INNOVATIVE GENE DISCOVERY FOR CLEFT LIP AND PALATE

唇腭裂是一种常见的出生缺陷，给社会和经济带来巨大的负担。他们需要广泛的手术，牙科，言语，儿科，听力和行为干预。虽然有超过400种个别罕见的裂缝原因，但大约70%被认为是孤立的或非综合征的，是多个基因-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，其中只有相对温和的进展，在过去的几年里，新的机会和技术正在使该领域受益。基因鉴定已经从强调仔细的家族收集和表型分析、高通量基因分型的进展、强大的新分析策略、精细结构作图和突变表征以及基因组工具的应用， 基因发现该项目将与该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的经验和许多合作者的基础上。我们将利用目前可用的高质量的人类基因组序列进行基因发现的创新方法，使用基因组重排来识别涉及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，我们已经确定了一个新的CLIP基因座，9 q上的LOD为6.6，以精细映射和识别该基因。最后，在一个平行的，但概念上不同的方法，我们将利用个人出生的祖先混合人口（非洲，欧洲，美洲印第安人），以确定基因组片段可能包含基因的主要影响CLIP。我们将 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，使用亚表型，包括三维面部成像，以更好地了解面部发育。这个项目将反过来喂养那些小鼠模型项目以及功能分析和表达核心，为他们更好地理解裂缝基因的基础生物学提供资源。通过识别在唇腭裂病因学中起作用的基因，我们可以推进基础生物学并改善临床护理。

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.