11Q DELETIONS AND HYPOPLASTIC LEFT HEART SYNDROME

左心发育不良综合征是最具破坏性的先天性心脏病之一，占所有先天性心脏病新生儿死亡的25%。 虽然没有已知的病因，但左心发育不良综合征确实以极高的频率发生在一种罕见的染色体缺失疾病中，称为雅各布森综合征。 这些患者有多种医疗问题，并已被发现是染色体11 q的远端区域半合子。 该项目旨在对患有Jacobsen综合征的人类进行初步研究，以确定心脏缺陷的11 q最小关键区域，并随后检查患有左心发育不良综合征的非Jacobsen患者的心脏11 q最小区域内的微缺失。 基于人类心脏最小区域的鉴定，将开发小鼠模型，利用CRE/LOX策略在小鼠9号染色体上的同线区域上产生缺失，该区域对应于关键心脏区域。 在小鼠中产生预期的心脏表型之后，将在人类患者中进行研究，最终应导致鉴定导致左心发育不全综合征（HLH-1）的基因，并允许利用小鼠模型系统对发育途径进行机械解剖。 因此，具体目的如下：1）所有具有Jacobsen和其它"q“缺陷的患者的临床表征; 2）Jacobsen综合征患者的遗传作图; 3）具有发育不全左心综合征的非Jacobsen综合征患者的筛选;和4）小鼠同线心脏最小区域的缺失和HLH-1基因的鉴定。

Hypoplastic left heart syndrome is one of the most devastating congenital heart lesions, accounting for as much as 25% of all deaths of neonates with congenital heart disease. Although there is no known etiology, hypoplastic left heart syndrome does occur at an extremely high frequency in a rare chromosomal deletion disorder called Jacobsen syndrome. These patients have multiple medical problems and have been found to be hemizygous for the distal region of chromosome 11q. This project is designed to perform initial studies in humans with Jacobsen syndrome to identify the minimal critical region in 11q for cardiac defects, and to subsequently examine non-Jacobsen patients with hypoplastic left heart syndrome for microdeletions within the cardiac minimal region at 11q. Based on the identification of the human cardiac minimal region, a mouse model will be developed, utilizing CRE/LOX strategies to generate a deletion on the mouse syntenic region on chromosome 9 that corresponds to the critical cardiac region. Generation of the anticipated cardiac phenotype in the mouse will be followed by studies in human patients that should ultimately lead to the identification of a gene(s) that causes hypoplastic left heart syndrome (HLH-1), and allow a mechanistic dissection of the developmental pathways exploiting mouse model systems. Accordingly, the Specific Aims are as follows: 1) Clinical characterization of all patients with Jacobsen and other ``q defects; 2) Genetic mapping of Jacobsen syndrome patients; 3) Screening of non-Jacobsen syndrome patients with hypoplastic left heart syndrome; and 4) Deletion of the mouse syntenic cardiac minimal region and identification of the HLH-1 gene.