Study of Genetic Basis of Fuchs Corneal Dystrophy

描述（由申请人提供）：Fuchs角膜营养不良（FCD）是一种常见的双侧角膜内皮晚发性疾病，其特征是角膜内皮细胞的缓慢进行性功能障碍，伴有这些细胞的丧失和赘生物（角膜guttae）的形成以及Descemet膜的过度增厚。这种与年龄有关的疾病明显以女性和男性为主。孟德尔型口蹄疫的证据来自多代口蹄疫家族。然而，大多数FCD发生在小家庭中，这些家庭表现出一种复杂的FCD形式。FCD也被定位到几个染色体上的位点。这个由经验丰富的多学科研究人员组成的应用程序的目的是扩大家庭招募，并通过遗传研究进一步了解FCD。本研究有五个具体目标：(1)继续招聘FCD和至少一个受影响的个人和家庭两兄弟姐妹以及多基因FCD家庭影响,(2)在每个影响COL8A2基因序列和基因型个体,(3)进行全基因组连锁屏幕使用Illumina公司的第四代SNP-based链接面板,(4)为四连杆执行关联映射区域确定候选基因与FCD和跟进相关的候选基因,(5)对大型多代家族进行位置克隆。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。COL8A2突变家族将从连锁和后续分析中删除。将对不同规模家庭的各种数据集进行连锁分析。这一策略将允许在FCD中确定负责孟德尔和复杂遗传形式的染色体区域。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，这将从开发早期诊断分子诊断测试和开发这种使人衰弱的疾病的新治疗方法的角度来看是有价值的。相关性声明：了解使个体有患口蹄疫风险的基因将有助于更好地了解这一重要疾病、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.