Copy number variation analysis in single-suture craniosynostosis: Multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis

Heather C. Mefford, Neil Shafer, Francesca Antonacci, Jesse M. Tsai, Sarah S. Park, Anne V. Hing, Mark J. Rieder, Matthew D. Smyth, Matthew L. Speltz, Evan E. Eichler, Michael L. Cunningham

Research output: Contribution to journalArticle

60 Scopus citations

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 1.1Mb 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, wefind 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.

Original languageEnglish
Pages (from-to)2203-2210
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume152
Issue number9
DOIs
StatePublished - Sep 1 2010

Keywords

  • Array comparative genomic hybridization
  • Copy number variant
  • Craniosynostosis
  • RUNX2

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    Mefford, H. C., Shafer, N., Antonacci, F., Tsai, J. M., Park, S. S., Hing, A. V., Rieder, M. J., Smyth, M. D., Speltz, M. L., Eichler, E. E., & Cunningham, M. L. (2010). Copy number variation analysis in single-suture craniosynostosis: Multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis. American Journal of Medical Genetics, Part A, 152(9), 2203-2210. https://doi.org/10.1002/ajmg.a.33557