Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles
- Howard Hughes Medical Institute, Yale University School of Medicine, United States
- Yale University School of Medicine, United States
- Craniosynostosis and Positional Plagiocephaly Support, United States
Abstract
Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2,000 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.
Data availability
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Yale Center for Mendelian GenomicsPublicly available at the dbGaP (accession no: phs000744).
Article and author information
Author details
Andrew T Timberlake
Funding
Yale Center for Mendelian Genomics (NIH M#UM1HG006504-05)
- Kaya Bilguvar
- Irina Tikhonova
- Shrikant Mane
Maxillofacial Surgeons Foundation/ASMS (M#M156301)
- Eric D Brooks
- John A Persing
NIH Medical Scientist Training Program (NIH/NIGMS T32GM007205)
- Andrew T Timberlake
- Samir Zaidi
Howard Hughes Medical Institute
- Andrew T Timberlake
- Jungmin Choi
- Samir Zaidi
- Carol Nelson-Williams
- Erin Loring
- Richard P Lifton
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: All participants or their parents provided written informed consent to participate in a study of genetic causes of craniosynostosis in their family. Written consent was obtained for publication of patient photographs. The study protocol was approved by the Yale Human Investigation Committee Institutional Review Board.
Copyright
© 2016, Timberlake et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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