetrant CFH variant (p.Arg1210Cys) in a Dutch-German non-CD-type AMD case-control cohort, and to describe the phenotype of patients carrying the p.Arg1210Cys variant.
Study subjects were selected from the European Genetic Database (EUGENDA), a joint AMD database of the Radboud University Medical Centre and the University Hospital of Cologne, and graded at the Cologne Image Reading Centre and Laboratory (CIRCL). Additionally, two CD cases were recruited from the VU Medical Centre in Amsterdam. The CFH gene was analyzed in 180 CD cases with Sanger sequencing. All identified variants were analyzed for potential damaging effects with prediction software tools Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen). In addition, we genotyped the p.Arg1210Cys variant in 813 non-CD type AMD cases and 1175 controls.
Sequencing identified 11 rare, heterozygous missense variants, one frameshift variant, and one splice acceptor site variant in 16 CD cases. The p.Arg1210Cys variant was identified in two CD cases but was not identified in our Dutch-German non-CD-type AMD case-control cohort.
The present study identified the presence of rare variants in the CFH gene in 16 (8.8%) of 180 patients with the CD subtype of AMD. The carriers of rare CFH variants displayed a significantly earlier age at onset than non-carriers (p=0.016). The rare missense variant p.Arg1210Cys was identified in two CD cases, but was not detected in 813 non-CD type AMD cases or in the 1,175 controls of our Dutch-German cohort. The current study suggests that the p.Arg1210Cys variant may be restricted to a subset of patients with the CD subtype of AMD. Detailed clinical phenotyping, including fluorescein angiography, of patients with AMD carrying the p.Arg1210Cys variant in other cohorts is required to confirm this finding.
年龄相关性黄斑变性（AMD）以及AMD的一种临床亚型——玻璃膜疣（CD），均与补体因子H（CFH）基因的遗传变异有关。在本研究中，我们旨在调查180例CD患者中CFH基因罕见变异的频率。此外，我们还旨在确定荷兰 - 德国非CD型AMD病例对照队列中先前报道的一种罕见、高外显率CFH变异（p.Arg1210Cys）的频率，并描述携带p.Arg1210Cys变异患者的表型。
研究对象选自欧洲遗传数据库（EUGENDA），这是拉德堡德大学医学中心和科隆大学医院联合建立的AMD数据库，并在科隆图像阅读中心和实验室（CIRCL）进行分级。此外，从阿姆斯特丹的VU医学中心招募了2例CD患者。采用桑格测序法对180例CD患者的CFH基因进行分析。使用预测软件工具“从耐受中筛选不耐受”（SIFT）和“多态性表型分析”（PolyPhen）对所有鉴定出的变异进行潜在有害效应分析。此外，我们对813例非CD型AMD病例和1175例对照进行了p.Arg1210Cys变异的基因分型。
测序在16例CD患者中鉴定出11种罕见的杂合错义变异、1种移码变异和1种剪接受体位点变异。在2例CD患者中鉴定出p.Arg1210Cys变异，但在我们的荷兰 - 德国非CD型AMD病例对照队列中未鉴定出该变异。
本研究在180例AMD的CD亚型患者中的16例（8.8%）中鉴定出CFH基因存在罕见变异。罕见CFH变异携带者的发病年龄显著早于非携带者（p = 0.016）。在2例CD患者中鉴定出罕见的错义变异p.Arg1210Cys，但在813例非CD型AMD病例或我们荷兰 - 德国队列的1175例对照中未检测到。目前的研究表明，p.Arg1210Cys变异可能仅限于AMD的CD亚型患者的一个亚组。需要对其他队列中携带p.Arg1210Cys变异的AMD患者进行详细的临床表型分析，包括荧光素血管造影，以证实这一发现。
