Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
Am J Ophthalmol. 2020 Mar;211:142-150. doi: 10.1016/j.ajo.2019.11.012. Epub 2019 Nov 14.
Gene therapy for Leber congenital amaurosis (LCA) is becoming available, and therefore it is crucial to identify eligible candidates. We report the spectrum and associated phenotype of CEP290 mutations in the largest German cohort observed by a single clinical site.
Prospective cohort study.
Twenty-three patients with mutations in CEP290 were included. Genomic DNA was analyzed by Sanger sequencing or high-throughput sequencing for all retinitis pigmentosa-associated genes in patients, and segregation analysis was done in family members. Patients underwent functional and morphologic examinations, including fundus autofluorescence and spectral-domain optical coherence tomography.
The most frequent mutation was c.2991+1655A>G, found in 87% of patients (20/23). Thirty percent of patients (7/23) carried the mutation in an apparent homozygous state and 57% (13/23) in a likely compound heterozygous state. The most common clinical diagnosis was LCA and/or early onset severe retinal dystrophy in 82% (19/23), followed by retinitis pigmentosa in 14% (3/23) and cone-rod dystrophy (4%, 1/23). Best-corrected visual acuity was severely reduced to residual light perception and hand motion vision, with the exception of 3 patients with best-corrected visual acuity of 0.8 (Snellen). The visual field was severely decreased and electroretinogram was undetectable in most cases; however, retinal layers at the fovea appeared to be relatively well preserved. Systemic disorders were not noticed.
c.2991+1655A>G is by far the most important CEP290 mutation, contributing to 87% of patients with the CEP290 mutation in Germany. In our cohort, a homozygous c.2991+1655A>G genotype presented with a more severe phenotype. National studies and further detailed phenotype analysis seem to be important to assess the need for and promise of specific gene therapies.
莱伯先天性黑矇（LCA）的基因治疗正在普及，因此确定合格的候选者至关重要。我们报告了由单一临床站点观察到的德国最大队列中 CEP290 突变的谱及其相关表型。
前瞻性队列研究。
共纳入 23 名 CEP290 基因突变患者。对所有患者的视网膜色素变性相关基因进行 Sanger 测序或高通量测序分析，对患者进行基因分析，并对家系成员进行分离分析。对患者进行功能和形态学检查，包括眼底自发荧光和光谱域光学相干断层扫描。
最常见的突变是 c.2991+1655A>G，在 87%的患者（20/23）中发现。30%的患者（7/23）携带明显的纯合突变，57%（13/23）携带可能的复合杂合突变。最常见的临床诊断是 LCA 和/或早发性严重视网膜营养不良（82%，19/23），其次是视网膜色素变性（14%，3/23）和 cone-rod 营养不良（4%，1/23）。除 3 名患者的最佳矫正视力为 0.8（Snellen）外，最佳矫正视力严重下降至光感和手动视力，视野严重下降，视网膜电图无法检测；然而，黄斑区视网膜层似乎相对保存完好。未发现系统性疾病。
c.2991+1655A>G 是迄今为止最重要的 CEP290 突变，占德国 CEP290 突变患者的 87%。在我们的队列中，纯合 c.2991+1655A>G 基因型表现出更严重的表型。国家研究和进一步详细的表型分析对于评估特定基因治疗的需求和前景似乎很重要。
