Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Elfriede-Aulhorn Strasse 7, 72076 Tübingen, Germany.
Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary.
Int J Mol Sci. 2023 May 17;24(10):8915. doi: 10.3390/ijms24108915.
To report the spectrum of Leber congenital amaurosis (LCA) associated genes in a large German cohort and to delineate their associated phenotype. Local databases were screened for patients with a clinical diagnosis of LCA and for patients with disease-causing variants in known LCA-associated genes independent of their clinical diagnosis. Patients with a mere clinical diagnosis were invited for genetic testing. Genomic DNA was either analyzed in a diagnostic-genetic or research setup using various capture panels for syndromic and non-syndromic IRD (inherited retinal dystrophy) genes. Clinical data was obtained mainly retrospectively. Patients with genetic and phenotypic information were eventually included. Descriptive statistical data analysis was performed. A total of 105 patients (53 female, 52 male, age 3-76 years at the time of data collection) with disease-causing variants in 16 LCA-associated genes were included. The genetic spectrum displayed variants in the following genes: (21%), (21%), (14%), (13%), (6%), (6%), and (5%), and few cases harbored pathogenic variants in , , , , , , , , and (altogether accounting for 14%). The most common clinical diagnosis was LCA (53%, 56/105) followed by retinitis pigmentosa (RP, 40%, 42/105), but also other IRDs were seen (cone-rod dystrophy, 5%; congenital stationary night blindness, 2%). Among LCA patients, 50% were caused by variants in (29%) and (21%), whereas variants in other genes were much less frequent ( 11%, 11%, 9%, and 7%, and sporadically , , , , and ). In general, the patients showed a severe phenotype hallmarked by severely reduced visual acuity, concentric narrowing of the visual field, and extinguished electroretinograms. However, there were also exceptional cases with best corrected visual acuity as high as 0.8 (Snellen), well-preserved visual fields, and preserved photoreceptors in spectral domain optical coherence tomography. Phenotypic variability was seen between and within genetic subgroups. The study we are presenting pertains to a considerable LCA group, furnishing valuable comprehension of the genetic and phenotypic spectrum. This knowledge holds significance for impending gene therapeutic trials. In this German cohort, and are the most frequently mutated genes. However, LCA is genetically highly heterogeneous and exhibits clinical variability, showing overlap with other IRDs. For any therapeutic gene intervention, the disease-causing genotype is the primary criterion for treatment access, but the clinical diagnosis, state of the retina, number of to be treated target cells, and the time point of treatment will be crucial.
报告一个大型德国队列中莱伯先天性黑蒙（LCA）相关基因的谱，并描绘其相关表型。对有临床诊断为 LCA 的患者和有已知与 LCA 相关基因的致病变异而无临床诊断的患者的本地数据库进行了筛选。对仅有临床诊断的患者进行了基因检测邀请。使用各种用于综合征性和非综合征性遗传性视网膜营养不良（IRDs）基因的捕获面板，对基因组 DNA 进行了诊断性遗传或研究性分析。主要回顾性获得临床数据。最终纳入具有遗传和表型信息的患者。进行了描述性统计数据分析。共纳入 105 例患者（53 名女性，52 名男性，数据采集时年龄 3-76 岁），其 16 个与 LCA 相关的基因中存在致病变异。遗传谱显示以下基因的变异： （21%）， （21%）， （14%）， （13%）， （6%）， （6%）和 （5%），少数病例存在致病性变异 （5%）， （4%）， （3%）， （3%）， （2%）， （2%）， （2%）， （2%）， （2%）， 和 （2%）。最常见的临床诊断是 LCA（53%，56/105），其次是色素性视网膜炎（40%，42/105），但也观察到其他 IRDs（锥杆营养不良，5%；先天性静止性夜盲，2%）。在 LCA 患者中，50%是由 （29%）和 （21%）中的变异引起的，而其他基因的变异则较少见（11%，11%，9%和 7%，偶尔还有 ， ， ， ，和 ）。一般来说，患者表现出严重的表型，特征为严重的视力下降、视野向心性缩小和视网膜电图熄灭。然而，也有一些例外情况，最佳矫正视力高达 0.8（Snellen），视野保存良好，光谱域光学相干断层扫描显示光感受器保存完好。在 和 基因亚组内和之间存在表型变异性。我们目前进行的研究涉及到相当大的 LCA 群体，为遗传和表型谱提供了有价值的理解。这一知识对于即将进行的基因治疗试验具有重要意义。在这个德国队列中， 和 是最常突变的基因。然而，LCA 在遗传上高度异质，表现出临床变异性，与其他 IRD 重叠。对于任何治疗基因的干预，致病基因型是治疗的主要标准，但临床诊断、视网膜状态、要治疗的靶细胞数量以及治疗的时间点都将是至关重要的。
