The Phenotypic Variability of Retinal Dystrophies Associated With Mutations in CRX, With Report of a Novel Macular Dystrophy Phenotype
The Phenotypic Variability of Retinal Dystrophies Associated With Mutations in CRX, With Report of a Novel Macular Dystrophy Phenotype
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DOI：
10.1167/iovs.14-14715
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发表时间：
2014-10-01
影响因子：
4.4
通讯作者：
Webster, Andrew R.
中科院分区：
文献类型：
--
作者：
Hull, Sarah;Arno, Gavin;Webster, Andrew R.
目的。对来自 11 个家族的 18 名因锥杆同源盒 (CRX) 基因突变而导致视网膜营养不良的患者进行了详细的表型和分子研究，并报告了一种新的表型。从英国的一家三级诊所确定了家庭，并参加了视网膜营养不良研究，研究遗传性视网膜疾病的表型和分子基础。 11 名患者是从研究队列中确定的，另外 7 名患者是通过对受影响亲属的调查确定的。详细的表型分析包括电诊断测试和视网膜成像。对所有 18 名报告的患者进行了 CRX 的所有外显子和内含子-外显子边界的双向桑格测序，并在现有亲属中证实了分离。 结果。根据临床特征和电生理学，11个家系中有5个家庭观察到4名患者患有Leber先天性黑蒙（LCA），2名患有视杆细胞营养不良（RCD），5名患有视锥细胞营养不良（CORD），1名患有视锥细胞营养不良（COD），6名患有不同表型的黄斑营养不良。黄斑营养不良患者年龄在 35 至 50 岁之间，上次复查时视力范围为 0.2 至 1.5 logMAR（20/32 至 20/630 Snellen）。所有 18 名患者均为 CRX 突变杂合子，并发现了 7 个新突变。发病年龄与 CRX 突变的位置或类型之间没有明显关联。在三名患者中证实了新生突变。结论。 CRX 突变表明谱系之间和谱系内部存在显着的表型异质性。一种新的、成人发病的黄斑营养不良表型的特征，进一步扩展了我们对显性黄斑营养不良病因学的了解。
PURPOSE. To present a detailed phenotypic and molecular study of a series of 18 patients from 11 families with retinal dystrophies consequent on mutations in the cone-rod homeobox (CRX) gene and to report a novel phenotype.METHODS. Families were ascertained from a tertiary clinic in the United Kingdom and enrolled into retinal dystrophy studies investigating the phenotype and molecular basis of inherited retinal disease. Eleven patients were ascertained from the study cohorts and a further seven from investigation of affected relatives. Detailed phenotyping included electrodiagnostic testing and retinal imaging. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 reported patients and segregation confirmed in available relatives.RESULTS. Based on clinical characteristics and electrophysiology, four patients had Leber congenital amaurosis (LCA), two had rod-cone dystrophy (RCD), five had cone-rod dystrophy (CORD), one had cone dystrophy (COD), and six had macular dystrophy with different phenotypes observed within 5 of 11 families. The macular dystrophy patients presented between 35 to 50 years of age and had visual acuities at last review ranging from 0.2 to 1.5 logMAR (20/32 to 20/630 Snellen). All 18 patients were heterozygous for a mutation in CRX with seven novel mutations identified. There was no evident association between age of onset and position or type of CRX mutation. De novo mutations were confirmed in three patients.CONCLUSIONS. Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies.