Genetics of Craniofacial Disorders and Related Phenotypes

 描述(申请人提供)：口面部裂(OFCs)是人类最常见的头面部出生缺陷，由多种遗传和环境风险因素引起。阐明唇裂的病因不仅对我们的发育生物学知识和唇裂是如何发生的至关重要，而且最终对于改善口面部裂伤患者的预防、治疗和预后也是至关重要的。我们识别口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，如上唇口轮匝肌不连续，与对照组相比，在未受影响的家庭成员中普遍增加，这提供了证据，表明它们是与OFCS相关的表型范围的一部分。这个K99/R00应用程序的目标是使用亚临床表型来识别OFCs的遗传风险因素，并提高我们对它们在导致唇裂中的作用的理解。这个项目的总体假设是，亚临床表型是OFC风险因素最温和的表达，遗传风险因素将在亚临床表型个体和OFCS个体之间共享。这些假说将在三个特定的目标中进行测试：在目标1中，我将检查一对双胞胎中的亚临床表型和遗传变异，这些双胞胎与口裂不协调。在目标2中，我将在OFCS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，我将对患有OFCs和亚临床表型的家系进行外显子组测序。该项目的K99阶段将在玛丽·马拉齐塔博士(导师)和埃莉诺·范戈尔德博士(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经验丰富的顾问和外部顾问小组，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的是提供亚临床表型和统计遗传学方面的额外培训，以促进候选人发展为一名独立的颅面遗传学家，将深层遗传资源与详细的表型相结合，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.