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0.8%的活产婴儿，并且在人类和动物模型系统中的充分证据支持CHD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提供了一个显着的障碍，在确定冠心病的遗传学。该提案的目标是将联合收割机在利夫顿实验室的最先进的基因组技术与在Brueckner实验室开发的CHD潜在的发育机制的理解相结合，以确定两种类型的CHD的遗传决定因素，即异位（Htx）和主动脉弓腹缩（AAA）。我们在288例Htx患者的初步研究中使用了拷贝数变异（CNV）分析，并在约20%的患者中鉴定了罕见的基因CNV。有趣的是，CNV将注意力集中到聚集在3个先前被鉴定为在LR不对称和血管系统的发展中起作用的途径中的新候选基因：纤毛结构和功能，TGF-β信号传导和糖基化。这些观察结果表明，通过将强大的基因组技术和大型患者队列与我们对心脏形态发生中涉及的发育途径的理解相结合，我们将在大量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并仔细表型> 2，000名患有所有CHD的患者，以与PCGC联盟共享。在特定目标2中，将首先分析来自联合体的Htx和AAA患者的CNV。随后，没有可检测的拷贝数变化的散发性Htx和AAA患者可以进行全外显子组测序以发现致病突变。在具体目标3中，我们将确定具有共享的、临床定义的Htx和AAA表型的离散基因型变体是否具有显著不同的短期和中期临床结局。在这里，我们将集中在三个方面的临床结果，有可能的因果关系的发展途径：心肌功能和肾功能，这两者都与模型动物系统中的纤毛功能，和主动脉根的大小，这是显着影响小鼠和人类的TGF-β信号。相关性（参见说明）：虽然先天性心脏病（CHD）的遗传病因一直被怀疑，但患者数量，基因组技术和对心脏发育生物学的理解的限制阻碍了CHD的一般原因的识别。该提案旨在使用最先进的基因组技术来确定两种主要CHD的病因，异位和主动脉弓异常。

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.