Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a common defect occurring in 1 in 2,500 live births. About 85% of infants with CS present as nonsyndromic (i.e., without unrelated, major birth defects or developmental delay). Nonsyndromic CS (NCS) is a heterogeneous condition with presumed multifactorial etiology; however, after nearly one-half century of study, its causes remain largely unknown. As such, primary prevention strategies for this defect are limited. Through our International Craniosynostosis Consortium (ICC), we have advanced understanding of the genetic etiology for the most common CS subtype, sagittal NCS (sNCS). Specifically, with our previous funding (R01 DE016866), we successfully conducted the first genome-wide association study for sNCS and identified robust associations to loci near BMP2 (rs1884302; P=1.1x10-39; OR=4.38) and within BBS9 (rs10262453; P=5.6x10-20; OR=0.24), both biologically plausible genes with a role in skeletal development. Building on our work, we propose to use a scaffold approach, moving from this discovery to confirmation through sequencing and functional assays; putative causative variants identified will be further characterized using zebrafish and mouse models. We hypothesize that identified variants contribute to the risk of sNCS by altering gene expression. Using the ICC infrastructure, we also propose to investigate metopic NCS (mNCS). Both sNCS and mNCS affect the midline sutures of the skull, are more likely to occur among non-Hispanic whites, and show a male excess. Given these similarities, we hypothesize that sNCS and mNCS may share common causative variants, and propose an array-based family study of mNCS case-parent trios and replication with an independent case-control sample; sequencing and functional assays of candidate genes and loci will be conducted together with those for sNCS. Subsequently, we propose to move from confirmation to interaction with environmental exposures, the apex of our scaffold approach. We will investigate environmental exposures and gene-environmental interaction effects associated with each subtype using maternal reports of pregnancy exposures obtained from the ICC and maternal reports and biological specimens obtained from the National Birth Defects Prevention Study (NBDPS). The NBDPS is the largest case-control study of birth defects in the United States. It uses population- based surveillance and systematic case review and classification to enumerate infants with one of over 30 major defects, including NCS. The NBDPS provides a rich resource to investigate environmental exposures and gene-environmental interaction effects. In summary, we propose comprehensive clinical, epidemiological, and molecular characterization of sNCS and mNCS through the collaborative efforts of clinicians and scientists with demonstrated expertise and long-standing interests in NCS. Given our accomplishments and substantial resources of the ICC and NBDPS, we are well-positioned to successfully complete the proposed research and contribute critical insights into the multifactorial etiology of sNCS and mNCS.
The International Craniosynostosis Consortium in collaboration with the National Birth Defects Prevention Study will extend and expand its leadership role in the investigation of genetic and environmental factors for nonsyndromic craniosynostosis (NCS). This research will provide important insights into our understanding of factors to help reduce the occurrence of NCS. Findings will be shared with other scientists and with professionals developing appropriate prevention interventions and resources for families affected by NCS.
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