Molecular approaches to gene identification in congenital heart disease

描述(由申请人提供)： 先天性心脏病(CHD)是最常见的出生缺陷，发病率占所有活产儿的1%。许多细胞遗传学异常与CHD有关，越来越多的证据表明，许多发育缺陷可能是由于在细胞遗传学水平上看不到的小基因组改变而导致的连续基因拷贝数的变化。我们建议使用全基因组高分辨率寡核苷酸微阵列，通过筛选基因拷贝数的变化来确定遗传因素对CHD的影响。我们还将在节段性非整倍体的间隔时间内筛选候选基因的遗传突变，并通过心脏遗传学联合会中的模型生物筛选，使用高通量测序和使用定制的寡核苷酸微阵列分析基因内缺失/重复来筛选确定的分子心脏发育途径的候选基因。我们的长期目标是定义一组在CHD病因学上重要的新的遗传和基因组异常，表征与CHD相关的新综合征，并开发改进的CHD临床遗传学诊断方法。我们相信，这些信息将提供更准确的临床预后信息，可以改善遗传咨询，并帮助家庭准确确定与CHD相关的复发风险和预后(参见说明)：随着CHD在产前诊断越来越多，以及成年CHD患者正活到生育年龄，对于未来的父母来说，一些最关键的临床问题是，他们的家族中的CHD是否有潜在的遗传基础，量化复发的风险，以及确定预后，包括对神经功能和全身疾病的预测。

DESCRIPTION (provided by applicant): Congenital heart disease (CHD) is the most common birth defect with an incidence of 1% of all live births. Many cytogenetic abnormalities have been associated with CHD, and evidence is accumulating that many developmental defects can result from small genomic alternations invisible at the cytogenetic level, resulting in changes in copy number of contiguous genes. We propose to identify genetic contributions to CHD by screening for changes in gene copy number, using genome-wide high resolution oligonucleotide microarrays. We will also screen for genetic mutations in candidate genes in intervals of segmental aneuploidies and in candidate genes identified molecular cardiac development pathways and through model organism screens in the Cardiac Genetics Consortium using high throughput sequencing and analysis of intragenic deletions/duplications using customized oligonucleotide microarrays. Our long-term goals are to define a set of novel genetic and genomic aberrations important in the etiology of CHD, to characterize new syndromes associated with CHD, and to develop improved methods of clinical genetic diagnostics for CHD. We believe this information will provide more accurate clinical prognostic information that can improve genetic counseling and assist families in accurately determining risk of recurrence and prognosis associated with CHD RELEVANCE (See instructions): As CHD is increasingly diagnosed within the second trimester prenatally and as adults with CHD are living to reproductive age, some of the most critical clinical questions for prospective parents are whether or not the CHD in their family has an underlying genetic basis, quantifying the risk of recurrence, and determining prognosis including predictions of neurological function and systemic disease.