Plastic Surgery Research Council
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Two Locus Inheritance Of Non-syndromic Midline Craniosynostosis Via Rare SMAD6 And Common BMP2 Alleles
Andrew T. Timberlake, B.S.1, Jungmin Choi, Ph.D1, Samir Zaidi, M.D., Ph.D.1, Qiongshi Lu, B.A.1, Carol Nelson-Williams, B.S.1, Eric D. Brooks, M.D.1, Kaya Bilguvar, M.D.1, Irina Tikhonova, B.S.1, Shrikant Mane, Ph.D.1, Jenny F. Yang, M.D.1, Rajendra Sawh-Martinez, M.D.1, Sarah Persing, M.D.1, Elizabeth G. Zellner, M.D.1, Erin Loring, M.S.1, Carolyn Chuang, B.S.1, Amy Galm, B.A.2, Peter W. Hashim, M.D.1, Derek Steinbacher, D.M.D., M.D.1, Michael L. DiLuna, M.D.1, Charles C. Duncan, M.D.1, Kevin A. Pelphrey, Ph.D.1, Hongyu Zhao, Ph.D.1, John A. Persing, M.D.1, Richard P. Lifton, M.D., Ph.D.3.
1Yale University School of Medicine, New Haven, CT, USA, 2Craniosynostosis and Plagiocephaly Support, New York, NY, USA, 3The Rockefeller University, New York, NY, USA.

PURPOSE: Non-syndromic sagittal and/or metopic craniosynostosis, occurring once in every 4,000 live births, accounts for half of all craniosynostosis cases. Despite success in identifying the genes underlying rare syndromic craniosynostoses, mutations in these genes are very rarely found in their non-syndromic counterparts. We considered that the often sporadic occurrence of non-syndromic craniosynostosis might frequently be attributable to de novo mutation or incomplete penetrance of rare transmitted variants.
METHODS: 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.
RESULTS: 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. A de novo mutation in SMURF1, a SMAD6 binding partner, was also identified.
CONCLUSION: 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.
Risk of craniosynostosis in SMAD6 mutation carriers in the presence or absence of a BMP2 risk allele
SMAD6/BMP2 Genotypes Craniosynostosis (+) Craniosynostosis (-)
SMAD6 (+) / BMP2 risk allele (+) 14 0
SMAD6 (+) / BMP2 risk allele (-) 3 13
SMAD6 (-) / BMP2 risk allele (+) 018


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