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首页> 外文期刊>Human mutation >Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel lca5 mutations and new genotype-phenotype correlations
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Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel lca5 mutations and new genotype-phenotype correlations

机译：对一大批先天性先天性黑蒙症和色素性视网膜炎患者进行筛查可确定新的lca5突变和新的基因型-表型相关性

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摘要

This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ～2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.
机译：这项研究的目的是调查患有Leber先天性黑蒙（LCA），早发性视网膜营养不良（EORD）和常染色体隐性色素性视网膜炎（arRP）的患者LCA5序列变异的患病率;描绘眼表型;并提供在线数据库中所有已发布的LCA5变体的概述。提供知情同意后，患者应接受标准的眼科评估。在某些患者中，光学相干断层扫描（OCT）和眼底自发荧光成像是可能的。通过对所有LCA5外显子和内含子/外显子连接点进行Sanger序列分析，筛选了797例不相关的LCA患者和211例不同类型的色素性视网膜炎（RP）患者的DNA样品。一些LCA患者通过APEX技术进行了预筛查，或根据纯合性作图进行选择。在计算机上进行分析以评估变体的致病性。在可能的情况下进行分离分析。收集已发布的和新颖的LCA5变体，对它们的正确命名进行修正，并列在Leiden开放变异数据库（LOVD）中。序列分析确定了具有19个不同LCA5变体的18个新先证者。 19个LCA5变体中有17个是新颖的。除了两个错义变体和一个剪接位点变体以外，所有变体均为蛋白截短突变。大多数患者表现出典型的LCA的严重表型。但是，一些LCA受试者在OCT成像上具有更好的视力和完整的内段/外段（IS / OS）连接。在具有LCA5变体的两个家族中，该表型与EORD更兼容，受影响的个体显示出视网膜色素上皮的保留岛。表型较温和的一个家庭有一个纯合的剪接位点突变。第二个家庭被发现具有终止突变和错义突变的组合。这是迄今为止最大的LCA5研究。我们对1,008例患者（797例LCA，211例arRP）进行了测序，并确定了18位具有LCA5突变的先证者。 LCA5突变是儿童视网膜营养不良的罕见原因，约占该人群疾病的2％，大多数LCA5突变可能无效。 LCA5蛋白截短突变主要与LCA相关。但是，在EORD较轻的两个家族中，LCA5基因分析显示一个纯合的剪接位点突变和一个终止突变与第二个家族的错义突变结合，这表明该较温和的表型是由于Lebercilin和扩大目前已知的表型谱，以包括较温和的早期发病的RP。一些患者保留了中央凹圆锥结构（OCT成像上完整的IS / OS连接）和视敏度，这对于即将进行的治疗试验可能是一个好兆头。

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