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

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 signific

SUBMITTER: Timberlake AT 

PROVIDER: S-EPMC5045293 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature