Craniosynostosis is the pathologic fusion of the calvaria. Over the past ten years significant advances have been made in our understanding of multiple malformation syndromes that involve craniosynostosis. It has been shown that mutations in the fibroblast growth factor receptors (FGFR1-3), TWIST1, MSX2, and the EFNB1 each cause craniosynostosis syndrome in humans. This extensive body of work, carried out in several international laboratories, has significantly impacted how we diagnose and counsel families with syndromic craniosynostosis. Despite the rapid growth of knowledge regarding syndromic forms, the causes of isolated synostosis remain elusive. Though vastly more common than syndromic forms, relatively little research has focused on the molecular pathogenesis of isolated craniosynostosis. The frequency of this group of calvarial malformations, the need for complex surgical management and its associated morbidity make isolated craniosynostosis a candidate for intense scientific investigation. We propose the use of three approaches to identify and characterize candidate genetic causes of isolated craniosynostosis: high throughput genomic sequencing, large-scale microarray expression analysis, and developmental gene expression. We have used knowledge gained from the investigation of normal calvarial development and syndromic forms of craniosynostosis to develop two interrelated hypotheses: (A) Rare sequence variants in two classes of genes result in isolated craniosynostosis: those that regulate suture development and those that, when mutated, cause syndromic craniosynostosis;and (B) Genetic pathways involved in cranial suture development and those impacted in the syndromic craniosynostoses are similarly affected in isolated, non-syndromic craniosynostosis. In this proposal, we describe a series of experiments designed to discover potential molecular causes of isolated craniosynostosis through the identification of rare genetic variants, altered calvarial osteoblast gene expression, and the temporal and spatial expression of candidate genes. The expertise of our research team and the availability of complementary high throughput approaches has allowed for the development of a comprehensive investigation of the genetic and developmental pathogenesis of isolated craniosynostosis.
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