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：
10461220
负责人：
Rolf W Stottmann
金额：
$ 52.78万
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/10461220
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 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 gene network gene regulatory network 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出生缺陷之一（>七百分之一活产）具有大量但知之甚少的遗传成分。总体目标该应用程序的目的是采用人类遗传方法来识别遗传原因先天性颅面畸形与补充动物模型研究。我们的中心假设是仔细选择（基于谱系分析、表型介绍等）和谱系的基因组测序将使我们能够识别新的颅面畸形的原因并促进实验揭示潜在的原因机制。这项研究的基本原理是识别变体导致颅面畸形将提高我们对潜在问题的理解致病机制，为患者提供咨询，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通过追求以下具体目标来实现本应用程序的目标：1) 使用全基因组测序以确定导致人类唇裂综合症的变异腭，2）确定Fzd2截断在骨骼中的发病机制开发，以及 3) 对新型人类中的候选变体进行功能分析颅面畸形。目标1将通过全基因组测序来实现从我们的 CCHMC 队列中选择的患者。在目标 2 中，我们将进一步研究一种新型小鼠 FZD2 发育不良模型来评估非经典 Wnt 信号传导在此过程中的作用紊乱。在目标 3 中，我们将运用我们在小鼠模型创建和研究方面的专业知识来了解受影响的人类先证者中发现的变异的分子机制。该提案的结果将进一步鉴定人类颅面所必需的基因发育并与颅面发育有直接和持续的相关性生物学、人类遗传学和遗传咨询。通过为单身人士确定新角色基因，整个基因调控网络通常都受到牵连，这可能会极大地影响扩大潜在治疗靶点的范围。此外，新颖的动物模型作为这些研究的一部分生成的内容可以进一步用作理解基本知识的工具疾病机制并可能作为测试治疗的平台对未来研究的干预。对于临床医生来说，增加对具体情况的了解参与颅面发育和连接的基因导致更有效诊断、治疗、风险评估和计划生育。