Genetic Analysis of Metopic Nonsyndromic Craniosynostosis

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 investigated 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. For each subtype, evidence for multifactorial determinants is supported by increased recurrence risk in families, increased concordance in monozygotic vs. dizygotic twins, and positive associations with variants in selected genes (e.g., FGFR). Given these similarities, we hypothesize that sNCS and mNCS may share common causative variants. This data represents an extension of our current study aimed to perform a comprehensive molecular characterization of sNCS and mNCS.]]>
Craniosynostosis QuestionnairePhysical Examination FormOur discovery sample was comprised of 410 families, of which 262 were International Craniosynostosis Consortium (ICC) case-parent trios, 13 were ICC multiplex families, and 135 were National Birth Defects Prevention Study (NBDPS) case-parent trios. After removing trios where the proband had multiple-suture involvement and performing principal components analysis, a transmission disequilibrim test (TDT) was performed using 215 non-Hispanic white case-parent trios.Inclusion Criteria: Presence of metopic craniosynostosis confirmed by head CT, surgical reports, and/or clinical genetics evaluation. Exclusion Criteria: Identification of single gene recognizable craniosynostosis syndrome with known etiology (i.e. Apert syndrome, Crouzon syndrome)]]>
The studies of nonsyndromic craniosynostosis were initiated by Dr. Simeon Bojadjiev Boyd in 2000 and have been continuously funded with multiple grants through NIH-NIDCR. The International Craniosynostosis Consortium (ICC) was formed to create a clinical database and sample repository of well-characterized families with craniosynostosis. The ICC involves multiple investigators with special expertise and interests in craniosynostosis.]]>