Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Clin Genet. 2022 Nov;102(5):414-423. doi: 10.1111/cge.14212. Epub 2022 Sep 13.
Early onset drusen maculopathy (EODM) can lead to advanced macular degeneration at a young age, affecting quality of life. However, the genetic causes of EODM are not well studied. We performed whole genome sequencing in 49 EODM patients. Common genetic variants were analysed by calculating genetic risk scores based on 52 age-related macular generation (AMD)-associated variants, and we analysed rare variants in candidate genes to identify potential deleterious variants that might contribute to EODM development. We demonstrate that the 52 AMD-associated variants contributed to EODM, especially variants located in the complement pathway. Furthermore, we identified 26 rare genetic variants predicted to be pathogenic based on in silico prediction tools or based on reported pathogenicity in literature. These variants are located predominantly in the complement and lipid metabolism pathways. Last, evaluation of 18 genes causing inherited retinal dystrophies that can mimic AMD characteristics, revealed 11 potential deleterious variants in eight EODM patients. However, phenotypic characteristics did not point towards a retinal dystrophy in these patients. In conclusion, this study reports new insights into rare variants that are potentially involved in EODM development, and which are relevant for future studies unravelling the aetiology of EODM.
早发性黄斑部玻璃膜疣（EODM）可导致年轻患者罹患晚期黄斑部退化，进而影响生活质量。然而，EODM 的遗传病因尚未得到充分研究。我们对 49 名 EODM 患者进行了全基因组测序。通过基于 52 个与年龄相关性黄斑变性（AMD）相关的变异计算遗传风险评分，分析常见遗传变异，我们还分析了候选基因中的稀有变异，以确定可能导致 EODM 发展的潜在有害变异。我们证明，52 个与 AMD 相关的变异与 EODM 有关，特别是位于补体途径中的变异。此外，我们根据计算预测工具或文献报道的致病性，鉴定出 26 个预测为致病性的罕见遗传变异。这些变异主要位于补体和脂质代谢途径中。最后，对可能模拟 AMD 特征的 18 种引起遗传性视网膜营养不良的基因进行评估，在 8 名 EODM 患者中发现了 11 个潜在有害变异。然而，这些患者的表型特征并未指向视网膜营养不良。总之，本研究报告了新的见解，即潜在涉及 EODM 发展的稀有变异，并为未来研究 EODM 的病因提供了依据。
