De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.

TitleDe novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.
Publication TypeJournal Article
Year of Publication2017
AuthorsTimberlake, AT, Furey, CG, Choi, J, Nelson-Williams, C, Loring, E, Galm, A, Kahle, KT, Steinbacher, DM, Larysz, D, Persing, JA, Lifton, RP
Corporate AuthorsYale Center for Genome Analysis
JournalProc Natl Acad Sci U S A
Date Published2017 08 29
KeywordsAdult, Animals, Bone Morphogenetic Proteins, Child, Child, Preschool, Cranial Sutures, Craniosynostoses, Exome, Female, Humans, Male, MAP Kinase Signaling System, Mutation, Osteogenesis, Penetrance, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction, Smad6 Protein, Whole Exome Sequencing

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, = 2.4 × 10). had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near increased the penetrance of mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28808027
PubMed Central IDPMC5584457
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States
S10 OD018521 / OD / NIH HHS / United States
T32 GM007205 / GM / NIGMS NIH HHS / United States
TL1 TR001864 / TR / NCATS NIH HHS / United States