CONGENITAL HEART DISEASE--MODELING AND GENETIC ANALYSIS

这些研究的长期目标是了解基因是如何导致 先天性心脏病（CHD）。 第一组目标涉及 通过统一两种方法来设计分析方法： 目前的应用，涉及获得临床数据和扩展 理论对这些数据的分析。 这些目标显然 协同作用，以及对经验数据的审查将继续刺激 理论的新想法，正如模型的探索所指出的那样， 可能揭示临床研究的途径。 在推广和发展遗传学方法方面取得了相当大的进展， 冠心病的分析已经实现。 充分探讨的主题， 经验数据的保证扩展包括：上位性;选择; 多房室模型;宾果模型;阈值和四分模型; 圆形分布和角稳态。 以下病症 将被研究。 (1)心血管旋转不良的几种形式， 说明角度稳态方面;理论预测心外 表现可能与一些，但不是所有，类型的 旋转不良 (2)乳头肌位置 可以通过应用于以下的方向统计学来研究心室内膜异位症： 超声心动图和磁共振图像。 错位已经 与血流病变如主动脉瓣狭窄有关。 乳头肌位置 将通过超声心动图和遗传因素研究来确定， 正常家庭，以及通过发生CHD血流而确定的家庭 病变，尤其是主动脉瓣狭窄。 (3)血流病变的轻度端 频谱包括二叶式主动脉瓣和主动脉缩窄;通常 与这些损伤相关的是近端主动脉的扩张。 的 这些病变的易感性可能是常染色体显性遗传 将通过搜索、磁共振成像和 超声心动图，用于亲属的亚临床解剖学改变， 先证者 广泛谱系的发展将使调查 上位性 (4)主动脉根部扩张的发生和发展 马凡氏综合征、遗传性环主动脉扩张症和先天性 二叶主动脉瓣将作为多点系统进行研究， 宾果-伽马模型 马方人的遗传和进化适应性 表型可以通过分支过程的方法来探索。 (5)二尖瓣 瓣膜脱垂被认为是一些人的常染色体显性特征， 家庭 先证带将根据是否存在冗余进行分类， 心脏瓣膜装置，以及通过超声心动图研究的亲属， 目的是检查孟德尔模型和探索在一个 年龄依赖性特征 (6)指端畸形与冠心病的关系 在某些孟德尔条件下，特别是Ellis-van Creveld和 Holt-Oram综合征，提供了一种方法来测试基于 四边形校正函数

The long-term goal of these investigations is to understand how genes cause congenital heart disease (CHD). The first set of objectives involved devising methods of analysis by unifying two approaches: the focus of the current application, involves obtaining clinical data and extending the theory to the analysis of these data. These sets of objectives are clearly synergistic, and examination of empiric data will continue to stimulate fresh ideas for theory, just as exploration of models has pointed to potentially revealing avenues of clinical study. Considerable progress in extending and developing the methods of genetic analysis for CHD has been achieved. Topics sufficiently explored to warrant extension to empiric data include: epistasis; selection; multicompartmental models; bingo models; threshold and tetrachoric models; circular distributions; and, angular homeostasis. The following disorders will be studied. (1) Cardiovascular malrotation in its several forms will illustrate aspects of angular homeostasis; theory predicts how extracardiac manifestations might be associated with some, but not all, types of maldevelopment of malrotation. (2) Papillary muscle position on the ventricular endocardium can be studied by directional statistics applied to echocardiographic and magnetic resonance images. Malposition has been related to flow lesions such as aortic stenosis. Papillary muscle position will be determined by echocardiography, and genetic factors studied in normal families, and in families ascertained through occurrence of CHD flow lesions, especially aortic stenosis. (3) The mild end of the flow lesion spectrum includes bicuspid aortic valve and aortic coarctation; often associated with these lesions is dilatation of the proximal aorta. The possibility that predisposition to these lesions is an autosomal dominant trait will be studied by searching, by magnetic resonance imaging and echocardiography, for subclinical anatomic alterations in relatives of probands. Development of extensive pedigrees will enable investigation of epistasis. (4) The occurrence and progression of aortic root dilatation in the Marfan syndrome, hereditary annuloaortic ectasia, and congenital bicuspid aortic valve will be studied as multiple-hit systems by means of bingo-gamma models. The genetic and evolutionary fitness of the Marfan phenotype can be explored by the method of branching processes. (5) Mitral valve prolapse is thought to be an autosomal dominant trait in some families. Probands will be categorized as to the presence of redundancy of valve apparatus, and relatives studied by echocardiography, with the dual aims of examining mendelian models and exploring ascertainment bias in an age-dependent trait. (6) The conjunction of digital abnormalities and CHD in certain mendelian conditions, notably the Ellis-van Creveld and the Holt-Oram syndromes, provides a way to test pathogenetic models based on quadrangular correction functions.