Genetics of Craniofacial Disorders and Related Phenotypes

颅面疾病的遗传学及相关表型

• 批准号: 9559944
• 负责人: ELIZABETH JANE LESLIE
• 金额: $ 19.87万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-10 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9559944
• 关键词: Accounting; Address; Affect; Biological; Candidate Disease Gene; Cleft Lip; Cleft Palate; Code; Complex; Congenital Abnormality; Craniofacial Abnormalities; Custom; Data; Development; Developmental Biology; Developmental Process; Disease; Dizygotic Twins; Environmental Risk Factor; Etiology; Failure; Family; Family member; Frequencies; Genes; Genetic; Genetic Enhancer Element; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genotype; Goals; Growth; Hearing; Heritability; Human; Human Genetics; Individual; Intervention; Knowledge; Lead; Lip structure; Medical; Mentors; Monozygotic twins; Morphology; Mus; Muscle; Orthodontic; Patients; Penetrance; Phase; Phenotype; Prevention; Recurrence; Regulatory Element; Research; Research Project Grants; Risk; Risk Factors; Role; Siblings; Speech; Targeted Resequencing; Technology; Testing; Training; Training Support; Treatment/Psychosocial Effects; Twin Multiple Birth; Universities; Untranslated RNA; Variant; Work; cancer type; cohort; craniofacial; craniofacial complex; craniofacial development; dental surgery; exome sequencing; experience; genetic resource; genetic risk factor; genetic variant; genome wide association study; high risk; improved; innovation; insight; life time cost; mortality; mouse model; next generation sequencing; nonsyndromic cleft lip with or without cleft palate; novel; orofacial; orofacial cleft; outcome forecast; personalized medicine; public health relevance; rare variant; repaired; trait; translational medicine; Accounting; Address; Affect; Biological; Candidate Disease Gene; Cleft Lip; Cleft Palate; Code; Complex; Congenital Abnormality; Craniofacial Abnormalities; Custom; Data; Development; Developmental Biology; Developmental Process; Disease; Dizygotic Twins; Environmental Risk Factor; Etiology; Failure; Family; Family member; Frequencies; Genes; Genetic; Genetic Enhancer Element; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genotype; Goals; Growth; Hearing; Heritability; Human; Human Genetics; Individual; Intervention; Knowledge; Lead; Lip structure; Medical; Mentors; Monozygotic twins; Morphology; Mus; Muscle; Orthodontic; Patients; Penetrance; Phase; Phenotype; Prevention; Recurrence; Regulatory Element; Research; Research Project Grants; Risk; Risk Factors; Role; Siblings; Speech; Targeted Resequencing; Technology; Testing; Training; Training Support; Treatment/Psychosocial Effects; Twin Multiple Birth; Universities; Untranslated RNA; Variant; Work; cancer type; cohort; craniofacial; craniofacial complex; craniofacial development; dental surgery; exome sequencing; experience; genetic resource; genetic risk factor; genetic variant; genome wide association study; high risk; improved; innovation; insight; life time cost; mortality; mouse model; next generation sequencing; nonsyndromic cleft lip with or without cleft palate; novel; orofacial; orofacial cleft; outcome forecast; personalized medicine; public health relevance; rare variant; repaired; trait; translational medicine

 DESCRIPTION (provided by applicant): Orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and are caused by multiple genetic and environmental risk factors. Elucidating the etiologies of clefting is critical not only for our knowledge of developmental biology and for how clefts arise, but ultimately for improved prevention, treatment, and prognosis for individuals affected by orofacial clefting. Our innovative approach for identifying genetic risk factors for orofacial clefts is to improve the power to detect associations by expanding the phenotypic spectrum to include subclinical phenotypes. These subclinical phenotypes, such as discontinuities of the orbicularis oris muscle of the upper lip, ar generally increased in unaffected family members compared to controls, providing evidence that they are part of the range of phenotypes associated with OFCs. The goal of this K99/R00 application is to use subclinical phenotypes to identify genetic risk factors for OFCs and improve our understanding of their role in causing clefts. The overall hypothesis for this project is that subclinical phenotypes are the mildest expression of OFC risk factors and genetic risk factors will be shared between individuals with subclinical phenotypes and individuals with OFCs. These hypotheses will be tested in three specific aims: In Aim 1, I will examine subclinical phenotypes and genetic variants in a cohort of twin pairs who are discordant for orofacial clefts. In Aim 2 I will conduct candidate gene association studies in OFCs and related subclinical phenotypes. In Aim 3, I will perform exome sequencing in families with OFCs and subclinical phenotypes. The K99 phase of this project will be completed at the University of Pittsburgh under the guidance of Dr. Mary Marazita (mentor) and Dr. Eleanor Feingold (co-mentor). The Candidate has also assembled an accomplished group of consultants and external advisors who will provide the necessary training and support to accomplish the proposed research, facilitate the growth of the Candidate, and provide guidance during the transition to independence. The proposed training and research aims are tailored to provide additional training in subclinical phentoyping and statistical genetics to facilitate the Candidate's development as an independent craniofacial geneticist who integrates deep genetic resources with detailed phenotyping to study complex craniofacial disorders.

 描述（应用程序提供）：Orofacic裂口（OFC）是人类中最常见的颅面出生缺陷，是由多种遗传和环境危险因素引起的。阐明裂纹的病因不仅至关重要，这对于我们对发育生物学的了解和裂口的产生方式至关重要，而且最终对于受到面fe裂影响的个体的预防，治疗和预后的改善至关重要。我们鉴定出种族裂缝的遗传危险因素的创新方法是通过扩展表型频谱来提高检测关联的能力，以包括亚临床表型。与对照组相比，这些亚临床表型，例如上唇的轨道肌的不连续性，在未受影响的家庭成员中通常会增加，这证明它们是与OFC相关的表型的一部分。该K99/R00应用的目的是使用亚临床表型来确定OFC的遗传危险因素，并提高我们对它们在引起裂口中的作用的理解。该项目的总体假设是亚临床表型是C危险因素的最温和表达，遗传危险因素将在具有亚临床表型和OFC的个体之间共享。这些假设将以三个特定的目的进行测试：在AIM 1中，我将检查亚临床表型和遗传变异，这是一组双胞胎对，这些双胞胎对，这些双胞胎对不一致。在AIM 2中，我将在OFC和相关亚临床表型中进行候选基因关联研究。在AIM 3中，我将在OFC和亚临床表型的家族中进行外显子组测序。该项目的K99阶段将在匹兹堡大学的玛丽·马拉齐塔（Mary Marazita）博士（导师）和埃莉诺·费奥德（Eleanor Feingold）（Co-Incortor）的指导下完成。候选人还组建了一群成就良好的顾问和外部顾问，他们将提供必要的培训和支持，以完成拟议的研究，支持候选人的成长，并在过渡到独立性期间提供指导。拟议的培训和研究目标是针对亚临床临床和统计遗传学提供的额外培训，以促进候选人作为独立的颅面遗传学家的发展，他们将深层遗传资源与详细的表型结合起来，以研究复杂的颅面疾病。