Human Genetics, Faculty VI - School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.
Junior Research Group, Genetics of Childhood Brain Malformations, Faculty VI - School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.
J Gene Med. 2020 Oct;22(10):e3211. doi: 10.1002/jgm.3211. Epub 2020 Jun 20.
Retinitis pigmentosa (RP) is one of the most common form of inherited retinal dystrophies. Identification of disease-causing mutations is a prerequisite for applying targeted therapeutic approaches. The present study aimed to identify disease-associated mutations in a large Serbian family, in which two brothers have suffered from RP starting in the first decade of their lives.
The index patient and 12 additional members of a four-generation family were analyzed. All participants underwent detailed ophthalmic examinations. Genomic DNA was isolated from family members to perform whole exome sequencing (WES) and Sanger sequencing of candidate genes.
An early onset RP phenotype was presented in both ocular fundi of the index patient and his brother: arteriolar attenuation, as well as retinal pigmentary changes in peripheral fundus and waxy disc pallor. Both brothers showed foveal thinning. The index patient showed epiretinal membranes in both eyes and a parafoveal cystic lesion in his right eye, whereas the brother of the index patient showed choroid folds and vitreomacular adhesion in his left eye. We identified compound heterozygous mutations in the RPE65 gene (a novel c.1338+1G>A splice donor site mutation in addition to the frame-shifting mutation c.1207_1210dup (p.Glu404Alafs*4)) using an in-house WES pipeline.
Evaluation of all previously described RPE65 mutations showed that the sequence variants identified in the present study located to rarely altered exons and likely effect a highly conserved region of the RPE65 protein. Gene augmentation therapies might be a promising treatment option for the patients described.
色素性视网膜炎（RP）是最常见的遗传性视网膜营养不良形式之一。确定致病突变是应用靶向治疗方法的前提。本研究旨在鉴定一个大型塞尔维亚家族中与疾病相关的突变，该家族中有两名兄弟在生命的第一个十年就患有 RP。
分析了索引患者和一个四代家族的另外 12 名成员。所有参与者都接受了详细的眼科检查。从家族成员中提取基因组 DNA，进行全外显子组测序（WES）和候选基因的 Sanger 测序。
索引患者和他的兄弟的眼底都出现了早发性 RP 表型：小动脉衰减，以及周边眼底的视网膜色素变化和蜡样盘苍白。两兄弟都表现出黄斑变薄。索引患者的双眼都有视网膜前膜，右眼有旁中心囊状病变，而索引患者的兄弟的左眼有脉络膜皱褶和玻璃体黄斑粘连。我们使用内部的 WES 管道在 RPE65 基因中发现了复合杂合突变（除了框移突变 c.1207_1210dup（p.Glu404Alafs*4）之外，还存在新的 c.1338+1G>A 剪接供体位点突变）。
对所有先前描述的 RPE65 突变的评估表明，本研究中鉴定的序列变异位于很少改变的外显子中，并且可能影响 RPE65 蛋白的高度保守区域。基因增强疗法可能是对所描述的患者有希望的治疗选择。
