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

TitleTwo locus inheritance of non-syndromic midline craniosynostosis via rare and common alleles.
Publication TypeJournal Article
Year of Publication2016
AuthorsTimberlake, AT, Choi, J, Zaidi, S, Lu, Q, Nelson-Williams, C, Brooks, ED, Bilguvar, K, Tikhonova, I, Mane, S, Yang, JF, Sawh-Martinez, R, Persing, S, Zellner, EG, Loring, E, Chuang, C, Galm, A, Hashim, PW, Steinbacher, DM, DiLuna, ML, Duncan, CC, Pelphrey, KA, Zhao, H, Persing, JA, Lifton, RP
Date Published2016 Sep 08
KeywordsAlleles, Bone Morphogenetic Protein 2, Craniosynostoses, Exome, Genetic Association Studies, Humans, Infant, Mutation, Penetrance, Sequence Analysis, DNA, Smad6 Protein

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 , an inhibitor of BMP - induced osteoblast differentiation (p<10). mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near 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.

Alternate JournalElife
PubMed ID27606499
PubMed Central IDPMC5045293
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
T32 GM007205 / GM / NIGMS NIH HHS / United States
TL1 TR001864 / TR / NCATS NIH HHS / United States
P30 CA016359 / CA / NCI NIH HHS / United States