Mutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.
Mutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.
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DOI：
10.1371/journal.pone.0027894
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Antiñolo G
中科院分区：
文献类型：
--
作者：
González-del Pozo M;Borrego S;Barragán I;Pieras JI;Santoyo J;Matamala N;Naranjo B;Dopazo J;Antiñolo G
色素性视网膜炎（RP）是一种异质性的遗传性视网膜营养不良症，最终以光感受器细胞的丧失为特征。RP是60岁以下人群视力丧失的主要原因，患病率约为1 / 4000。常染色体隐性RP （arRP）的分子遗传学诊断具有挑战性，因为它具有很大的遗传和临床异质性。传统的arRP基因测序方法往往费力且不易获得，而一种能够快速检测遗传原因的筛选技术将在临床实践中非常有帮助。本研究的目标是开发和应用基于微阵列的重测序技术，该技术能够在单个高通量平台上检测已知和新的突变。因此，我们对102例临床诊断为arRP的西班牙患者的16个arRP基因的编码区和外显子/内含子边界进行了微阵列测序。所有检测到的变异均通过直接测序证实，并通过功能预测和对照中的频率评估潜在致病性。为了验证目的，在阵列上杂交了4个由先前确定的变化组成的变异阳性对照。作为筛选的结果，我们检测到44个变异，其中15个在14个arRP家族中检测到非常可能致病（14%）。最后，该阵列的设计可以很容易地转化为基于靶向富集的等效诊断系统，然后进行下一代测序。
Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing.
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