CONGENITAL HEART DISEASE: MODELING AND GENETIC ANALYSIS

这些研究的长期目标是了解基因是如何引起 先天性心脏病(CHD)。涉及的第一组目标 统一两种方法设计分析方法： 目前的应用包括获取临床数据和扩展 对这些数据进行理论分析。这些目标是明确的 协同效应，对经验数据的检验将继续刺激 理论的新想法，正如对模型的探索所指出的那样 潜在地揭示了临床研究的途径。 遗传方法的推广和发展取得了长足的进展 已经实现了对CHD的分析。充分探索的主题 经验数据的权证扩展包括：上位性；选择； 多室模型；宾果模型；阈值模型和四色模型； 圆形分布；以及角动态平衡。以下是精神障碍 将会被研究。(1)几种形式的心血管旋转不良将 说明角度动态平衡的各个方面；理论预测心外循环 表现形式可能与某些类型(但不是全部)有关 旋转不良发育不良。(2)乳头肌位置 应用方向性统计研究心内膜 超声心动图和磁共振成像。错位一直是 与血流损害有关，如主动脉瓣狭窄。乳头肌位置 将通过超声心动图确定，遗传因素研究在 正常家系和通过发生CHD血流而确定的家系 病变，尤其是主动脉狭窄。(3)流行性病变的轻度末端 频谱包括二尖瓣、主动脉瓣和主动脉缩窄；通常 伴随这些病变的是近端主动脉扩张。这个 这些皮损的易感性可能是常染色体显性遗传 特征将通过搜索、磁共振成像和 超声心动图对老年人亲属亚临床解剖改变的研究 先驱们。发展广泛的家系将使研究 上位主义。(4)腹主动脉根部扩张的发生和发展 马凡综合征、遗传性环主动脉扩张症和先天性 二尖瓣主动脉瓣将作为多点撞击系统进行研究。 宾果-伽马模型。马凡的遗传和进化适合度 表型可以用分枝过程的方法来探索。(5)二尖瓣 瓣膜脱垂被认为是某些常染色体显性遗传特征。 家人。先证者将被归类为存在冗余的 经超声心动图研究的瓣膜装置和亲属，具有双重功能 检验孟德尔模型和探索确定偏差的目的 年龄相关的特征。(6)数字异常与冠心病的结合 在某些孟德尔条件下，特别是Ellis-van Creveld和 Holt-Oram综合征，提供了一种基于 四边形修正函数。

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.