Extending the Phenotype of Nonsyndromic Orofacial Clefts

描述(申请人提供)：口腔裂隙(OFCs)，特别是非综合征性唇裂伴或不伴腭裂(NS CL/P)是一个主要的公共卫生问题，全世界每500-1000名新生儿中就有一名受到影响。因此，许多研究小组试图确定与CL/P病因有关的遗传位点，我们的研究小组和其他研究小组最近取得了一些成功。看来，遗传因素对口腔颌面裂病因的影响是复杂的，可能是异质性的，在某些情况下可能是由于多个基因座的相互作用所致。 目前的建议是对1-R01-DE016148资助的竞争性延续，该资助的目标是识别代表CL/P基因的亚临床表型表现或CL/P基因的额外表达的扩展表型特征。我们成功地完成了以下具体目标：(1)确定匹兹堡和圣路易斯的家系并进行表型鉴定；(2)鉴定内表型，特别是口轮匝肌(OO：上唇)肌肉缺陷和唇纹螺纹；(3)确定内表型的候选基因(OO缺陷的BMP4和唇纹螺纹的IRF6)；(4)进行CL/P和内表型的其他遗传分析。现在我们已经有了很好的证据证明这些表型特征在多基因CL/P家族中的重要性，这一竞争延续的主要目标是(1)在普通的NS CL/P家族(即单基因和多基因以及其他种族)中研究这些特征，以确定这些表型的潜在临床相关性；(2)进一步研究这些特征如何能够阐明所观察到的CL/P家族的外显模式；以及(3)进行候选基因、全基因组连锁和全基因组关联研究，以确定与扩展的表型特征相关的基因。为了实现这些目标，将在匹兹堡、圣路易斯、德克萨斯州和丹麦确定核心家庭、扩大的多重亲属和双胞胎对。所有参与者都将接受以下特征的评估：高分辨率超声对Oo肌肉的解剖，皮肤纹唇纹和指纹，3D图像的头面部测量，利手和其他偏侧特征，轻微的身体异常，以及通过感知语音筛查的腭咽闭合能力。候选基因(BMP4，IRF6)和区域(6q，9q)中的SNP将进行基因分型，以及密集的全基因组SNP小组，随后将进行统计遗传分析。在阳性基因发现之后，将进行额外的精细测绘和/或突变筛查。公共卫生相关性：该项目将确定与唇腭裂出生缺陷相关的身体特征(表型)，并将确定与这些表型相关的基因。这一知识将改善唇腭裂家庭的遗传咨询，并最终将导致改善这些非常常见的出生缺陷的治疗方法。

DESCRIPTION (provided by applicant): Abstract Orofacial clefts (OFCs), particularly nonsyndromic cleft lip with or without cleft palate (NS CL/P) are a major public health problem, affecting one in every 500-1000 births worldwide. Therefore, many research groups have attempted to identify genetic loci contributing to the etiology of CL/P, with some recent successes by our research group and others. It appears that the genetic contribution to the etiology of oral-facial clefting is complex, probably heterogeneous, and probably due to interacting effects of multiple loci in some cases. The current proposal is a competing continuation of grant #1-R01-DE016148 that had the goal of identifying extended phenotypic features that represent either subclinical phenotypic manifestations of CL/P genes or additional expression of CL/P genes. We successfully completed the specific aims of (1) ascertaining and phenotyping families from Pittsburgh and St. Louis, (2) identifying endophenotypes, notably orbicularis oris (OO: upper lip) muscle defects and lip print whorls in affected and unaffected members of the multiplex CL/P families; (3) identifying candidate genes for the endophenotypes (BMP4 for OO defects and IRF6 for lip print whorls), (4) performing other genetic analyses of CL/P and the endophenotypes. Now that we have good evidence for the significance of these phenotypic features in multiplex CL/P families, the major goals of this competing continuation are (1) to investigate these features in general NS CL/P families (i.e., simplex as well as multiplex, plus in other ethnicities) in order to determine the potential clinical relevance of these phenotypes; (2) to investigate further how these features can clarify the observed penetrance patterns of CL/P in families; and (3) to perform candidate gene, genome-wide linkage, and genome-wide association studies to identify genes related to the extended phenotypic features. To reach these goals nuclear families, extended multiplex kindreds and twin pairs will be ascertained in Pittsburgh, St. Louis, Texas, and Denmark. All participants will be assessed for the following features: OO muscle anatomy by high-resolution ultrasound, dermatoglyphic lip and finger prints, craniofacial measurements from 3D images, handedness and other laterality traits, minor physical anomalies, and velopharyngeal competence via perceptual speech screening. SNPs in candidate genes (BMP4, IRF6) and regions (6q, 9q) will be genotyped, as will a dense genome-wide SNP panel, followed by statistical genetic analyses. Positive genetic findings will be followed by additional fine-mapping and/or mutational screens. PUBLIC HEALTH RELEVANCE: This project will identify physical features (phenotypes) associated with cleft lip and palate birth defects, and will identify genes related to these phenotypes. This knowledge will lead to improved genetic counseling in families with cleft lip and palate, and also will eventually lead to improved therapies for these very common birth defects.