INNOVATIVE GENE DISCOVERY FOR CLEFT LIP AND PALATE

唇腭裂是常见的先天缺陷，造成巨大的经济和社会负担。它们需要广泛的外科、牙科、言语、儿科、听力和行为干预。虽然有400多种罕见的个体致裂原因，但大约70%被认为是孤立的或非综合征性的，是多种基因-基因和基因环境相互作用的结果。经过十多年的病因学研究，只取得了相对不大的进展，在过去的几年里，新的机会和技术正在使该领域受益。基因鉴定从强调仔细的家系收集和表型鉴定、高通量基因分型的进展、强大的新分析策略、精细结构图谱和突变表征以及基因组工具的应用等方面都有所改进。 基因发现。该项目将与P50中心的其他项目和核心紧密结合，并建立在我们以前使用这些方法及其许多合作者的经验的基础上。我们将利用目前可用的高质量人类基因组序列，采用一种创新的方法来寻找基因，使用基因组重排来识别参与CL/P的基因。我们将建立在Lidral、Marazita和Murray实验室的富有成效的合作基础上，其中我们已经识别了一个新的CLIP基因座，该基因在9q上的LOD为6.6，以精细定位和鉴定该基因。最后，在一种平行但概念上不同的方法中，我们将利用祖先混合种群(非洲、欧洲、美洲印第安人)出生的个体来识别可能包含CLIP中主要影响基因的基因组片段。我们会 通过Core E的合作者开发的全球基因表达分析，对这些基因座进行精细定位。我们的项目将与Marazita的项目紧密结合，使用子表型，包括三维面部成像，以更好地了解面部发育。该项目将反过来为小鼠模型项目以及功能分析和表达核心提供资源，为他们更好地了解构成裂隙的基因的基本生物学提供资源。通过识别在唇腭裂病因中起作用的基因，我们可以促进基础生物学的发展，改善临床护理。

Clefts of the lip and/or palate are common birth defects with a substantial economic and societal burden. They require extensive surgical, dental, speech, pediatric, hearing and behavioral interventions. While there are over 400 individual rare causes of clefting, approximately 70% are considered isolated or non-syndromic and the result of multiple gene-gene and gene environment interactions. After more than a decade of etiologic investigations in which there were only relatively modest advances, in the last few years new opportunities and technologies are benefiting the field. Gene identification has improved from an emphasis on careful family collection and phenotyping, advances in high throughput genotyping, powerful new analytic strategies, fine-structure mapping and mutation characterization, and the application of genomic tools to gene finding. This project will integrate closely with other projects and cores of this P50 center and to build on our previous experience with these approaches and with many of its collaborators. We will exploit the currently available high quality human genomic sequence to undertake an innovative approach to gene finding using genomic rearrangements to identify genes involved in CL/P. We will build on a productive collaboration of the Lidral, Marazita and Murray Labs in which we have already identified a novel CLIP locus with a LOD of 6.6 on 9q to fine map and identify this gene. Finally, in a parallel but conceptually different approach we will make use of individuals born of ancestrally mixed populations (African, European, American Indian) to identify genomic segments likely to contain genes of major effect in CLIP. We will pursue fine-mapping of these loci assisted by global gene expression analysis developed through the collaborators in Core E. Our project will be closely integrated with that of Marazita to use sub-phenotyping, including three-dimensional facial imaging to provide a better understanding of facial development. This project will in turn feed those of the mouse model projects as well as the fuctional analysis and expression cores to provide resources for their development of a better understanding of the basic biology of the genes that underlie clefts. By identifying genes playing a role in the etiology of cleft lip and palate we can advance basic biology and improve clinical care.