Extending the Phenotype of Nonsyndromic Orofacial Clefts

描述（由申请人提供）：摘要口面裂（OFC），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，影响全世界每500-1000名新生儿中的一个。因此，许多研究小组都试图确定导致CL/P病因的遗传位点，我们的研究小组和其他研究小组最近取得了一些成功。看来遗传因素对口面裂的病因学的贡献是复杂的，可能是异质性的，并且可能是由于在某些情况下多个位点的相互作用。 当前提案是资助#1-R 01-DE 016148的竞争性延续，其目标是鉴定代表CL/P基因亚临床表型表现或CL/P基因额外表达的扩展表型特征。我们成功地完成了以下特定目标：（1）确定匹兹堡和圣路易斯的家族并进行表型分析，（2）确定内表型，特别是口轮匝肌（OO：上唇）肌肉缺陷和唇纹涡在多重CL/P家族的受影响和未受影响的成员;（3）鉴定内表型的候选基因（OO缺陷的BMP 4和唇纹螺纹的IRF 6），（4）进行CL/P和内表型的其他遗传分析。既然我们有很好的证据证明这些表型特征在多重CL/P家族中的重要性，这种竞争性延续的主要目标是（1）在一般NS CL/P家族中研究这些特征（即，（2）进一步研究这些特征如何阐明在家族中观察到的CL/P的多态性模式;（3）进行候选基因、全基因组连锁和全基因组关联研究，以鉴定与扩展表型特征相关的基因。为了达到这些目标，在匹兹堡、圣路易斯、得克萨斯和丹麦将确定核心家庭、扩展的多重基因组和双胞胎对。所有参与者将评估以下特征：通过高分辨率超声进行OO肌肉解剖，皮纹唇和指纹，来自3D图像的颅面测量，惯用手和其他偏侧特征，轻微的身体异常，以及通过感知语音筛选进行的咽功能。将对候选基因（BMP 4、IRF 6）和区域（6 q、9 q）中的SNP进行基因分型，以及密集的全基因组SNP组，然后进行统计遗传分析。阳性遗传结果之后将进行额外的精细定位和/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物理特征（表型），并将确定与这些表型相关的基因。这些知识将导致改善唇腭裂家庭的遗传咨询，并最终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.