CRANIOFACIAL AND GENETIC VARIATION IN 22Q11.2 DELETION SYNDROME

描述（由申请人提供）：本提案的目的是培养Carrie Heike博士成为一名独立的研究者，从事多学科儿科临床研究，以了解颅面畸形的病因。候选人建议获得Michael Cunningham博士、Karen Edwards博士和Mark Rieder博士（她的咨询委员会成员）的指导，以提高她表征22q11.2缺失综合征儿童颅面和基因序列变异的能力。染色体22q11.2缺失综合征（也称为心面快速综合征或VCFS）是一种基因组疾病，估计患病率为1:4000。虽然大多数22q11.2缺失综合征患者在22号染色体上都有3兆碱基缺失，但该综合征具有复杂且高度可变的表型表现，包括特征面部特征以及腭和口咽的解剖和功能异常。最近的工作旨在了解22q11.2缺失综合征的表型变异性，主要集中在心脏和精神表型上。我们将重点关注颅面特征。本提案中的四项相关研究旨在提供客观和具体的描述，以提高我们对22q11.2缺失儿童的遗传和颅面变异性的理解。我们将在可能改变颅面表型的途径中确定候选基因的遗传变异，即TBX1途径。我们还旨在通过使用人体测量和三维摄影测量结合耳和口腔异常的系统表征，对22q11.2缺失个体的颅面差异进行客观描述。最后，我们将与第二家机构的专家调查员一起调查我们测量的评估者之间的可靠性。这些目标的完成将为Heike博士提供必要的培训和初步数据，以设计一项足够有力的多中心表型-基因型关联研究，以确定22q11.2缺失个体的颅面特征与TBX1通路的遗传变异之间是否存在关系。颅面变异性和基因型之间的关系的论证将为这种基因组疾病的发病机制和普通人群面部特征的遗传控制提供额外的见解。

DESCRIPTION (provided by applicant): The purpose of this proposal is to cultivate the career development of Dr. Carrie Heike into an independent investigator performing multidisciplinary, pediatric clinical research to understand the etiologies of craniofacial malformations. The candidate proposes to obtain mentorship from Dr. Michael Cunningham, as well as Dr. Karen Edwards and Dr. Mark Rieder (members of her advisory committee) to develop skills that will enhance her ability to characterize the craniofacial and genetic sequence variation in children with 22q11.2 deletion syndrome. Chromosome 22q11.2 deletion syndrome (also known as Velocardiofacial syndrome or VCFS) is a genomic disorder with an estimated prevalence of 1:4000. Although most individuals with 22q11.2 deletion syndrome share a three megabase deletion on chromosome 22, this syndrome has complex and highly variable phenotypic presentation that can include characteristic facial features as well as anatomic and functional abnormalities of the palate and oropharynx. Recent work aimed at understanding the phenotypic variability in 22q11.2 deletion syndrome has primarily focused on the cardiac and psychiatric phenotypes. We will focus on the craniofacial features. The four interrelated studies in this proposal are designed to provide objective and specific descriptions to improve our understanding of the genetic and craniofacial variability in children with the 22q11.2 deletion. We will identify genetic variation in candidate genes in a pathway that likely modifies the craniofacial phenotype, the TBX1 pathway. We also aim to provide an objective description of craniofacial differences in individuals with the 22q11.2 deletion through the use of anthropometric measurements and three dimensional photogrammetry combined with systematic characterization of ear and oral anomalies. Finally, we will investigate the inter-rater reliability of our measurements with an expert investigator at a second institution. Completion of these aims will provide Dr. Heike with the necessary training and preliminary data for design of an adequately powered, multicenter phenotype-genotype association study to determine if there is a relationship between the craniofacial features and genetic variation in the TBX1 pathway in individuals with the 22q11.2 deletion. Demonstration of a relationship between the craniofacial variability and genotype will provide additional insight into the pathogenesis of this genomic disorder and genetic control of the facial features in the general population.