High Throughput Genotyping and DNA Sequencing for Studying the Genetic Contributions to Human Disease: Genetic Analysis of Metopic Nonsyndromic Craniosynostosis (Boyadjiev Boyd)

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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, its causes remain largely unknown. As such, primary prevention strategies for this defect are limited. Through our International Craniosynostosis Consortium (ICC), we have advanced the understanding of the genetic etiology for the most common NCS subtype, sagittal NCS (sNCS). As a result of our previous funding (R01 DE016866), we successfully conducted the first genome-wide association study (GWAS) for sNCS and identified robust associations to loci near BMP2 (rs1884302; P=1.1x10-39; OR=4.38) and intronic to BBS9 (rs10262453; P=5.6x10-20; OR=0.24), both biologically plausible genes with a role in skeletal development. Building on our work, we hypothesize that the identified variants contribute to the risk of NCS by altering gene expression. In this application we propose to investigate 400 case-parent trios with metopic NCS (mNCS) by GWAS. 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 independent case-control samples. Next generation sequencing and functional assays of candidate genes and loci identified in GWAS of mNCS will be conducted together with those for sNCS. In summary, the current proposal represents an extension of our current study aimed to perform a comprehensive molecular characterization of sNCS and mNCS. Given our accomplishments and substantial resources of the ICC and the previous collaboration with the Center for Disease Research (CIDR), we are well-positioned to successfully complete the proposed research and contribute critical insights into the multifactorial etiology of sNCS and mNCS.