Genetics of Craniofacial Disorders and Related Phenotypes

 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。阐明唇腭裂的病因不仅对我们了解发育生物学和唇腭裂是如何产生的至关重要，而且最终对改善受口面唇腭裂影响的个体的预防、治疗和预后至关重要。我们识别口面裂遗传风险因素的创新方法是通过扩大表型谱以包括亚临床表型来提高检测相关性的能力。这些亚临床表型，如上唇口轮匝肌的不连续性，与对照组相比，在未受影响的家族成员中通常增加，这提供了证据表明它们是与OFC相关的表型范围的一部分。这项K99/R 00应用的目标是利用亚临床表型来识别OFC的遗传风险因素，并提高我们对OFC在引起唇腭裂中作用的理解。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，并且具有亚临床表型的个体和具有OFC的个体之间将共享遗传风险因素。这些假设将在三个特定的目标进行测试：在目标1中，我将研究亚临床表型和遗传变异的双胞胎对谁是不和谐的口面裂队列。在目标2中，我将在OFC和相关的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和亚临床表型的家族中进行外显子组测序。该项目的K99阶段将在玛丽马拉齐塔博士（导师）和埃莉诺法因戈尔德博士（共同导师）的指导下在匹兹堡大学完成。候选人还组建了一个由顾问和外部顾问组成的成熟团队，他们将提供必要的培训和支持，以完成拟议的研究，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是量身定制的，以提供亚临床表型和统计遗传学方面的额外培训，以促进候选人作为独立的颅面遗传学家的发展，将深层遗传资源与详细的表型相结合，以研究复杂的颅面疾病。

 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.