2. Academic Validation
  3. Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles

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

  • Elife. 2016 Sep 8;5:e20125. doi: 10.7554/eLife.20125.
Andrew T Timberlake 1 2 3,  Jungmin Choi 1 2,  Samir Zaidi 1 2,  Qiongshi Lu 4,  Carol Nelson-Williams 1 2,  Eric D Brooks 3,  Kaya Bilguvar 1 5,  Irina Tikhonova 5,  Shrikant Mane 1 5,  Jenny F Yang 3,  Rajendra Sawh-Martinez 3,  Sarah Persing 3,  Elizabeth G Zellner 3,  Erin Loring 1 2 5,  Carolyn Chuang 3,  Amy Galm 6,  Peter W Hashim 3,  Derek M Steinbacher 3,  Michael L DiLuna 7,  Charles C Duncan 7,  Kevin A Pelphrey 8,  Hongyu Zhao 4,  John A Persing 3,  Richard P Lifton 1 2 5 9
Affiliations

Affiliations

  • 1 Department of Genetics, Yale University School of Medicine, New Haven, United States.
  • 2 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
  • 3 Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
  • 4 Department of Biostatistics, Yale University School of Medicine, New Haven, United States.
  • 5 Yale Center for Genome Analysis, New Haven, United States.
  • 6 Craniosynostosis and Positional Plagiocephaly Support, New York, United States.
  • 7 Department of Neurosurgery, Yale University School of Medicine, New Haven, United States.
  • 8 Child Study Center, Yale University School of Medicine, New Haven, United States.
  • 9 The Rockefeller University, New York, United States.
PMID: 27606499 DOI: 10.7554/eLife.20125
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.

Keywords

BMP2; SMAD6; SMURF1; SPRY1; SPRY4; chromosomes; craniofacial; craniosynostosis; de novo mutation; evolutionary biology; exome sequencing; genes; genomics; human; human genetics; incomplete penetrance.

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