Study of Genetic Basis of Fuchs Corneal Dystrophy

描述（由申请人提供）：Fuchs角膜营养不良（FCD）是一种常见的双侧迟发性角膜内皮疾病，其特征为角膜内皮细胞缓慢进行性功能障碍，与这些细胞的丧失和赘生物（角膜滴）的形成以及后弹力膜过度增厚相关。这种与年龄有关的疾病有一个惊人的女性：男性优势。FCD的孟德尔形式的证据来自大型多代FCD家庭。然而，大多数FCD发现在小家庭，表现出复杂的FCD形式。FCD也被定位在几条染色体上的基因座上。由经验丰富的多学科研究人员团队提出的这项申请的目的是扩大家庭招募，并通过遗传研究进一步了解FCD。这项研究有五个具体目标：（1）继续招募具有至少一个受影响个体和多达两个未受影响兄弟姐妹的FCD家族以及多代FCD家族，（2）对每个受影响个体中的COL 8A 2基因进行测序和基因分型，（3）使用Illumina的第四代基于SNP的连锁面板进行全基因组连锁筛选，（4）对多达4个连锁区域进行关联定位，以确定与FCD相关的候选基因，并对这些候选基因进行随访;（5）对多代大家庭进行定位克隆。为了实现这些目标，将对所有参与者进行眼部检查，以确定他们是否受到影响。具有COL 8A 2突变的家族将从连锁和随访分析中删除。将对不同规模家庭的各种数据集进行连锁分析。这一策略将允许染色体区域，负责孟德尔和复杂形式的遗传FCD被确定。本研究的长期目标是了解FCD的基本病理生物学，并确定该疾病的遗传成分，从开发用于早期诊断的分子诊断测试和开发用于这种使人衰弱的疾病的新治疗程序的角度来看，这将是有价值的。相关性声明：了解使个体处于FCD风险中的基因将有助于更好地了解这种重要疾病，早期诊断测试和新的非手术治疗方法。

DESCRIPTION (provided by applicant): Fuchs corneal dystrophy (FCD) is a common bilateral late onset disorder of the corneal endothelium chracterized by a slowly progressive dysfunction of corneal endothelial cells associated with the loss of these cells and the formation of excrescences (corneal guttae) and excessive thickening of Descemet's membrane. This age-related disorder has a striking female:male preponderance. Evidence for Mendelian forms of FCD comes from large multigenerational FCD families. However, the majority of FCD are found in small families, which exhibit a complex form of FCD. FCD has also been mapped to loci on several chromosomes. The objective of this application by an experienced multidisciplinary team of investigators is to expand family recruitment and further our understanding of FCD with genetic studies. This study has five specific aims: (1) To continue recruiting families of FCD with at least one affected individual and up to two unaffected siblings as well as multigenerational FCD families, (2) To sequence and genotype the COL8A2 gene in each affected individual, (3) To perform a whole genome linkage screen using Illumina's fourth-generation SNP-based linkage panel, (4) To perform association mapping for up to four linkage regions to identify candidate genes associated with FCD and to follow up of these candidate genes, and (5) To perform positional cloning for large multigenerational families. To achieve these goals, an ocular examination will be performed on all participants to determine whether they are affected or not. Families with COL8A2 mutations will be removed from the linkage and follow-up analyses. Linkage analysis will be performed on various datasets of families of different size. This strategy will allow chromosonal regions that are responsible for Mendelian and complex forms of genetics in FCD to be identified. The long-term objective of this study is to understand the basic pathobiology of FCD and to identify genetic components of the disorder that will be valuable from the standpoint of developing molecular diagnostic tests for early diagnosis and for developing novel therapeutic procedures for this debilitating disease. Statement of Relevance: Knowledge about the genes that place individuals at risk for FCD will lead to a better understanding of this important disease, early diagnostic tests and novel non surgical methods of treatment.