Genetic determinants of human heterotaxy and aortic arch malformation

描述(由申请人提供)： 先天性心脏病是最常见的严重出生缺陷，影响了0.8%的活产婴儿，人类和动物模型系统中的大量证据都支持先天性心脏病的遗传基础。然而，低复发率、小样本量和基因组技术的局限性为定义CHD的遗传学提供了重大障碍。这项建议的目标是将Lifton实验室最先进的基因组技术与Brueckner实验室开发的对CHD潜在的发育机制的了解相结合，以确定两种类型CHD的遗传决定因素，即先天性心脏病(HTX)和主动脉弓畸形(AAA)。我们对288例HTX患者进行了拷贝数变异(CNV)分析，发现罕见的基因CNV在-20%。有趣的是，CNV将注意力集中在新的候选基因上，这些基因聚集在3条途径中，以前被认为在LR不对称和血管系统的发展中起作用：纤毛结构和功能、转化生长因子-β信号和糖基化。这些观察表明，通过结合强大的基因组技术和大量的患者队列，以及我们对心脏形态发生所涉及的发育途径的理解，我们将在相当数量的CHD患者中确定遗传原因。在具体目标1中，我们将从耶鲁大学、罗切斯特大学和伦敦大学学院招募2,000名来自耶鲁大学、罗切斯特大学和伦敦大学学院的CHD患者，并仔细进行表型分析，与PCGC财团分享。在具体目标2中，来自HTX和AAA联合的患者将首先进行CNV分析。随后，没有检测到拷贝数变化的散发性HTX和AAA患者可以进行完整的外显子测序来发现致病突变。在具体目标3中，我们将确定具有共同的临床定义的HTX和AAA表型的离散基因变异体是否具有显著不同的短期和中期临床结果。在这里，我们将重点关注可能与致病发育途径有关的三个方面的临床结果：心肌功能和肾功能，这两个功能都与模型动物系统中的纤毛功能有关，以及在小鼠和人类中，主动脉根部大小显著受转化生长因子-β信号的影响。相关性(见说明)：尽管先天性心脏病(CHD)的遗传病因长期以来一直被怀疑，但患者数量、基因组技术和对控制心脏发育的生物学的了解的限制阻碍了对CHD一般原因的确定。这项建议寻求使用最先进的基因组技术来确定两种类型的主要CHD的原因，即先天性心脏病和主动脉弓畸形。

DESCRIPTION (provided by applicant): Congenital heart disease is the most common serious birth defect, affecting .8% of live born infants, and ample evidence in both humans and animal model systems supports a genetic basis for CHD. However, low recurrence rates, small sample size and limitation in genomic technology have provided a significant hurdle in defining the genetics of CHD. The goal of this proposal is to combine the state-of-the art genomic technology in the Lifton laboratory with the understanding of the developmental mechanism underlying CHD developed in the Brueckner laboratory to determine the genetic determinants of two types of CHD, Heterotaxy (Htx) and Aortic Arch Abnormalities (AAAs). We have used copy number variation (CNV) analysis in a pilot study of 288 patients with Htx and identified rare genie CNVs in -20%. Interestingly, the CNVs direct attention to novel candidate genes that cluster in 3 pathways previously identified to have a role in the development of LR asymmetry and vasculature: ciliary structure and function, TGF-P signaling and glycosylation. These observations suggest that by combining powerful genomic techniques and large patient cohorts with our understanding of the developmental pathways implicated in cardiac morphogenesis we will identify a genetic cause in a significant number of CHD patients. In Specific Aim 1, we will recruit and carefully phenotype >2,000 pts with all CHD from Yale, University of Rochester and University College London to share with the PCGC consortium. In Specific Aim 2, patients from the consortium with Htx and AAAs will first be analyzed for CNVs. Subsequently, sporadic Htx and AAA patients with no detectable copy-number changes can undergo whole exome sequencing to discover causative mutations. In Specific Aim 3, we will determine whether discrete genotype variants with shared, clinically defined Htx and AAA phenotypes have significantly different short and mid-term clinical outcomes. Here we will focus on three aspects of clinical outcome that have possible links to the causative developmental pathways: myocardial function and renal function, both of which have been associated with ciliary function in model animal systems, and aortic root size, which is prominently affected by TGF-P signaling in mice and humans. RELEVANCE (See instructions): Although a genetic etiology for congenital heart disease (CHD) has long been suspected, limitations in patient number, genomic technology and understanding of the biology governing heart development have hampered identification of generic causes of CHD. This proposal seeks to use state-of-the-art genomic technology to identify the cause of two types of major CHD, heterotaxy and aortic arch abnormalities.