Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1
Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1
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DOI：
10.1136/bjo.2010.186882
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发表时间：
2011-06-01
影响因子：
4.1
通讯作者：
Moore, Anthony T.
中科院分区：
文献类型：
--
作者：
Henderson, Robert H.;Mackay, Donna S.;Moore, Anthony T.
目的在大量隐性视网膜营养不良患者中鉴定CRB1突变，并记录视网膜表型和视力预后。设计一项以医院为基础的儿童和成人隐性视网膜营养不良的横断面研究。研究招募了306名患有莱伯先天性黑朦（LCA）、早发性儿童视网膜营养不良或青少年性视网膜色素变性的患者，并提供了血液样本进行分子遗传分析。方法对患者进行详细的临床检查，包括：logMAR视力、屈光、Goldmann视野、裂隙灯生物显微镜、眼底摄影、自体荧光成像和光学相干断层扫描。所有患者均可获得电生理测试结果。提取DNA进行分子遗传学分析。使用LCA芯片进行突变的初始筛选。在芯片上鉴定出一个或多个CRB1突变的患者，以及其他表型显示CRB1基因型的患者，进行了直接测序。此外，使用Affymetrix基因芯片对分离隐性RP的近亲家庭进行全基因组扫描，并对与RP12位点有连锁关系的受影响家庭成员进行CRB1基因测序。主要结果指标：CRB1突变患者的鉴定和临床表型的详细记录。结果来自32个家庭的41例患者中发现了CRB1突变，其中包括17个新突变。作者在来自26个家族的34名患者中发现了这两种疾病突变，并对这些患者进行了详细的表型分析。常见的表型特征包括远视屈光不正，RPE水平的numular色素沉着和光学相干断层扫描视网膜厚度增加。大多数患者的临床和电生理表型与LCA或杆状锥体营养不良的诊断一致，但有3例患者的视网膜电图显示锥状锥体变性。少数患者发生视网膜外周毛细血管扩张，在某些情况下导致闭合性瞳孔和闭角型青光眼。结论CRB1基因突变与一系列隐性遗传性视网膜营养不良有关，包括LCA、儿童期和青少年发病的视锥杆营养不良和视锥杆营养不良。虽然表型通常是严重的，但在较轻的病例中，在儿童早期有机会进行治疗干预。
Objectives To identify CRB1 mutations in a large cohort of patients with recessive retinal dystrophies and to document the retinal phenotype and visual prognosis.Design A hospital-based cross-sectional study of children and adults with recessive retinal dystrophies.Participants Three hundred and six patients with Leber congenital amaurosis (LCA), early-onset childhood retinal dystrophy or juvenile onset retinitis pigmentosa were recruited to the study and gave blood samples for molecular genetic analysis.Methods A detailed clinical examination was performed, including: logMAR visual acuity, refraction, Goldmann visual fields, slit-lamp biomicroscopy, fundus photography, autofluorescence imaging and optical coherence tomography. The results of electrophysiology testing were available in all patients. DNA was obtained for molecular genetic analysis. Initial screening for mutations was performed using the LCA chip. Patients who had one or more CRB1 mutations identified on the chip, and other patients whose phenotype suggested a CRB1 genotype, underwent direct sequencing. In addition, consanguineous families segregating recessive RP underwent a whole genome scan using Affymetrix gene chips, and affected family members showing linkage to the RP12 locus underwent sequencing of the CRB1 gene.Main outcome measures Identification of patients with mutations in CRB1 and detailed documentation of the clinical phenotype.Results Mutations in CRB1, including 17 novel mutations, were identified in 41 patients from 32 families. The authors identified both disease mutations in 34 patients from 26 families, and these patients underwent detailed phenotyping. Common phenotypic features included hypermetropic refractive error, nummular pigmentation at the level of the RPE and increased retinal thickness on optical coherence tomography. Most patients had a clinical and electrophysiological phenotype consistent with a diagnosis of LCA or rod-cone dystrophy, but three patients had electroretinogram evidence of cone-rod degeneration. A minority of patients developed peripheral retinal telangiectasia, which in some cases led to seclusio pupillae and angle-closure glaucoma.Conclusion Mutations in CRB1 are associated with a range of recessively inherited retinal dystrophies, including LCA, childhood-and juvenile-onset rod-cone and cone-rod dystrophies. Although the phenotype is usually severe, in milder cases there is a window of opportunity for therapeutic intervention in early childhood.