1. Chromosomes and Gene Expression
  2. Genetics and Genomics
Download icon

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

  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  Is a corresponding author
  1. Howard Hughes Medical Institute, Yale University School of Medicine, United States
  2. Yale University School of Medicine, United States
  3. Craniosynostosis and Positional Plagiocephaly Support, United States
Research Article
  • Cited 62
  • Views 7,382
  • Annotations
Cite this article as: eLife 2016;5:e20125 doi: 10.7554/eLife.20125

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.

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.

Reviewing Editor

  1. David Ginsburg, Howard Hughes Medical Institute, University of Michigan, United States

Publication history

  1. Received: July 28, 2016
  2. Accepted: August 30, 2016
  3. Accepted Manuscript published: September 8, 2016 (version 1)
  4. Accepted Manuscript updated: September 9, 2016 (version 2)
  5. Version of Record published: September 30, 2016 (version 3)
  6. Version of Record updated: October 26, 2016 (version 4)

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

  • 7,382
    Page views
  • 1,197
    Downloads
  • 62
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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)

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

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

  1. Further reading

Further reading

    1. Chromosomes and Gene Expression
    2. Immunology and Inflammation
    Kevin W Ng et al.
    Research Article
    1. Chromosomes and Gene Expression
    2. Microbiology and Infectious Disease
    Arunava Roy et al.
    Research Article Updated