Whole-exome sequencing reveals a novel CHM gene mutation in a family with choroideremia initially diagnosed as retinitis pigmentosa.
Whole-exome sequencing reveals a novel CHM gene mutation in a family with choroideremia initially diagnosed as retinitis pigmentosa.
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全外显子组测序揭示了一个最初诊断为色素性视网膜炎的无脉络膜血症家族中存在一种新的 CHM 基因突变。
DOI：
10.1186/s12886-015-0081-4
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发表时间：
2015-07-28
影响因子：
2
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Guo H;Li J;Gao F;Li J;Wu X;Liu Q
大约200个基因的基因组突变与遗传性视网膜疾病有关。在这项研究中，我们筛选致病基因突变的一个家庭与X连锁视网膜变性疾病。收集家系资料，提取家系成员外周血基因组DNA，并在山东大学齐鲁医院进行视力、裂隙灯检查、眼底检查和视野检查。全外显子组基因组测序用于筛查男性先证者的基因突变。桑格测序用于确认在该家族中发现的突变。两名受影响的男性进行了眼科检查;视网膜色素变性（RP）的诊断基础上夜盲开始在早期的年龄，视力下降，进行性丧失周边视力，衰减的视网膜血管和色素障碍的眼底检查。然而，全外显子组测序显示RP相关基因没有突变。相反，我们确定了一种新的半合子c.1475_1476insCA突变的无脉络膜相关基因（CHM）。通过桑格测序证实了该突变，并进一步排除了作为罕见多态性的可能性。根据遗传数据和临床表现，诊断被纠正为无脉络膜（CHM）。进一步的分子遗传学分析表明，这种新的CHM突变引起了移码（p.Leu492PhefsX7），并编码截短的非功能性Rab护送蛋白1（REP-1），这导致了该家族的CHM。最后，一名怀孕女性成员的测序数据证实，她没有携带突变，因此怀了一个健康的婴儿。我们报告了一个新的CHM突变，c.1475_1476insCA，在一个家庭与X连锁CHM最初诊断为RP的全外显子组测序确定。我们的研究结果强调了将遗传学和眼科学数据相关联的诊断方法的价值，以促进罕见遗传性视网膜疾病（如CHM）的正确临床诊断。
Genomic mutations in about 200 genes are associated with hereditary retinal diseases. In this study, we screened for the disease-causing gene mutation in a family with X-linked retinal degenerative disease. Pedigree data were collected and genomic DNA was isolated from peripheral blood of family members, who also underwent comprehensive ophthalmic examination including visual acuity, slit-lamp examination, fundus examination and visual field testing at Qilu Hospital of Shandong University. Whole-exome genomic sequencing was used to screen for gene mutations in the male proband. Sanger sequencing was used to confirm the mutation revealed in this family. Two affected males underwent ophthalmic examination; retinitis pigmentosa (RP) was diagnosed on the basis of night blindness beginning at an early age, decreasing visual acuity, progressive loss of peripheral vision, attenuation of retinal vessels and pigment disturbance on fundus examination. However, whole-exome sequencing revealed no mutation in RP-associated genes. Instead, we identified a novel hemizygous c.1475_1476insCA mutation in the choroideremia-associated gene (CHM). The mutation was confirmed by Sanger sequencing and further excluded from the possibility as a rare polymorphism. From the genetic data and clinical findings, the diagnosis was corrected to choroideremia (CHM). Further molecular genetic analysis suggested that this novel CHM mutation caused a frame shift (p.Leu492PhefsX7) and encoded a truncated nonfunctional Rab escort protein 1 (REP-1), which caused CHM in this family. Finally, sequencing data for a pregnant female member confirmed that she did not carry the mutation and thus was carrying a healthy infant. We report a novel CHM mutation, c.1475_1476insCA, identified by whole-exome sequencing in a family with X-linked CHM initially diagnosed as RP. Our findings emphasize the value of a diagnostic approach that associates genetic and ophthalmologic data to facilitate the proper clinical diagnosis of rare hereditary retinal diseases such as CHM.