Craniofacial Microsomia: Genetic Causes and Pathway Discovery

颅面微小症：遗传原因和途径发现

• 批准号: 10224167
• 负责人: Carrie Lyn Heike
• 金额: $ 36万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224167
• 关键词: Address; Adolescence; Affect; Andean; Animal Model; Asians; Award; Basic Science; Birth; Breathing; Candidate Disease Gene; Cardiac; Child; Childhood; Classification; Clinical; Clinical Management; Collaborations; Complex; Counseling; Cranial Nerves; Craniofacial Abnormalities; Critical Pathways; Cystic Fibrosis; Data; Deglutition; Dentition; Dermoid Cyst; Development; Diagnosis; Disease; Ear; Ear ossicles; Embryo; Enrollment; Enteral Feeding; Esthetics; Etiology; Evaluation; External Ear; Face; Facial asymmetry; Facial nerve structure; Family; Family health status; Funding; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic study; Genomics; Goals; Grant; Health; Healthcare; Healthcare Systems; Hearing; Heterogeneity; High Prevalence; High-Throughput Nucleotide Sequencing; Hispanics; Human; Individual; Infrastructure; International; Intervention; Jaw; Kidney; Knowledge; Lateral; Life; Macrostomia; Mandible; Mastication; Mission; Molecular Diagnosis; Multicenter Studies; Mutation; National Institute of Dental and Craniofacial Research; Native Americans; Neuraxis; Neurofibromatosis 1; Operative Surgical Procedures; Parents; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Prevalence; Prevention; Prevention strategy; Primary Prevention; Procedures; Public Health; Recurrence; Research; Risk; Role; SNP array; Sampling; Savings; Side; Site; Skeleton; Societies; South America; Speech; Technology; Temporal bone structure; Tissues; Tracheostomy procedure; Translations; United States National Institutes of Health; Variant; Zygomatic bone; base; case control; cohort; craniofacial; craniofacial development; craniofacial disorder; craniofacial microsomia; design; feeding; functional outcomes; genetic risk factor; genome sequencing; genomic locus; health economics; high risk population; human model; human tissue; improved; individualized medicine; innovation; insight; malformation; microtia; middle ear; molecular pathology; mouse model; multidisciplinary; non-genetic; optimal treatments; prospective; reproductive; spine bone structure; surgery outcome; tool; transcriptome sequencing; whole genome; Address; Adolescence; Affect; Andean; Animal Model; Asians; Award; Basic Science; Birth; Breathing; Candidate Disease Gene; Cardiac; Child; Childhood; Classification; Clinical; Clinical Management; Collaborations; Complex; Counseling; Cranial Nerves; Craniofacial Abnormalities; Critical Pathways; Cystic Fibrosis; Data; Deglutition; Dentition; Dermoid Cyst; Development; Diagnosis; Disease; Ear; Ear ossicles; Embryo; Enrollment; Enteral Feeding; Esthetics; Etiology; Evaluation; External Ear; Face; Facial asymmetry; Facial nerve structure; Family; Family health status; Funding; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic study; Genomics; Goals; Grant; Health; Healthcare; Healthcare Systems; Hearing; Heterogeneity; High Prevalence; High-Throughput Nucleotide Sequencing; Hispanics; Human; Individual; Infrastructure; International; Intervention; Jaw; Kidney; Knowledge; Lateral; Life; Macrostomia; Mandible; Mastication; Mission; Molecular Diagnosis; Multicenter Studies; Mutation; National Institute of Dental and Craniofacial Research; Native Americans; Neuraxis; Neurofibromatosis 1; Operative Surgical Procedures; Parents; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Prevalence; Prevention; Prevention strategy; Primary Prevention; Procedures; Public Health; Recurrence; Research; Risk; Role; SNP array; Sampling; Savings; Side; Site; Skeleton; Societies; South America; Speech; Technology; Temporal bone structure; Tissues; Tracheostomy procedure; Translations; United States National Institutes of Health; Variant; Zygomatic bone; base; case control; cohort; craniofacial; craniofacial development; craniofacial disorder; craniofacial microsomia; design; feeding; functional outcomes; genetic risk factor; genome sequencing; genomic locus; health economics; high risk population; human model; human tissue; improved; individualized medicine; innovation; insight; malformation; microtia; middle ear; molecular pathology; mouse model; multidisciplinary; non-genetic; optimal treatments; prospective; reproductive; spine bone structure; surgery outcome; tool; transcriptome sequencing; whole genome

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.

项目摘要 颅面微粒细胞（CFM）是一种常见的先天性疾病（1：3,500），影响面部骨骼， 耳朵和面神经等其他面部和颅外畸形。结果，患有CFM的孩子 通常需要多种干预措施来恢复其气道，喂养，听力和面部对称性。这 与CFM相关的终身医疗保健需求极大地影响了家庭，医疗保健系统和 社会。这种情况的遗传危险因素在很大程度上仍然未知和大型多中心研究 尚未实现这一知识的基本差距。在此应用程序中，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 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 CFM在我们对29个三重奏的研究中（患有CFM和未受影响的父母的人）。基于我们的初步 调查结果和使用面部网络，这是由专门设计的NIH资助的已建立网络 研究CFM，我们建议进行以下研究：目标1）定义基因和基因途径 在发育中有助于CFM表型的发育中的面部组织中，表达受到破坏。目标2）识别 CFM的新候选基因通过在170个三重点中使用整个基因组测序（n = 70） 和预期入学（n = 100）；目标3）检测我们在我们的50个候选基因中的突变 先前在CFM和AIM 1和2中使用靶向捕获测序对490的样品进行的遗传研究 患有CFM的人。深度高通量测序和基因表达研究的结合 来自人类和动物模型的相关组织将促进鉴定有意义的遗传原因 这个疾病。我们的多学科面部网络具有研究遗传复杂性的基础设施 在CFM中。包括CFM患病率更高的国家和国际遗址，面部 网络具有在大型（n = 660）和特征良好的人群上收集高质量数据的能力。我们 期望我们提出的研究将确定引起CFM并产生洞察力的基因 调节颅面发育，从而为CFM和其他的研究提供了有用的信息 颅面疾病。这项研究将通过确定选择来积极影响该人群的医疗保健 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 高风险人群的主要预防策略。这与NIDCR的使命最高 通过研究改善颅面健康。