Genetics of Craniofacial Disorders and Related Phenotypes

颅面疾病的遗传学及相关表型

基本信息

批准号：
9011520
负责人：
ELIZABETH JANE LESLIE
金额：
$ 9.39万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9011520
关键词：
Accounting Address Affect Biological Candidate Disease Gene Cleaved cell 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 Health 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 Research Training 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 novel orofacial orofacial cleft outcome forecast personalized medicine rare variant repaired trait translational medicine

项目摘要

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（由申请人提供）：口面裂（OFC）是人类最常见的颅面出生缺陷，由多种遗传和环境风险因素引起，阐明裂口的病因不仅对于我们对发育生物学的了解以及如何进行研究至关重要。唇裂的出现，但最终是为了改善受口颌面裂影响的个体的预防、治疗和预后。我们用于识别口颌面遗传风险因素的创新方法。唇裂的目的是通过扩大表型谱以包括亚临床表型来提高检测关联的能力，这些亚临床表型，例如上唇口轮匝肌的不连续性，与对照组相比，在未受影响的家庭成员中通常有所增加，这提供了证据：它们是与 OFC 相关的表型范围的一部分。K99/R00 应用的目标是使用亚临床表型来识别遗传风险因素。该项目的总体假设是，亚临床表型是 OFC 风险因素的最温和表达，并且遗传风险因素将在具有亚临床表型的个体和具有 OFC 的个体之间共享。在三个特定目标中进行测试：在目标 1 中，我将检查一组口面部裂痕不一致的双胞胎的亚临床表型和遗传变异。在 OFC 和相关亚临床表型中进行候选基因关联研究在目标 3 中，我将在具有 OFC 和亚临床表型的家庭中进行外显子组测序，该项目的 K99 阶段将在 Mary 博士的指导下完成。 Marazita（导师）和 Eleanor Feingold 博士（共同导师）还组建了一支经验丰富的顾问和外部顾问团队，他们将提供必要的培训和支持来完成目标。拟议的研究，促进候选人的成长，并在向独立过渡期间提供指导拟议的培训和研究目标旨在提供亚临床表型分析和统计遗传学方面的额外培训，以促进候选人发展成为一名独立的颅面遗传学家，并融入深度学习。具有详细表型的遗传资源，用于研究复杂的颅面疾病。