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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Mentored Patient-Oriented Research Career Development Award (K23)
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NIDCR Special Grants Review Committee (DSR)
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Hardwick, Kevin S
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Seattle Children's Hospital
United States
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Heike, Carrie L; Stueckle, Laura P; Stuhaug, Erik T et al. (2011) Photographic protocol for image acquisition in craniofacial microsomia. Head Face Med 7:25
Heike, Carrie L; Starr, Jacqueline R; Rieder, Mark J et al. (2010) Single nucleotide polymorphism discovery in TBX1 in individuals with and without 22q11.2 deletion syndrome. Birth Defects Res A Clin Mol Teratol 88:54-63
Heike, Carrie L; Upson, Kristen; Stuhaug, Erik et al. (2010) 3D digital stereophotogrammetry: a practical guide to facial image acquisition. Head Face Med 6:18
Atmosukarto, Indriyati; Shapiro, Linda G; Heike, Carrie (2010) The Use of Genetic Programming for Learning 3D Craniofacial Shape Quantifications. Proc IAPR Int Conf Pattern Recogn 2010:2444-2447
Atmosukarto, I; Shapiro, L G; Starr, J R et al. (2010) Three-dimensional head shape quantification for infants with and without deformational plagiocephaly. Cleft Palate Craniofac J 47:368-77
Shapiro, Linda; Wilamowska, Katarzyna; Atmosukarto, Indriyati et al. (2009) Shape-Based Classification of 3D Head Data. Proc Int Conf Image Anal Process 5716:692-700
Heike, Carrie L; Cunningham, Michael L; Hing, Anne V et al. (2009) Picture perfect? Reliability of craniofacial anthropometry using three-dimensional digital stereophotogrammetry. Plast Reconstr Surg 124:1261-72
Wu, Jia; Wilamowska, Katarzyna; Shapiro, Linda et al. (2009) Automatic analysis of local nasal features in 22q11.2DS affected individuals. Conf Proc IEEE Eng Med Biol Soc 2009:3597-600