Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing

Abstract

To date, 70 different TGFBI mutations that cause epithelial-stromal corneal dystrophies have been described. At present one commercially available test examines for the five most common of these mutations: R124H, R124C, R124L, R555W, and R555Q. To expand the capability of identifying the causative mutation in the remaining cases, 57 mutations would need to be added. The aim of this study was to obtain a better understanding of the worldwide distribution and population differences of TGFBI mutations and to assess which mutations could be included or excluded from any potential assay. A total of 184 published papers in Human Gene Mutation Database (HGMD) and PubMed from 34 countries worldwide reporting over 1600 corneal dystrophy cases were reviewed. Global data from 600,000 samples using the commercially available test were analyzed. Case studies by University College of London (UCL), Moorfield’s Corneal Dystrophy Study data and 19 samples from patients with clinical abnormality or uncertainty for which the current test detected no mutation were used to predict an achievable detection rate. Data from the literature search showed no difference in the spectrum and frequency of each mutation in different populations or geographical locations. According to our analysis, an increase to the worldwide detection rate in all populations from 75 to 90% could be achieved by the addition of six mutations—H626R, A546D, H572R, G623D, R124S, and M502V—to the currently available test and that may be beneficial for LASIK pre-screening worldwide.

摘要

到目前为止, 已经发现62种不同的TGFBI突变导致角膜上皮间质性营养不良。商业化的检测方法用来检测这些突变中最常见的5个突变位点:R124H、R124C、R124L、R555W和R555Q。为了扩大此基因在病例中识别致病突变的能力, 需要添加57个突变。本研究的目的是为了更好地了解TGFBI突变在世界范围内的分布和种群差异, 并评估哪些突变可以被纳入或排除在任何潜在的分析中。来自全球34个国家的184篇发表在人类基因突变数据库(HGMD)和PubMed上的论文报道了超过1600例角膜营养不良病例。研究人员分析了来自全球60万个样本的数据, 这些样本使用的是市面上可以买到的检测方法。来自伦敦大学学院(UCL)、Moorfield’s角膜营养不良的病例研究数据和目前检测未发现突变的19例临床异常或不确定的患者样本进行分析, 预测出可获得的检出率。文献检索的数据显示, 在不同种群或地理位置, 每个突变的频谱和频率没有差异。根据我们的分析, 在现有的检测方法基础上, 通过增加H626R、A546D、H572R、G623D、R124S和M502V六种突变, 可以将全球所有人群的检出率从75%提高到90%, 这将有利于全世界LASIK的预先筛分。