波兰莱伯先天性黑蒙（LCA）患者中的新型基因变异
Novel gene variants in Polish patients with Leber congenital amaurosis (LCA).
作者信息
Skorczyk-Werner Anna, Niedziela Zuzanna, Stopa Marcin, Krawczyński Maciej Robert
机构信息
Department of Medical Genetics, Poznan University of Medical Sciences, 8, Rokietnicka St, 60-806, Poznan, Poland.
Department of Ophthalmology, Chair of Ophthalmology and Optometry, Poznan University of Medical Sciences, Poznan, Poland.
出版信息
Orphanet J Rare Dis. 2020 Dec 11;15(1):345. doi: 10.1186/s13023-020-01634-y.
BACKGROUND
Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. To date, 25 genes have been implicated in the pathogenesis of LCA. As gene therapy is becoming available, the identification of potential treatment candidates is crucial. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 Polish families.
METHODS
Single Nucleotide Polymorphism-microarray for LCA genes or Next Generation Sequencing diagnostic panel for LCA genes (or both tests) were performed to identify potentially pathogenic variants. Bidirectional Sanger sequencing was carried out for validation and segregation analysis of the variants identified within the families.
RESULTS
The molecular background was established in 22 families. From a total of 24 identified variants, 23 were predicted to affect protein-coding or splicing, including 10 novel variants. The variants were identified in 7 genes: CEP290, GUCY2D, RPE65, NMNAT1, CRB1, RPGRIP1, and CRX. More than one-third of the patients, with clinical LCA diagnosis confirmed by the results of molecular analysis, appeared to be affected with a severe form of the disease: LCA10 caused by the CEP290 gene variants. Intronic mutation c.2991+1655A>G in the CEP290 gene was the most frequent variant identified in the studied group.
CONCLUSIONS
This study provides the first molecular genetic characteristics of patients with Leber congenital amaurosis from the previously unexplored Polish population. Our study expands the mutational spectrum as we report 10 novel variants identified in LCA genes. The fact that the most frequent causes of the disease in the studied group of Polish patients are mutations in one out of three genes that are currently the targets for gene therapy (CEP290, GUCY2D, and RPE65) strongly emphasizes the importance of the molecular background analyses of LCA in Polish patients.
背景
莱伯先天性黑蒙（LCA）是一种罕见的视网膜疾病，是儿童先天性失明最常见的原因，也是遗传性视网膜营养不良最严重的形式。迄今为止，已有25个基因与LCA的发病机制有关。随着基因治疗的出现，确定潜在的治疗候选基因至关重要。本研究的目的是报告22个波兰家庭中莱伯先天性黑蒙的分子基础。
方法
采用LCA基因单核苷酸多态性微阵列或LCA基因二代测序诊断 panel（或两种检测方法）来鉴定潜在的致病变异。对家庭中鉴定出的变异进行双向Sanger测序以进行验证和分离分析。
结果
确定了22个家庭的分子背景。在总共鉴定出的24个变异中，23个被预测会影响蛋白质编码或剪接，其中包括10个新变异。这些变异存在于7个基因中：CEP290、GUCY2D、RPE65、NMNAT1、CRB1、RPGRIP1和CRX。经分子分析结果确诊为临床LCA的患者中，超过三分之一似乎患有严重形式的疾病：由CEP290基因变异引起的LCA10。CEP290基因内含子突变c.2991+1655A>G是研究组中最常见的变异。
结论
本研究提供了来自此前未被探索的波兰人群的莱伯先天性黑蒙患者的首个分子遗传学特征。我们的研究扩展了突变谱，因为我们报告了在LCA基因中鉴定出的10个新变异。在波兰患者研究组中，该疾病最常见的病因是目前基因治疗靶点的三个基因之一发生突变（CEP290、GUCY2D和RPE65），这一事实强烈强调了对波兰患者LCA进行分子背景分析的重要性。
Zotero 插件