Forward genetic analysis of congenital craniofacial malformations

颅面畸形是最常见的先天性出生缺陷之一(1/700 活产)具有大量但鲜为人知的遗传成分。总体目标 这一应用的目的是采用人类遗传学的方法来识别 先天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(基于系谱分析，表型 陈述等)而家系的基因组测序将使我们能够识别新的 颅面畸形的原因和促进实验发现潜在的 机械装置。这项拟议研究的基本原理是确定变种 导致颅面畸形将提高我们对潜在的 致病机制，告知患者咨询，并最终导致改善 诊断、治疗和病人护理。我们计划测试这一中心假设，并 通过追求以下特定目标来实现此应用程序的目标：1)使用 全基因组测序以确定导致人类综合征性唇裂和 2)确定Fzd2截断在骨骼中的发病机制 3)对新人候选变异体进行功能分析 头面部畸形。目标1将通过全基因组测序来实现 从我们的CCHMC队列中挑选患者。在目标2中，我们将进一步研究一种新的小鼠 FZD2核发育不良模型评价非典型性Wnt信号在此中的作用 无序。在目标3中，我们将应用我们在创造和研究老鼠模型方面的专业知识来 了解在受影响的人类先证者中发现的变异的分子机制。 这项研究的结果将进一步确定人类头面部必需的基因。 并与颅面发育有直接和持久的相关性 生物学、人类遗传学和遗传咨询。通过确定单身人士的新角色 基因，整个基因调控网络经常被牵连，这可以戏剧性地 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生成的，可以进一步用作理解基本知识的工具 疾病机制(S)及其潜在的治疗试验平台 未来研究中的干预措施。对于临床医生，增加了对特定疾病的理解 参与头面部发育和连通性的基因导致更有效 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.