Forward genetic analysis of congenital craniofacial malformations

颅面畸形是最常见的先天性出生缺陷（>1/700 活产），具有大量但知之甚少的遗传成分。总体目标 本申请的目的是采用人类遗传学方法来确定 先天性颅面畸形与补充动物模型研究。我们 中心假设是，仔细选择（基于系谱分析，表型 介绍等）和基因组测序的谱系将使我们能够确定新的 颅面畸形的原因，并促进实验，以揭示潜在的 机制等这项研究的基本原理是， 会导致颅面畸形， 致病机制，为患者咨询提供信息，并最终导致改善 诊断、治疗和病人护理。我们计划测试这个中心假设， 通过追求以下具体目标来实现本申请的目标：1）使用 全基因组测序，以确定导致人类综合征性唇裂的变异， 2）确定骨骼中Fzd 2截短发病机制 开发，以及3）在新的人类中进行候选变体的功能分析。 颅面畸形目标1将通过全基因组测序来实现， 从我们的CCHMC队列中选择患者。在目标2中，我们将进一步研究一种新的小鼠， FZD 2骨骼发育不良模型，以评估非经典Wnt信号传导在这一过程中的作用。 disorder.在目标3中，我们将运用我们在创建和研究小鼠模型方面的专业知识， 了解在受影响的人类先证者中鉴定的变异的分子机制。 这项研究的结果将进一步确定人类颅面结构所必需的基因。 发展，并有直接和持久的关系，颅面发育 生物学人类遗传学和遗传咨询通过为单身人士确定新的角色， 基因，整个基因调控网络往往可以牵连，这可以显着 增加潜在治疗靶点的范围。此外，新的动物模型 作为这些研究的一部分，可以进一步利用这些工具来了解基本的 疾病的机制，并可能作为测试治疗的平台 在未来的研究干预。对于临床医生来说， 基因参与颅面发育和连接导致更有效的 诊断、治疗、风险评估和计划生育。

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.