Craniofacial Microsomia: Genetic Causes and Pathway Discovery

项目总结 颅面巨大症(CFM)是一种常见的先天性疾病(1：3500)，影响面部骨骼， 耳朵、面神经和其他面部和颅外畸形。因此，患有CFM的儿童 经常需要多项干预才能恢复他们的呼吸道、进食、听力和面部对称性。这个 与CFM相关的终身医疗保健需求对家庭、医疗保健系统以及 社会。这种疾病的遗传风险因素仍然很大程度上是未知的，也是大规模的多中心研究。 解决这一知识上的根本差距的工作还没有进行。在本申请中，我们建议 研究CFM的遗传病因学。我们的长期目标是确定遗传和非遗传风险因素 这有助于CFM并评估受影响的遗传途径。我们已经确定了18个候选基因 我们对29个三联体(患CFM的个体和未患CFM的父母)进行了研究。根据我们的初步调查 发现并使用面部网络，一个由NIH资助的已建立的网络，专门设计用于 为了研究CFM，我们建议进行以下研究：目的1)定义其基因和基因途径 在发育中的面部组织中，导致CFM表型的表达中断；目的2)确定 文库样本170个三联体中新的CFM候选基因(n=70) 和预期登记(n=100)；以及目标3)检测在我们的 先前在CFM和AIMS 1和2中使用靶向捕获测序对490个样本进行的遗传研究 患有CFM的个人。深层高通量测序与基因表达研究的结合 来自人类和动物模型的相关组织将有助于识别有意义的遗传原因 这种紊乱。我们的多学科面部网络拥有研究遗传复杂性的基础设施 在CFM中。包括国内和国际上CFM患病率较高的网站，面部 网络有能力收集大量(n=660)和特征良好的人口的高质量数据。我们 期望我们提出的研究将确定导致CFM的基因，并对这些途径产生洞察力 从而为CFM和其他疾病的研究提供有用的信息 头面部疾病。这项研究将通过确定选项对这一人群的医疗保健产生积极影响 用于分子诊断、精确的家庭和生殖咨询，以及量身定制的临床管理和 针对高危人群的初级预防战略。这与NIDCR的任务具有最高的相关性 通过研究改善头面部健康。

PROJECT SUMMARY Craniofacial microsomia (CFM) is a common congenital condition (1:3,500) that affects the facial skeleton, ears, and facial nerve among other facial and extracranial malformations. As a result, children with CFM frequently require multiple interventions to restore their airway, feeding, hearing, and facial symmetry. The lifelong health care needs associated with CFM substantially impact families, the health care system, and society. The genetic risk factors for this condition remain largely unknown and large multi-center studies addressing this fundamental gap in knowledge have not yet been conducted. In this application, we propose to study the genetic etiology of CFM. Our long term objective is to identify the genetic and non-genetic risk factors that contribute to CFM and evaluate the affected genetic pathways. We have identified 18 candidate genes for CFM in our study of 29 trios (affected individual with CFM and non-affected parents). Based on our preliminary findings and using the FACIAL network, an established network funded by the NIH specifically designed to study CFM, we propose to conduct the following studies: Aim 1) define genes and gene pathways whose expression is disrupted in the developing facial tissue that contributes to the CFM phenotype; Aim 2) identify new candidate genes for CFM by using whole genome sequencing in 170 trios from banked samples (n=70) and prospective enrollment (n=100); and Aim 3) detect mutations in 50 candidate genes identified in our previous genetic studies in CFM and in Aims 1 and 2 using targeted capture sequencing on samples from 490 individuals with CFM. The combination of deep high throughput sequencing and gene expression studies in relevant tissues from human and animal models will facilitate the identification of meaningful genetic causes for this disorder. Our multidisciplinary FACIAL network has the infrastructure to investigate the genetic complexity in CFM. Including both national and international sites, which have a higher prevalence of CFM, the FACIAL network has the ability to collect high-quality data on a large (n=660) and well-characterized population. We expect that our proposed studies will identify genes that cause CFM and generate insights into the pathways that regulate craniofacial development, thus providing useful information for the study of CFM and other craniofacial disorders. This research will positively impact health care for this population by identifying options for molecular diagnosis, precise family and reproductive counseling, and for tailored clinical management and primary prevention strategies for high-risk populations. This is of highest relevance to the NIDCR mission to improve craniofacial health through research.