Pathogenesis, Phenotypic Variation, and Prevention of Craniofacial Anomalies - Project Summary Craniofacial anomalies account for about one-third of all birth defects and consequently are a major cause of infant mortality. To date over 700 distinct craniofacial syndromes having been described, and anomalies such as cleft lip and palate, micrognathia and craniosynostosis have serious lifetime functional, aesthetic and social consequences that are devastating to both children and parents alike. Comprehensive surgery together with well-coordinated and integrated dental care, psychological counselling and rehabilitation can help ameliorate and manage each condition. However, the results are often variable and rarely fully corrective, hence considerable effort needs to be invested in developing preventative therapies. This can only come from a thorough appreciation of the etiology and pathogenesis of individual craniofacial malformation syndromes, which is built upon a deep foundational knowledge and understanding of normal craniofacial development. Advances in genomics continues to elucidate the complex etiology underlying birth defects, but knowing the molecular genotype of a single locus is often insufficient for predicting the phenotype of many malformation syndromes. Furthermore, birth defect disorders are typically characterized by considerable phenotypic variance, often due to gene-environment interactions, but our understanding of environmental risk factors is poor, as biological and technical constraints have made defining gene-environment interactions in birth defect etiology challenging. Craniofacial morphogenesis is one example of a complex trait in which epistatic and gene-environment interactions likely contribute extensively to phenotypic variation during normal development and in the pathogenesis of craniofacial dysmorphology. However, while it has been posited that most craniofacial variation is genetically determined, a large gap in knowledge exists with respect to the contributions of environmental factors and genetic background in the pathogenesis of craniofacial anomalies. Focusing on the craniofacial disorder, Treacher Collins syndrome, this research proposal: (i) uncovers and validates specific gene-environment interactions which underlie the etiology and pathogenesis of anomalies of the head and face; (ii) identifies and validates genetic modifiers that contribute to inter-familial and intra-familial variability characteristic of craniofacial syndromes; and (iii) defines and validates in utero therapeutic approaches to prevent craniofacial anomalies.
