Xu Yan, Guan Liping, Shen Tao, Zhang Jianguo, Xiao Xueshan, Jiang Hui, Li Shiqiang, Yang Jianhua, Jia Xiaoyun, Yin Ye, Guo Xiangming, Wang Jun, Zhang Qingjiong
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou, 510060, China.
Hum Genet. 2014 Oct;133(10):1255-71. doi: 10.1007/s00439-014-1460-2. Epub 2014 Jun 18.
Retinitis pigmentosa (RP) is the most common and highly heterogeneous form of hereditary retinal degeneration. This study was to identify mutations in the 60 genes that were known to be associated with RP in 157 unrelated Chinese families with RP. Genomic DNA from probands was initially analyzed by whole exome sequencing. Sanger sequencing was used to confirm potential candidate variants affecting the encoded residues in the 60 genes, including heterozygous variants from genes that are related to autosomal dominant RP, homozygous or compound heterozygous variants from genes that are related to autosomal recessive RP, and hemizygous variants from genes that are related to X-linked RP. Synonymous and intronic variants were also examined to confirm whether they could affect splicing. A total of 244 candidate variants were detected by exome sequencing. Sanger sequencing confirmed 240 variants out of the 244 candidates. Informatics and segregation analyses suggested 110 potential pathogenic mutations in 28 out of the 60 genes involving 79 of the 157 (50%) families, including 31 (39%, 31/79) families with heterozygous mutations in autosomal dominant genes, 37 (47%, 37/79) families with homozygous (9) or compound heterozygous (28) mutations in autosomal recessive genes, and 11 (14%, 11/79) families with hemizygous mutations in X-linked genes. Of the 110 identified variants, 74 (67%) were novel. The genetic defects in approximately half of the 157 studies families were detected by exome sequencing. A comprehensive analysis of the 60 known genes not only expanded the mutation spectrum and frequency of the 60 genes in Chinese patients with RP, but also provided an overview of the molecular etiology of RP in Chinese patients. The analysis of the known genes also supplied the foundation and clues for discovering novel causative RP genes.
视网膜色素变性（RP）是遗传性视网膜变性中最常见且高度异质性的形式。本研究旨在鉴定157个无亲缘关系的中国RP家系中已知与RP相关的60个基因的突变情况。先证者的基因组DNA最初通过全外显子组测序进行分析。桑格测序用于确认影响60个基因中编码氨基酸残基的潜在候选变异，包括与常染色体显性RP相关基因的杂合变异、与常染色体隐性RP相关基因的纯合或复合杂合变异，以及与X连锁RP相关基因的半合子变异。还检查了同义变异和内含子变异，以确认它们是否会影响剪接。通过外显子组测序共检测到244个候选变异。桑格测序确认了244个候选变异中的240个。信息学和分离分析表明，60个基因中的28个基因存在110个潜在致病突变，涉及157个家系中的79个（50%），其中31个（39%，31/79）家系的常染色体显性基因存在杂合突变，37个（47%，37/79）家系的常染色体隐性基因存在纯合（9个）或复合杂合（28个）突变，11个（14%，11/79）家系的X连锁基因存在半合子突变。在鉴定出的110个变异中，74个（67%）是新发现的。通过外显子组测序检测到了157个研究家系中约一半的遗传缺陷。对60个已知基因的全面分析不仅扩大了中国RP患者中60个基因的突变谱和频率，还提供了中国RP患者分子病因的概述。对已知基因的分析也为发现新的RP致病基因提供了基础和线索。
