Craniofacial Microsomia: Genetic Causes and Pathway Discovery

项目摘要 颅面矮小症（CFM）是一种常见的先天性疾病（1：3，500），影响面部骨骼， 耳和面神经以及其他面部和颅外畸形。因此，患有CFM的儿童 经常需要多种干预来恢复他们的气道、进食、听力和面部对称性。的 与CFM相关的终身医疗保健需求对家庭、医疗保健系统和 社会这种情况的遗传风险因素在很大程度上仍然未知， 尚未着手解决这一根本性的知识差距。在本申请中，我们建议 研究CFM的遗传病因。我们的长期目标是确定遗传和非遗传风险因素 有助于CFM和评估受影响的遗传途径。我们已经确定了18个候选基因， CFM在我们对29个三人组（患有CFM的受影响个体和未受影响的父母）的研究中。根据我们初步的 研究结果和使用FACIAL网络，这是一个由NIH资助的已建立的网络，专门用于 研究CFM，我们建议进行以下研究：目的1）定义基因和基因通路， 在发育中的面部组织中表达被破坏，这有助于CFM表型;目的2）鉴定 通过对来自库存样本的170个trios进行全基因组测序，获得CFM的新候选基因（n=70） 和前瞻性入组（n=100）;和目标3）检测我们的研究中鉴定的50个候选基因的突变 在CFM和目标1和2中使用靶向捕获测序对来自490个样本进行的先前遗传研究 个人CFM深度高通量测序和基因表达研究相结合， 来自人类和动物模型的相关组织将有助于确定有意义的遗传原因， 这种混乱。我们的多学科FACIAL网络具有调查遗传复杂性的基础设施 在CFM。包括CFM患病率较高的国家和国际研究中心， 网络有能力收集大量（n=660）和特征明确的人群的高质量数据。我们 我希望我们提出的研究将确定导致CFM的基因，并产生对途径的见解 调节颅面发育，从而为CFM和其他 颅面疾病这项研究将通过确定选择方案，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的使命最为相关， 通过研究改善颅面健康。

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.