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

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.

项目概要 颅面微小症 (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 经常需要多种干预措施来恢复气道、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着家庭、医疗保健系统和 社会。这种情况的遗传风险因素仍然很大程度上未知，并且进行了大型多中心研究 解决这一基本知识差距的工作尚未开展。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 有助于 CFM 并评估受影响的遗传途径。我们已经鉴定出 18 个候选基因 我们对 29 名三人组（患有 CFM 的受影响个体和未受影响的父母）进行的研究中存在 CFM。根据我们的初步 研究结果并使用 FACIAL 网络，这是一个由 NIH 资助的既定网络，专门设计用于 研究CFM，我们建议进行以下研究： 目标1）定义基因和基因通路，其 正在发育的面部组织中的表达被破坏，从而导致 CFM 表型；目标 2) 识别 通过对来自银行样本的 170 个三人组（n=70）进行全基因组测序，获得新的 CFM 候选基因 和预期入学（n=100）；目标 3) 检测我们在我们的研究中发现的 50 个候选基因中的突变 之前在 CFM 以及目标 1 和 2 中使用靶向捕获测序对 490 个样本进行的基因研究 患有 CFM 的个人。深度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 CFM 患病率较高的国家和国际站点、FACIAL 网络有能力收集大量（n=660）且特征良好的人群的高质量数据。我们 期望我们提出的研究能够识别导致 CFM 的基因并深入了解其途径 调节颅面发育，从而为 CFM 和其他研究提供有用的信息 颅面疾病。这项研究将通过确定选择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定制的临床管理和 高危人群的一级预防策略。这与 NIDCR 的使命最为相关 通过研究改善颅面健康。

项目成果

Parental Reports of Intervention Services and Prevalence of Teasing in a Multinational Craniofacial Microsomia Pediatric Study.

• DOI: 10.1097/scs.0000000000007999
• 发表时间: 2021-11-01
• 期刊: The Journal of craniofacial surgery

Haploinsufficiency of SF3B2 causes craniofacial microsomia.

• DOI: 10.1038/s41467-021-24852-9
• 发表时间: 2021-08-03
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Timberlake AT;Griffin C;Heike CL;Hing AV;Cunningham ML;Chitayat D;Davis MR;Doust SJ;Drake AF;Duenas-Roque MM;Goldblatt J;Gustafson JA;Hurtado-Villa P;Johns A;Karp N;Laing NG;Magee L;University of Washington Center for Mendelian Genomics;Mullegama SV;Pachajoa H;Porras-Hurtado GL;Schnur RE;Slee J;Singer SL;Staffenberg DA;Timms AE;Wise CA;Zarante I;Saint-Jeannet JP;Luquetti DV
• 通讯作者: Luquetti DV

Damaging variants in FOXI3 cause microtia and craniofacial microsomia.

• DOI: 10.1016/j.gim.2022.09.005
• 发表时间: 2023-01
• 期刊: GENETICS IN MEDICINE
• 影响因子: 8.8
• 作者: Quiat, Daniel;Timberlake, Andrew T.;Curran, Justin J.;Cunningham, Michael L.;McDonough, Barbara;Artunduaga, Maria A.;DePalma, Steven R.;Duenas-Roque, Milagros M.;Gorham, Joshua M.;Gustafson, Jonas A.;Hamdan, Usama;V. Hing, Anne;Hurtado-Villa, Paula;Nicolau, Yamileth;Osorno, Gabriel;Pachajoa, Harry;Porras-Hurtado, Gloria L.;Quintanilla-Dieck, Lourdes;Serrano, Luis;Tumblin, Melissa;Zarante, Ignacio;V. Luquetti, Daniela;Eavey, Roland D.;Heike, Carrie L.;Seidman, Jonathan G.;Seidman, Christine E.
• 通讯作者: Seidman, Christine E.