11Q DELETIONS AND HYPOPLASTIC LEFT HEART SYNDROME

左心发育不全综合征是最具破坏性的先天性心脏病变之一，占先天性心脏病新生儿死亡总数的25%。虽然没有已知的病因，但左心发育不全综合征在一种罕见的染色体缺失疾病——雅各布森综合征中确实以极高的频率发生。这些患者有多种医学问题，并发现染色体11q远端区域为半合子。该项目旨在对Jacobsen综合征患者进行初步研究，以确定11q心脏缺陷的最小临界区域，并随后检查患有左心发育不全综合征的非Jacobsen患者在11q心脏最小区域内的微缺失。在确定人类心脏最小区域的基础上，将开发小鼠模型，利用CRE/LOX策略在9号染色体上对应心脏临界区域的小鼠合成区域上产生缺失。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，最终将导致识别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Jacobsen和其他‘ ’ q缺陷患者的临床特征；2) Jacobsen综合征患者基因定位；3)非jacobsen综合征合并左心发育不全综合征患者的筛查；4)小鼠合成心脏极小区缺失及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.