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

Document Type

Article

Abstract

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, P = 2.4 × 10). SMAD6 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 BMP2 increased the penetrance of SMAD6 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.

Medical Subject Headings

Adult; Animals; Bone Morphogenetic Proteins (antagonists & inhibitors, genetics, metabolism); Child; Child, Preschool; Cranial Sutures; Craniosynostoses (genetics, metabolism, physiopathology); Exome (genetics); Female; Humans; MAP Kinase Signaling System (genetics, physiology); Male; Mutation (genetics); Osteogenesis (genetics); Penetrance; Phenotype; Sequence Analysis, DNA (methods); Signal Transduction; Smad6 Protein (genetics, physiology); Exome Sequencing (methods); ras Proteins (antagonists & inhibitors, genetics, metabolism)

Publication Date

8-29-2017

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

E-ISSN

1091-6490

Volume

114

Issue

35

First Page

E7341

Last Page

E7347

PubMed ID

28808027

Digital Object Identifier (DOI)

10.1073/pnas.1709255114

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