Extending the Phenotype of Nonsyndromic Orofacial Clefts

扩展非综合征性口面裂的表型

• 批准号: 7909897
• 负责人: Mary L. Marazita
• 金额: $ 30.53万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909897
• 关键词: Affect; Anatomy; BMP4; Birth; Candidate Disease Gene; Cleaved cell; Clinic; Clinical; Collaborations; Competence; Complex; Congenital Abnormality; Defect; Denmark; Dermatoglyphics; Development; Ethnic Origin; Etiology; Extended Family; Face; Family; Family Study; Family member; Fingers; Funding; Gender; Genes; Genetic; Genetic Counseling; Genome; Genome Scan; Genomics; Genotype; Goals; Grant; Hand; Handedness; Incidence; Individual; Knowledge; Lead; Lip structure; Maps; Measurement; Microforms; Minor; Modeling; Muscle; Mutation; Nuclear Family; Oral; Other Genetics; Participant; Pattern; Penetrance; Phenotype; Population; Printing; Probability; Progress Reports; Public Health; Recurrence; Relative (related person); Research; Resolution; Risk; SNP genotyping; Screening procedure; Series; Specificity; Speech; Testing; Texas; Text; Three-Dimensional Image; Twin Multiple Birth; Ultrasonography; Universities; abstracting; base; candidate marker; cleft lip and palate; clinically relevant; craniofacial; endophenotype; genetic analysis; genome wide association study; genome-wide; genome-wide linkage; improved; kindred; member; nonsyndromic cleft lip with or without cleft palate; orofacial; public health relevance; segregation; success; trait

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.

描述（由申请人提供）：抽象的口面裂口（OFC），尤其是有或不带有裂口裂（NS Cl/p）的非杂质裂唇唇（NS CL/P）是一个主要的公共卫生问题，在全球每500-1000个出生中都会影响一个。因此，许多研究小组试图识别有助于Cl/P的病因的遗传基因座，而我们的研究小组和其他人最近取得了一些成功。看来对口腔裂裂病因的遗传学贡献很复杂，可能是异质的，并且可能是由于多个基因座在某些情况下的相互作用。 当前的提案是拨款1-R01-DE016148的竞争延续，其目标是识别代表Cl/P基因的亚临床表型表现的扩展表型特征或Cl/P基因的其他表达。我们成功地完成了（1）确定和表型家族的具体目标，（2）识别内型型，尤其是Orbicularis Oris（OO：上唇）肌肉缺陷和肌肉缺陷和唇部构成多发性CL/P家族的受影响和未受影响的成员； （3）鉴定候选基因的候选基因（用于OO缺陷的BMP4和唇部印刷螺纹的IRF6），（4）进行CL/P和末日型的其他遗传分析。既然我们有很好的证据证明了这些表型特征在多重Cl/p家族中的重要性，那么（1）在一般NS Cl/p家族（即单纯形和多重种族中，以及其他种族）中调查这些特征的主要目标是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阐明家庭中CL/P的外观模式； （3）执行候选基因，全基因组联系和全基因组关联研究，以鉴定与扩展表型特征有关的基因。为了实现这些目标核心家庭，将在匹兹堡，圣路易斯，德克萨斯州和丹麦确定扩展的多重亲戚和双子双对。将对所有参与者进行以下特征进行评估：高分辨率超声，皮肤玻璃唇部和指纹的OO肌肉解剖结构，3D图像中的颅面测量，手工和其他横向性状，较小的物理异常，以及通过感知语音筛查的速溶性能力。候选基因中的SNP（BMP4，IRF6）和区域（6Q，9Q）将被基因分型，遍布较密集的基因组SNP面板，然后进行统计遗传分析。阳性遗传发现将遵循其他细微映射和/或突变筛选。公共卫生相关性：该项目将识别与唇裂和唇唇出生缺陷相关的物理特征（表型），并将识别与这些表型相关的基因。这些知识将导致唇裂和口感的家庭改善遗传咨询，并最终导致改善这些非常常见的先天缺陷的疗法。