Familial Dilated Cardiomyopathy: Detection/Gene Mapping

描述（由申请人提供）：心力衰竭通常由扩张型心肌病（DCM）引起，一种常见形式是特发性扩张型心肌病（IDC）。现在有相当多的证据表明，多达一半的IDC患者有类似的家庭成员，有两个或两个以上受影响的家庭被指定为患有家族性扩张型心肌病（FDC）。超过20个基因的突变与FDC相关，支持其遗传基础。尽管取得了这些进展，我们估计FDC的遗传病因中只有不到30%已经被确定，而且几乎所有的病因都发生在高加索人中，尽管黑人的DCM发病率更高。1993年，俄勒冈州健康与科学大学（OHSU）建立了FDC研究项目，以确定FDC的遗传基础。我们已经评估了>300个FDC家族，包括五个适合连锁分析的非常大的家系;一个是非常大的非洲裔美国人家族。我们在几个感兴趣的区域的联系分析方面取得了实质性进展。所有的临床和谱系数据都被放入了Progeny，这是一个专为家族研究设计的关系数据库程序，大大提高了我们的效率。2007年中期，该研究项目搬迁到佛罗里达州迈阿密的迈阿密大学米勒医学院/杰克逊纪念医院，为研究提供了大量的黑人和西班牙裔人口。该计划还与新的迈阿密人类基因组学研究所（MIHG）有关，提供了大大加强的合作，实验方法和研究基础设施。对于这个更新，我们建议（1）重新筛选我们的五个大的连锁家系，最初筛选1995-2000年，以确定新的受影响的家庭成员。我们提供了令人信服的数据表明，新受影响的受试者很可能被识别，从而加强了连锁分析的统计能力，并加强了我们对致病FDC疾病基因的搜索。我们还将继续确定任何规模的新的FDC家系，我们招募少数民族家庭的努力，特别是黑人，应该在南佛罗里达州非常成功。我们还将（2）在21个已知DCM疾病基因的突变被测序排除后，在我们的连锁家系中绘制负责FDC的基因。MIHG将协助对5个连锁家系进行全基因组SNP基因分型，并通过连锁分析分析结果。基因定位研究将缩小感兴趣的区域，定向候选基因研究将用于鉴定新的FDC疾病基因。 公共卫生相关性：扩张型心肌病在很大程度上是一种心肌遗传性疾病，但只有一小部分遗传原因已被确定。我们的目标是确定更多的疾病基因，这将导致更好地了解人类心力衰竭的原因。

DESCRIPTION (provided by applicant): Heart failure usually results from dilated cardiomyopathy (DCM), and one common form is idiopathic dilated cardiomyopathy (IDC). Considerable evidence now indicates that up to one-half of patients with IDC have similarly affected family members, and families with two or more affected are designated as having familial dilated cardiomyopathy (FDC). Mutations in >20 genes have been associated with FDC, supporting its genetic basis. Despite this progress, we estimate < 30% of the genetic causation of FDC has been identified, and almost all in Caucasians even though blacks have more DCM. An FDC research program was established in 1993 at the Oregon Health & Sciences University (OHSU) to determine the genetic basis of FDC. We have evaluated >300 families for FDC, including five very large pedigrees suitable for linkage analysis; one is a very large African-American family. We have made substantial progress with linkage analysis with several regions of interest. All clinical and pedigree data have been placed into Progeny, a relational database program designed for family studies, greatly improving our efficiency. In mid 2007 this research program relocated to the University of Miami Miller School of Medicine/Jackson Memorial Hospital complex in Miami, FL providing a dramatically enriched population of blacks and Hispanics for study. This program is also associated with the new Miami Institute for Human Genomics (MIHG), providing greatly strengthened collaboration, experimental methods and research infrastructure. For this renewal we propose to (1) rescreen our five large linkage pedigrees, initially screened 1995-2000, to identify newly affected family members. We provide compelling data suggesting that that newly affected subjects are likely to be identified, thereby strengthening the statistical power at linkage analysis and enhancing our search for causative FDC disease genes. We will also continue to identify new FDC pedigrees of any size, and our efforts to recruit families of minorities, particularly blacks, should be highly successful in south FL. We will also (2) map the genes responsible for FDC in our linkage pedigrees after mutations in 21 known DCM disease genes have been excluded by sequencing. The MIHG will assist with genome-wide SNP genotyping for the 5 linkage pedigrees, and results analyzed by linkage analysis. Gene mapping studies will narrow regions of interest, and directed candidate gene studies will be used to identify novel FDC disease genes. PUBLIC HEALTH RELEVANCE: Dilated cardiomyopathy is largely a genetic disease of the heart muscle, but only a small fraction of genetic cause has been identified. We aim to identify more of the disease genes, which will lead to greater understanding of the causes of human heart failure.