A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.
A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.
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DOI：
10.1038/ejhg.2014.283
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Webster AR
中科院分区：
文献类型：
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作者：
Lenassi E;Vincent A;Li Z;Saihan Z;Coffey AJ;Steele-Stallard HB;Moore AT;Steel KP;Luxon LM;Héon E;Bitner-Glindzicz M;Webster AR
USH2A缺陷可引起孤立性视网膜疾病和Usher综合征（即视网膜疾病和耳聋）。为了深入了解孤立性/非综合征性USH2A视网膜病变，我们在186名患有隐性视网膜疾病且儿童期无听力疾患的先显者（发现队列）和84名患有隐性视网膜疾病的先显者（复制队列）中筛选了USH2A。详细的表型分析，包括视网膜成像和听力学评估，在两种可能致病的USH2A变异个体中进行。进一步的基因检测，包括筛选深层内含子致病变异和大量缺失/重复，对那些可能有一个致病变化的人进行。总体而言，186个先证者（发现队列）中有23个被发现携带两种可能致病的USH2A变异。其中一些变异主要与非综合征性视网膜变性（“视网膜疾病特异性”）相关；其中包括常见的c.2276 G> G, p.（Cys759Phe）突变和5个额外的变异：c.2802 T>G, p.(Cys934Trp)；c.10073 G>A, p.(Cys3358Tyr)；c.11156 G>A, p.(Arg3719His)；c.12295-3 T >;和c.12575 G>A, p.（Arg4192His）。在发现队列中观察到等位基因层次结构，并在复制队列中得到证实。在非综合征性USH2A疾病中，视网膜病变与视网膜色素变性一致，听力学表型是可变的。USH2A视网膜病变是非综合征性隐性视网膜变性的常见原因，其突变谱与Usher综合征不同。提出以下模型：USH2A相关疾病患者中存在至少一个“视网膜疾病特异性”USH2A等位基因导致正常听力的保存。像这样细致的基因型-表型研究将变得越来越重要，特别是现在高通量测序在临床环境中广泛使用。
Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration (‘retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one ‘retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype–phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.