High-Resolution Homozygosity Mapping Is a Powerful Tool to Detect Novel Mutations Causative of Autosomal Recessive RP in the Dutch Population
High-Resolution Homozygosity Mapping Is a Powerful Tool to Detect Novel Mutations Causative of Autosomal Recessive RP in the Dutch Population
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DOI：
10.1167/iovs.10-6185
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发表时间：
2011-04-01
影响因子：
4.4
通讯作者：
Cremers, Frans P. M.
中科院分区：
文献类型：
--
作者：
Collin, Rob W. J.;van den Born, L. Ingeborgh;Cremers, Frans P. M.
目的.确定荷兰人群和来自其他国家的患者亚组中常染色体隐性视网膜色素变性（arRP）的遗传缺陷。假设是，因为在过去的几个世纪里，在荷兰的某些地区几乎没有移民，所以荷兰arRP患者的很大一部分携带纯合子状态的遗传缺陷。高分辨率全基因组SNP基因分型SNP阵列和随后的纯合性定位进行了一个大的队列的186个主要是非血缘arRP家庭生活在荷兰。对纯合区域中的候选基因进行测序。在94%的受影响个体中，在其基因组中鉴定出大的纯合序列。在42个先证者中，这些纯合区域中至少有一个包含26个已知arRP基因中的一个。对这些患者的相应基因进行序列分析，发现了21个突变和两个可能的致病性变化，其中14个是新的。所有突变仅在一个家庭中被鉴定，说明了荷兰人群中的遗传多样性。这份报告表明，纯合性定位是一个强大的工具，用于确定潜在的遗传异质性隐性疾病，如RP的遗传缺陷，即使在人群中几乎没有血缘关系。（Invest Ophthalmol维斯科学。2011;52：2227-2239）DOI：10.1167/iovs.10-6185
PURPOSE. To determine the genetic defects underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch population and in a subset of patients originating from other countries. The hypothesis was that, because there has been little migration over the past centuries in certain areas of The Netherlands, a significant fraction of Dutch arRP patients carry their genetic defect in the homozygous state.METHODS. High-resolution genome-wide SNP genotyping on SNP arrays and subsequent homozygosity mapping were performed in a large cohort of 186 mainly nonconsanguineous arRP families living in The Netherlands. Candidate genes residing in homozygous regions were sequenced.RESULTS. In similar to 94% of the affected individuals, large homozygous sequences were identified in their genome. In 42 probands, at least one of these homozygous regions contained one of the 26 known arRP genes. Sequence analysis of the corresponding genes in each of these patients revealed 21 mutations and two possible pathogenic changes, 14 of which were novel. All mutations were identified in only a single family, illustrating the genetic diversity within the Dutch population.CONCLUSIONS. This report demonstrates that homozygosity mapping is a powerful tool for identifying the genetic defect underlying genetically heterogeneous recessive disorders like RP, even in populations with little consanguinity. (Invest Ophthalmol Vis Sci. 2011;52:2227-2239) DOI:10.1167/iovs.10-6185