CRANIOFACIAL AND GENETIC VARIATION IN 22Q11.2 DELETION SYNDROME

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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.