Two locus inheritance of non-syndromic midline craniosynostosis via rareSMAD6and commonBMP2alleles.
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 inSMAD6, an inhibitor of BMP - induced osteoblast differentiation (p<10-20).SMAD6mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant nearBMP2that 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.
Department of Genetics, Yale University School of Medicine, New Haven, United States.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.|Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Andrew T
http://orcid.org/0000-0002-8926-9692
AT
Timberlake
Department of Genetics, Yale University School of Medicine, New Haven, United States.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
Jungmin
J
Choi
Department of Genetics, Yale University School of Medicine, New Haven, United States.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
Samir
S
Zaidi
Department of Biostatistics, Yale University School of Medicine, New Haven, United States.
Qiongshi
Q
Lu
Department of Genetics, Yale University School of Medicine, New Haven, United States.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
Carol
C
Nelson-Williams
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Eric D
ED
Brooks
Department of Genetics, Yale University School of Medicine, New Haven, United States.|Yale Center for Genome Analysis, New Haven, United States.
Kaya
K
Bilguvar
Yale Center for Genome Analysis, New Haven, United States.
Irina
I
Tikhonova
Department of Genetics, Yale University School of Medicine, New Haven, United States.|Yale Center for Genome Analysis, New Haven, United States.
Shrikant
S
Mane
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Jenny F
JF
Yang
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Rajendra
R
Sawh-Martinez
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Sarah
S
Persing
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Elizabeth G
EG
Zellner
Department of Genetics, Yale University School of Medicine, New Haven, United States.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.|Yale Center for Genome Analysis, New Haven, United States.
Erin
E
Loring
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Carolyn
C
Chuang
Craniosynostosis and Positional Plagiocephaly Support, New York, United States.
Amy
A
Galm
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Peter W
PW
Hashim
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
Derek M
DM
Steinbacher
Department of Neurosurgery, Yale University School of Medicine, New Haven, United States.
Michael L
ML
DiLuna
Department of Neurosurgery, Yale University School of Medicine, New Haven, United States.
Charles C
CC
Duncan
Child Study Center, Yale University School of Medicine, New Haven, United States.
Kevin A
KA
Pelphrey
Department of Biostatistics, Yale University School of Medicine, New Haven, United States.
Hongyu
H
Zhao
Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, United States.
John A
JA
Persing
Department of Genetics, Yale University School of Medicine, New Haven, United States.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.|Yale Center for Genome Analysis, New Haven, United States.|The Rockefeller University, New York, United States.
Richard P
RP
Lifton
D000483:Alleles; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D003398:Craniosynostoses / Q000235:genetics*; D059472:Exome; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D009154:Mutation; D019683:Penetrance; D017422:Sequence Analysis, DNA; D051905:Smad6 Protein / Q000235:genetics*
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C497802:SMAD6 protein, human; D051905:Smad6 Protein
BMP2; SMAD6; SMURF1; SPRY1; SPRY4; chromosomes; craniofacial; craniosynostosis; de novo mutation; evolutionary biology; exome sequencing; genes; genomics; human; human genetics; incomplete penetrance