Craniosynostosis (CS) is a common malformation occurring in ~4 per 10,000 live births in which the sutures close too early, causing long-term problems with normal brain and skull growth. Infants with CS typically require extensive surgical treatment and may experience many perioperative complications, including hemorrhage and re-synostosis. Even with successful surgery, children can experience developmental and learning disabilities or vision problems. Most often, CS appears as isolated nonsyndromic CS (NSC). Unilateral or bilateral fusion of the coronal suture is the second most common form of CS accounting for 20-30% of all NSC cases. The etiology of coronal NSC (cNSC) is not well understood, although the published literature suggests that it is a multifactorial condition. About 5-14% of coronal craniosynostosis patients have a positive family history, with a specific genetic etiology identified in >25% of cNSC cases - the largest proportion among any NSC cases, suggesting a strong genetic component in this birth defect pathogenesis. The causes for NSC and its phenotypic heterogeneity remain largely unknown. In the first and only genome-wide association study of NSC, our group identified two regions, downstream of BMP2 and within BBS9, associated with a 4-5 fold increased risk of sagittal NSC. While both BMP2 and BBS9 are genes with a role in skeletal development, only the BMP2 locus was borderline significant in coronal cases, suggesting that synostosis of each suture represents a different disease caused by different sets of genes. Therefore, we will collaborate with multiple sites to establish the largest collection of cNSC cases to date in order to identify biological pathways contributing to common forms of cNSC. We hypothesize that genetic variation explains a significant portion of cNSC risk.
Our specific aims are to: 1) Detect novel functional variants associated with cNSC. We will perform whole exome sequencing of 50 cases with the most severe disease manifestation and impute these data in all un-sequenced individuals;2) Conduct the first genome-wide screening of several millions common and low frequency variants using ~850 trios with no known mutations to identify genetic loci over-transmitted to children with cNSC;3) Perform validation studies to replicate the top genetic signals using an independent cohort of ~850 cNSC cases and controls, and 4) Perform imaging studies to examine morphometric patterns associated with the genetic risk burden and functional studies to determine functional consequences of the most promising genetic mutations. Synergy: specific parameters characterizing severity of craniofacial phenotypes in mice in Project I will inform morphometric analyses of human CS. The promising variants associated with cNSC will be incorporated into the network analysis and validated using functional assays in Project III. Identification of susceptibility genes will be the first step toward understanding the biological mechanisms of cNSC that may suggest novel postnatal therapeutics that in addition to surgery can provide a better result and prevent re- stenosis.