Chen Xue, Gao Xiang, Zhao Kan-xing, Pan Xin-yuan, Zhang Xiu-mei, Wang Xiu-ying, Yuan Song-tao, Liu Qing-huai, Zhao Chen
Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine,Nanjing 210029, China.
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Zhonghua Yan Ke Za Zhi. 2013 Dec;49(12):1104-10.
To identify the pathogenic mutation in a four-generation Chinese family with autosomal dominant retinitis pigmentosa (ADRP) and to analyze its associated clinical phenotypes.
Twelve participants from the index family were recruited, including 5 patients, 6 asymptomatic siblings, and one spouse. All participants underwent ophthalmic examinations, including best-corrected visual acuity (BCVA), visual field (VF) testing, fundus photography, and full-field flash electroretinography (ERG). Targeted sequence capture array technique with next-generation of high throughput sequencing(NGS) was performed to detect variants in 189 hereditary retinal disease (HRD) related genes, comprising 179 identified HRD-causing genes and 10 potential causative genes which were involved in pre-messenger RNA(pre-mRNA) splicing. Variants detected by targeted sequencing were filtered by bioinformatic analyses, validated by Sanger sequencing and intra-familiar analysis.Genotype-phenotype correlation was also analyzed.
SNRNP200 p.S1087L was identified as the disease causative mutation for this family by targeted sequencing and optimized bioinformatic analyses. This family demonstrated early onset of the disease by presenting nyctalopia among 6 to 8 years old, performed rapid disease progression and severely impaired visual function by displaying loss of VF among 14 to 17 years old and decreased central vision among 21 to 28 years old. The fundus presentations and ERG results showed typical RP presentations.
SNRNP200 p.S1087L is identified as a hotspot mutation but correlates with distinct phenotypes in the present family, including early onset of the disease, rapid disease progression, and severely impaired visual function. This study also give evidence to that molecular diagnostic platform for HRD can improve the detection rate of causative genes/mutations in HRD patients, thus providing important approaches for further investigation of the genetic causes for HRD.
鉴定一个患常染色体显性遗传性视网膜色素变性（ADRP）的四代中国家系中的致病突变，并分析其相关临床表型。
招募了该索引家系中的12名参与者，包括5名患者、6名无症状的兄弟姐妹和1名配偶。所有参与者均接受了眼科检查，包括最佳矫正视力（BCVA）、视野（VF）测试、眼底照相和全视野闪光视网膜电图（ERG）。采用靶向序列捕获阵列技术结合新一代高通量测序（NGS）检测189个遗传性视网膜疾病（HRD）相关基因中的变异，其中包括179个已确定的导致HRD的基因和10个参与信使前体RNA（pre-mRNA）剪接的潜在致病基因。通过生物信息学分析对靶向测序检测到的变异进行筛选，通过桑格测序和家系内分析进行验证。还分析了基因型与表型的相关性。
通过靶向测序和优化的生物信息学分析，确定SNRNP200 p.S1087L为此家系的致病突变。该家系疾病发病较早，6至8岁时出现夜盲，疾病进展迅速，14至17岁时视野丧失，21至28岁时中心视力下降，视觉功能严重受损。眼底表现和ERG结果显示为典型的视网膜色素变性表现。
SNRNP200 p.S1087L被确定为一个热点突变，但在本家系中与不同的表型相关，包括疾病发病早、疾病进展迅速和视觉功能严重受损。本研究还证明，HRD分子诊断平台可提高HRD患者致病基因/突变的检测率，从而为进一步研究HRD的遗传病因提供重要途径。
