Genetic analysis of congenital diaphragmatic hernia

描述（由申请人提供）：长期目标：我们想研究人类先天性膈疝（CDH）的遗传病因。这种常见的出生缺陷与显著的产前死亡率和长期发病率有关。有显著的证据表明，基因是重要的CDH的病因，但孟德尔谱系适合基因定位在这种散发条件是罕见的。我们目前正在使用阵列比较基因组杂交（阵列CGH）来识别患有CDH和染色体易位的患者的亚微观染色体畸变。我们已经发现了一个CDH先证者，他有一个从头染色体易位和单个细菌人工染色体（BAG）克隆的拷贝数减少，该克隆位于CGH阵列易位断点区域。我们希望证实CGH的结果，并表明易位断点与CDH发病机制中涉及的基因缺失或基因表达改变有关。如果我们能识别出这个基因，我们将确定该基因在非综合征性CDH和CDH合并畸形患者队列中CDH发病机制中的参与程度。我们还将使用系统发育/基因组学方法来确定与所鉴定的基因和蛋白质具有相似结构和功能基序的基因和蛋白质同源物。我们的具体目标是1。在CDH患者和新发染色体易位中鉴定染色体断点处缺失基因或基因表达改变。2. 通过对48例非综合征性CDH患者和24例CDH及其他畸形患者进行基因测序，确定所鉴定基因在人类CDH发病机制中的参与程度。3. 使用基因组/系统发育方法确定与已鉴定的基因和蛋白质具有相似结构和功能的基因和蛋白质同源物，并通过直接测序在同一CDH患者队列中筛选这些新基因的序列改变。

DESCRIPTION (provided by applicant): Long term objectives: We would like to investigate the genetic etiology of congenital diaphragmatic hernia (CDH) in humans. This common birth defect is associated with a significant prenatal mortality and long-term morbidity. There is significant evidence that genes are important in the etiology of CDH but Mendelian pedigrees suitable for gene mapping in this sporadic condition are rare. We are currently using array comparative genomic hybridization (array CGH) to identify submicroscopic chromosome aberrations in patients who have CDH and chromosome translocations. We have identified a proband with CDH who has a de novo chromosome translocation and reduced copy number for a single bacterial artificial chromosome (BAG) clone localized to the region of a translocation breakpoint on array CGH. We would like to confirm the CGH result and show that the translocation breakpoint is associated with a gene deletion or altered expression of a gene involved in the pathogenesis of CDH. If we can identify this gene, we would determine the degree of involvement of the gene in the pathogenesis of CDH in a cohort of patients with non-syndromic CDH and with CDH and malformations. We would also use a phylogenetic/genomic approach to ascertain gene and protein homologues with similar structural and functional motifs to the identified gene and protein. Our specific aims are 1. To identify a deleted gene(s) or altered expression of a gene at a chromosome breakpoint in a patient with CDH and a de novo chromosome translocation. 2. To determine the degree of involvement of the identified gene in the pathogenesis of CDH in humans by sequencing this gene in a cohort of 48 patients with non-syndromic CDH and in 24 patients CDH and additional malformations. 3. To use a genomic/phylogenetic approach to ascertain gene and protein homologues with similar structure and function to the identified gene and protein and to screen these new genes for sequence alterations by direct sequencing in the same patient cohort with CDH.