Forward genetic analysis of congenital craniofacial malformations

先天性颅面畸形的正向遗传学分析

基本信息

批准号：
10453490
负责人：
Rolf W Stottmann
金额：
$ 56.1万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453490
关键词：
Address Affect Alleles Animal Model Biological Birth CRISPR/Cas technology Candidate Disease Gene Cell Line Centers for Disease Control and Prevention (U.S.)Cleft Lip Cleft Palate Cleft lip with or without cleft palate Clustered Regularly Interspaced Short Palindromic Repeats Congenital Abnormality Counseling Craniofacial Abnormalities DNA Defect Derivation procedure Development Developmental Biology Developmental Disabilities Diagnosis Diagnostic Disease Disease Pathway Embryology Etiology FZD2 gene Face Family Planning Future Genes Genetic Genetic Counseling Genome Genomics Goals Hand Head Human Human Genetics Image In Vitro Intervention Investigation Knowledge Lead Lip structure Live Birth Medical Genetics Mendelian disorder Modeling Molecular Molecular Biology Mus Mutant Strains Mice Mutation Oral cavity Pathogenesis Pathogenicity Pathway interactions Patient Care Patients Pediatric Hospitals Phenotype Population Pregnancy Privatization Process Proteins Provider Publishing Regulator Genes Research Risk Assessment Role Sampling Series Side Skeletal Development Structure Study models Syndrome Technology Testing Therapeutic Intervention Transgenic Model Variant WNT Signaling Pathway Work base causal variant cleft lip and palate cohort craniofacial craniofacial development craniofacial tissue design experimental study genetic analysis genetic approach genetic pedigree genetic variant genome sequencing improved induced pluripotent stem cell interest malformation mouse model next generation sequencing novel orofacial patient population pediatric patients proband recruit skeletal targeted treatment therapeutic evaluation therapeutic target tool treatment risk whole genome

项目摘要

Craniofacial anomalies are among the most common congenital birth defects (>1 in 700 live births) with a large, but poorly understood, genetic component. The overall objective of this application is to take a human genetic approach to identify the genetic causes of congenital craniofacial malformations with complementary animal model studies. Our central hypothesis is that careful selection (based on pedigree analysis, phenotypic presentation, etc.) and genomic sequencing of pedigrees will allow us to identify novel causes of craniofacial malformations and facilitate experiments to uncover the underlying mechanisms. The rationale of this proposed research is that identification of variants causing craniofacial malformations will improve our understanding of the underlying pathogenic mechanisms, inform patient counseling, and ultimately lead to improved diagnosis, treatment, and patient care. We plan to test this central hypothesis and accomplish the goals of this application by pursuing the following specific aims: 1) use whole genome sequencing to identify variants leading to human syndromic cleft lip and palate, 2) determine the mechanism of Fzd2 truncation pathogenesis in skeletal development, and 3) perform functional analysis of candidate variants in novel human craniofacial malformations. Aim 1 will be accomplished by whole genome sequencing of selected patients from our CCHMC cohort. In Aim 2, we will further study a novel mouse model of FZD2 omodysplasia to evaluate the role on non-canonical Wnt signaling in this disorder. In Aim 3, we will apply our expertise in creation and study of mouse models to understand the molecular mechanism of variants identified in affected human probands. The results from this proposal will further identify genes essential for human craniofacial development and have direct and persistent relevance for craniofacial developmental biology, human genetics and genetic counseling. By identifying novel roles for single genes, entire gene regulatory networks can often be implicated which can dramatically increase the range of potential therapeutic targets. Moreover, the novel animal models generated as part of these studies can be further utilized as tools for understanding basic mechanism(s) of disease and potentially as platforms for testing therapeutic interventions in future studies. For clinicians, increased understanding of the specific genes involved in craniofacial development and connectivity leads to more effective diagnosis, treatment, risk-assessment, and family planning.

颅面异常是最常见的先天性先天缺陷（> 1分之一活出生）具有较大但知之甚少的遗传成分。总体目标这种应用是采用人类遗传学方法来确定与互补动物模型研究有关的先天颅颅畸形。我们的中心假设是仔细的选择（基于谱系分析，表型呈现等）和谱系的基因组测序将使我们能够识别新颖的颅面畸形的原因并促进实验以发现基础机制。这项拟议的研究的理由是识别变体引起颅面畸形将提高我们对基础的理解致病机制，告知患者咨询并最终导致改善诊断，治疗和患者护理。我们计划检验这个中心假设和通过追求以下特定目的来实现此应用程序的目标：1）使用整个基因组测序以识别导致人类综合征裂唇的变异和口感，2）确定骨骼中FZD2截断发病机理的机制开发和3）对新人的候选变异进行功能分析颅面畸形。 AIM 1将通过整个基因组测序来完成来自我们CCHMC队列的患者。在AIM 2中，我们将进一步研究新的鼠标 FZD2型浮肿的模型，以评估在此中对非典型Wnt信号的作用紊乱。在AIM 3中，我们将应用我们的专业知识来创建和研究鼠标模型了解在受影响的人类概率中鉴定出的变体的分子机制。该提案的结果将进一步确定人类颅面所必需的基因发展并与颅面发展具有直接和持续的相关性生物学，人类遗传学和遗传咨询。通过识别单身的新作用基因，整个基因调节网络通常可能涉及可以显着的增加潜在的治疗靶标的范围。而且，新型动物模型作为这些研究的一部分生成的可以进一步用作理解基本的工具疾病的机制，并有可能作为测试治疗的平台未来研究的干预措施。对于临床医生，对特定的了解增加了涉及颅面发展和连通性的基因会导致更有效诊断，治疗，风险评估和计划生育。