Comprehensive Mutation Analysis by Whole-Exome Sequencing in 41 Chinese Families With Leber Congenital Amaurosis
Comprehensive Mutation Analysis by Whole-Exome Sequencing in 41 Chinese Families With Leber Congenital Amaurosis
复制标题
41个中国Leber先天性黑蒙家系的全外显子组测序综合突变分析
DOI：
10.1167/iovs.13-11606
复制
发表时间：
2013-06-01
影响因子：
4.4
通讯作者：
Zhang, Qingjiong
中科院分区：
文献类型：
--
作者：
Chen, Yabin;Zhang, Qingyan;Zhang, Qingjiong
目的. Leber先天性黑蒙（LCA）是一种遗传异质性疾病，迄今已确定19个致病基因。本研究的目的是检测中国人LCA家系中19个基因的突变情况。本研究共纳入41个无亲缘关系的LCA患者家系，其中25个家系未进行基因分析，16个家系经桑格测序筛查，均未发现突变。通过全外显子组测序筛选遗传变异，然后使用桑格测序进行验证。通过全外显子组测序检测到总共41个预测影响蛋白质编码或剪接的变异体，并且通过桑格测序确认了40个。生物信息学和分离分析揭示了15个先证者中的22个潜在致病性变异（17个新的），包括16个先前分析的家族中的3个和25个先前未分析的家族中的12个（48%）。在后12个家族中，在CEP 290（3个先证者）、GUCY2D（2个先证者）和CRB 1、CRX、RPE 65、IQCB 1、LCA 5、TULP1和IMPDH 1（各1个先证者）中发现了突变。根据87例先证者和25例新发病例的分析结果，GUCY2D、CRB1、RPGRIP1、CEP290和CRX是5个最常见的突变基因，这与在白人受试者中的研究结果相似。全外显子组测序在约一半的中国LCA家族中检测到19个已知LCA基因的突变。这些结果，加上我们以前的结果，证明了频谱和频率的突变的19个基因负责LCA在中国汉族人。全外显子组测序是检测高度异质性遗传性疾病突变的有效方法。
PURPOSE. Leber congenital amaurosis (LCA) is a genetically heterogeneous disease with, to date, 19 identified causative genes. Our aim was to evaluate the mutations in all 19 genes in Chinese families with LCA.METHODS. LCA patients from 41 unrelated Chinese families were enrolled, including 25 previously unanalyzed families and 16 families screened previously by Sanger sequencing, but with no identified mutations. Genetic variations were screened by whole-exome sequencing and then validated using Sanger sequencing.RESULTS. A total of 41 variants predicted to affect protein coding or splicing was detected by whole-exome sequencing, and 40 were confirmed by Sanger sequencing. Bioinformatic and segregation analyses revealed 22 potentially pathogenic variants (17 novel) in 15 probands, comprised of 3 of 16 previously analyzed families and 12 of 25 (48%) previously unanalyzed families. In the latter 12 families, mutations were found in CEP290 (three probands); GUCY2D (two probands); and CRB1, CRX, RPE65, IQCB1, LCA5, TULP1, and IMPDH1 (one proband each). Based on the results from 87 previously analyzed probands and 25 new cases, GUCY2D, CRB1, RPGRIP1, CEP290, and CRX were the five most frequently mutated genes, which was similar to the results from studies in Caucasian subjects.CONCLUSIONS. Whole-exome sequencing detected mutations in the 19 known LCA genes in approximately half of Chinese families with LCA. These results, together with our previous results, demonstrate the spectrum and frequency of mutations of the 19 genes responsible for LCA in Han Chinese individuals. Whole-exome sequencing is an efficient method for detecting mutations in highly heterogeneous hereditary diseases.