CRANIOFACIAL AND GENETIC VARIATION IN 22Q11.2 DELETION SYNDROME

描述(由申请人提供)：本建议的目的是将Carrie Heike博士的职业发展培养成一名独立的调查员，进行多学科的儿科临床研究，以了解颅面畸形的病因。这位候选人建议从迈克尔·坎宁安博士、凯伦·爱德华兹博士和马克·里德博士(她的咨询委员会成员)那里获得指导，以发展技能，提高她描述22q11.2缺失综合征儿童头面部和基因序列变异的能力。染色体22q11.2缺失综合征(又称血管畸形综合征或VCFS)是一种基因组疾病，估计患病率为1：4000。虽然大多数22q11.2缺失综合征患者都有22号染色体上3兆碱基的缺失，但这种综合征具有复杂和高度可变的表型表现，包括特征性的面部特征以及腭部和口咽部的解剖和功能异常。最近旨在了解22q11.2缺失综合征表型变异的工作主要集中在心脏和精神表型上。我们将重点关注头面部特征。这项建议中的四项相互关联的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可变性的理解。我们将在可能改变头面部表型的一条可能改变头面部表型的途径--TBX1途径中识别候选基因的遗传变异。我们还旨在通过人体测量和三维摄影测量，结合耳和口腔畸形的系统特征，提供22q11.2缺失个体头面部差异的客观描述。最后，我们将与另一家机构的专家调查员一起调查我们的测量结果在评分者之间的可靠性。这些目标的完成将为Heike博士提供必要的培训和初步数据，以设计一项足够强大的多中心表型-基因关联研究，以确定22q11.2缺失个体的头面部特征与TBX1途径的遗传变异之间是否存在关系。颅面部变异性和基因之间关系的证明将为进一步了解这种基因组疾病的发病机制和普通人群中面部特征的遗传控制提供新的见解。

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.