FAMILY STUDY OF CONGENITAL CARDIOVASCULAR MALFORMATIONS

先天性心血管畸形的家族聚集性 已经得到了很好的证实，但潜在的致病机制还没有 明白了。来自我们在一个 巴尔的摩-华盛顿地区CCVM的人口调查 指家族聚集地，可能是单基因聚集地 一些左侧流出道缺陷的遗传；我们的额外临床 研究已经确定了可能形成的心脏表现在 一些家庭。在拟议的项目中，综合临床评估 家谱和正式的遗传分析将确定可能的来源 各种心脏表型的家族聚集性。分析将是 对来自核心家庭成员的表型数据进行了分析 临床评估和二维及多普勒超声心动图， 包括M模式测量。调查与以下各项相关的风险 左流出道畸形，发育不全儿童家庭 将对心脏综合征或主动脉缩窄进行研究。以供比较 发生的家庭风险和缺陷的类型、儿童的亲属 大动脉转位的情况将会被评估。临床 对照家庭获得额外亲属的评估 有记录的心脏缺陷的成员。该协议将最大化 Logistic回归在形式遗传分析中的有效性 方法：研究方法。这项研究将提供：(A)更好地了解病因 异常心脏表型之间的关系；(B)关于 特定类型先证者亲属发生CCVM的风险 心脏畸形；(C)危险因素或协变量的说明 与这些畸形有关；(D)遗传模型拟合以确定 这些缺陷最节俭的遗传模式；(E) 通过对人类进行分子研究来检验假说的产生 和/或发展动物模型；和(F)鉴定 为未来的遗传学研究提供信息的家谱。

Familial aggregation of congenital cardiovascular malformations (CCVM) has been well established, but the underlying etiologic mechanisms are not understood. Preliminary studies from our collaborative efforts in a population-based investigation of CCVM in the Baltimore-Washington area suggest a concentration of familial aggregation and possibly monogenic inheritance of some left outflow tract defects; our additional clinical studies have identified possible forme fruste cardiac manifestations in some families. In the proposed project, comprehensive clinical evaluation of pedigrees and formal genetic analyses will identify possible sources of familial aggregation of variable cardiac phenotypes. Analyses will be performed on phenotypic data from nuclear family members obtained during clinical assessments and 2 dimensional and Doppler echocardiography, including M-mode measurements. To investigate the risks associated with left outflow tract defects, the families of children with hypoplastic left heart syndrome or coarctation of the aorta will be studied. For comparison of familial risk for occurrence and types of defects, relatives of children with d-transposition of the great arteries will be evaluated. Clinical assessment of control families obtain additional relatives of family members with documented heart defects. This protocol will maximize the efficiency of the formal genetic analysis using logistic regressive methods. This study will provide: (a) better understanding of etiologic relationships among abnormal cardiac phenotypes; (b) information concerning risk of occurrence of CCVM in relatives of probands with specific types of cardiac malformations; (c) elucidation of risk factors or covariates associated with these malformations; (d) genetic model fitting to determine the most parsimonious patterns of inheritance for these defects; (e) generation of hypotheses to be tested through molecular studies in humans and/or the development of animal models; and (f) identification of informative pedigrees for future genetic studies.