Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles

Andrew T. Timberlake, Jungmin Choi, Samir Zaidi, Qiongshi Lu, Carol Nelson-Williams, Eric D. Brooks, Kaya Bilguvar, Irina Tikhonova, Shrikant Mane, Jenny F. Yang, Rajendra Sawh-Martinez, Sarah Persing, Elizabeth G. Zellner, Erin Loring, Carolyn Chuang, Amy Galm, Peter W. Hashim, Derek M. Steinbacher, Michael L. DiLuna, Charles C. DuncanKevin A. Pelphrey, Hongyu Zhao, John A. Persing, Richard P. Lifton

Research output: Contribution to journalArticle

Abstract

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP - induced osteoblast differentiation (p<10-20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

Original languageEnglish (US)
Article numbere20125
JournaleLife
Volume5
Issue numberSeptember2016
DOIs
StatePublished - Sep 8 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Timberlake, A. T., Choi, J., Zaidi, S., Lu, Q., Nelson-Williams, C., Brooks, E. D., Bilguvar, K., Tikhonova, I., Mane, S., Yang, J. F., Sawh-Martinez, R., Persing, S., Zellner, E. G., Loring, E., Chuang, C., Galm, A., Hashim, P. W., Steinbacher, D. M., DiLuna, M. L., ... Lifton, R. P. (2016). Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles. eLife, 5(September2016), [e20125]. https://doi.org/10.7554/eLife.20125