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

The following data sets were generated

Article and author information

Author details

  1. Andrew T Timberlake

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8926-9692
  2. Jungmin Choi

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Samir Zaidi

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Qiongshi Lu

    Department of Biostatistics, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Carol Nelson-Williams

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Eric D Brooks

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kaya Bilguvar

    Department of Genetics, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Irina Tikhonova

    Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Shrikant Mane

    Department of Genetics, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jenny F Yang

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Rajendra Sawh-Martinez

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Sarah Persing

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Elizabeth G Zellner

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Erin Loring

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Carolyn Chuang

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Amy Galm

    Craniosynostosis and Positional Plagiocephaly Support, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Peter W Hashim

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Derek M Steinbacher

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Michael L DiLuna

    Department of Neurosurgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Charles C Duncan

    Department of Neurosurgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Kevin A Pelphrey

    Child Study Center, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Hongyu Zhao

    Department of Biostatistics, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. John A Persing

    Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Richard P Lifton

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    For correspondence
    richard.lifton@yale.edu
    Competing interests
    The authors declare that no competing interests exist.

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.

Metrics

  • 9,666
    views
  • 1,428
    downloads
  • 160
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Andrew T Timberlake
  2. Jungmin Choi
  3. Samir Zaidi
  4. Qiongshi Lu
  5. Carol Nelson-Williams
  6. Eric D Brooks
  7. Kaya Bilguvar
  8. Irina Tikhonova
  9. Shrikant Mane
  10. Jenny F Yang
  11. Rajendra Sawh-Martinez
  12. Sarah Persing
  13. Elizabeth G Zellner
  14. Erin Loring
  15. Carolyn Chuang
  16. Amy Galm
  17. Peter W Hashim
  18. Derek M Steinbacher
  19. Michael L DiLuna
  20. Charles C Duncan
  21. Kevin A Pelphrey
  22. Hongyu Zhao
  23. John A Persing
  24. Richard P Lifton
(2016)
Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles
eLife 5:e20125.
https://doi.org/10.7554/eLife.20125

Share this article

https://doi.org/10.7554/eLife.20125

Further reading

    1. Chromosomes and Gene Expression
    Ester Vazquez-Fernandez, Jing Yang ... David Barford
    Research Article

    The anaphase-promoting complex/cyclosome (APC/C) is a large multi-subunit E3 ubiquitin ligase that controls progression through the cell cycle by orchestrating the timely proteolysis of mitotic cyclins and other cell cycle regulatory proteins. Although structures of multiple human APC/C complexes have been extensively studied over the past decade, the Saccharomyces cerevisiae APC/C has been less extensively investigated. Here, we describe medium resolution structures of three S. cerevisiae APC/C complexes: unphosphorylated apo-APC/C and the ternary APC/CCDH1-substrate complex, and phosphorylated apo-APC/C. Whereas the overall architectures of human and S. cerevisiae APC/C are conserved, as well as the mechanism of CDH1 inhibition by CDK-phosphorylation, specific variations exist, including striking differences in the mechanism of coactivator-mediated stimulation of E2 binding, and the activation of APC/CCDC20 by phosphorylation. In contrast to human APC/C in which coactivator induces a conformational change of the catalytic module APC2:APC11 to allow E2 binding, in S. cerevisiae apo-APC/C the catalytic module is already positioned to bind E2. Furthermore, we find no evidence of a phospho-regulatable auto-inhibitory segment of APC1, that in the unphosphorylated human APC/C, sterically blocks the CDC20C-box binding site of APC8. Thus, although the functions of APC/C are conserved from S. cerevisiae to humans, molecular details relating to their regulatory mechanisms differ.

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Hasiba Asma, Ellen Tieke ... Marc S Halfon
    Tools and Resources

    Annotation of newly sequenced genomes frequently includes genes, but rarely covers important non-coding genomic features such as the cis-regulatory modules—e.g., enhancers and silencers—that regulate gene expression. Here, we begin to remedy this situation by developing a workflow for rapid initial annotation of insect regulatory sequences, and provide a searchable database resource with enhancer predictions for 33 genomes. Using our previously developed SCRMshaw computational enhancer prediction method, we predict over 2.8 million regulatory sequences along with the tissues where they are expected to be active, in a set of insect species ranging over 360 million years of evolution. Extensive analysis and validation of the data provides several lines of evidence suggesting that we achieve a high true-positive rate for enhancer prediction. One, we show that our predictions target specific loci, rather than random genomic locations. Two, we predict enhancers in orthologous loci across a diverged set of species to a significantly higher degree than random expectation would allow. Three, we demonstrate that our predictions are highly enriched for regions of accessible chromatin. Four, we achieve a validation rate in excess of 70% using in vivo reporter gene assays. As we continue to annotate both new tissues and new species, our regulatory annotation resource will provide a rich source of data for the research community and will have utility for both small-scale (single gene, single species) and large-scale (many genes, many species) studies of gene regulation. In particular, the ability to search for functionally related regulatory elements in orthologous loci should greatly facilitate studies of enhancer evolution even among distantly related species.