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）：摘要口面裂 (OFC)，特别是伴或不伴腭裂的非综合征性唇裂 (NS CL/P) 是一个重大的公共卫生问题，全世界每 500-1000 名新生儿中就有一人受到影响。因此，许多研究小组试图确定导致 CL/P 病因的遗传位点，我们的研究小组和其他人最近取得了一些成功。看来，口面部裂病因的遗传贡献是复杂的，可能是异质的，并且可能是由于某些情况下多个基因座的相互作用造成的。 目前的提案是拨款#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或 CL/P 基因的额外表达的扩展表型特征。我们成功完成了以下具体目标：(1) 对来自匹兹堡和圣路易斯的家族进行确定和表型分析，(2) 识别多重 CL/P 家族受影响和未受影响成员的内表型，特别是口轮匝肌（OO：上唇）肌肉缺陷和唇纹螺纹； (3) 识别内表型的候选基因（用于 OO 缺陷的 BMP4 和用于唇印螺纹的 IRF6），(4) 对 CL/P 和内表型进行其他遗传分析。现在我们已经有充分的证据证明这些表型特征在多重 CL/P 家族中的重要性，这一竞争性延续的主要目标是 (1) 研究一般 NS CL/P 家族（即单纯型和多重型，以及其他种族）中的这些特征，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阐明观察到的 CL/P 在家庭中的外显率模式； (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、大家庭和双胞胎。所有参与者都将接受以下特征评估：通过高分辨率超声进行的 OO 肌肉解剖结构、唇纹和指纹、3D 图像的颅面测量、用手习惯和其他侧向特征、轻微的身体异常以及通过感知言语筛查进行的腭咽能力。候选基因（BMP4、IRF6）和区域（6q、9q）中的 SNP 以及密集的全基因组 SNP 组合将进行基因分型，然后进行统计遗传分析。阳性基因发现之后将进行额外的精细定位和/或突变筛选。公共健康相关性：该项目将识别与唇裂和腭裂出生缺陷相关的身体特征（表型），并将识别与这些表型相关的基因。这些知识将改善唇裂和腭裂家庭的遗传咨询，并最终改善这些非常常见的出生缺陷的治疗方法。