title: Copy number variation analysis in single-suture craniosynostosis: multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis.
abstract: Little is known about genes that underlie isolated single-suture craniosynostosis. In this study, we hypothesize that rare copy number variants (CNV) in patients with isolated single-suture craniosynostosis contain genes important for cranial development. Using whole genome array comparative genomic hybridization (CGH), we evaluated DNA from 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications. We identified a 1.1 Mb duplication encompassing RUNX2 in two affected cousins with metopic synostosis and hypodontia. Given that RUNX2 is required as a master switch for osteoblast differentiation and interacts with TWIST1, mutations in which also cause craniosynostosis, we conclude that the duplication in this family is pathogenic, albeit with reduced penetrance. In addition, we find that a total of 7.5% of individuals with single-suture synostosis in our series have at least one rare deletion or duplication that contains genes and that has not been previously reported in unaffected individuals. The genes within and disrupted by CNVs in this cohort are potential novel candidate genes for craniosynostosis.
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. hmefford@uw.edu
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.forename: Neil
authors.initials: N
authors.lastname: Shafer
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonacci
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Tsai
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Park
authors.forename: Anne V
authors.initials: AV
authors.lastname: Hing
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Smyth
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Speltz
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
mesh_terms: D055028:Comparative Genomic Hybridization; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D003398:Craniosynostoses / Q000235:genetics*; D005190:Family; D018628:Gene Dosage / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D011446:Prospective Studies
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human