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 journalArticlepeer-review

150 Citations (Scopus)


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
Article numbere20125
Issue numberSeptember2016
Publication statusPublished - 2016 Sept 8
Externally publishedYes

Bibliographical note

Publisher Copyright:
© Timberlake et al.

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology


Dive into the research topics of 'Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles'. Together they form a unique fingerprint.

Cite this