Journal Article

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

Choi, Jungmin, Loring, Erin, Furey, Charuta G., Steinbacher, Derek M., Larysz, Dawid, Galm, Amy, Timberlake, Andrew T., Kahle, Kristopher T., Persing, John A., Nelson-Williams, Carol, Lifton, Richard P.

2017

Overview

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 × 10−11). 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.

• Publisher: National Academy of Sciences
• Subject: Adult / Animal models / Animals / Biological Sciences / Bone growth / Bone morphogenetic protein 2 / Bone Morphogenetic Proteins - antagonists & inhibitors / Bone Morphogenetic Proteins - genetics / Bone Morphogenetic Proteins - metabolism / Child / Child, Preschool / Congenital defects / Congenital diseases / Cranial Sutures / Craniosynostoses - genetics / Craniosynostoses - metabolism / Craniosynostoses - physiopathology / Craniosynostosis / Damage / Exome - genetics / Extracellular signal-regulated kinase / Female / Genes / Genetics / Haploinsufficiency / Heterogeneity / Humans / Male / MAP Kinase Signaling System - genetics / MAP Kinase Signaling System - physiology / Medical Sciences / Metabolic pathways / Mutation / Mutation - genetics / Neurodegeneration / Offspring / Osteogenesis / Osteogenesis - genetics / Pathogenesis / Penetrance / Phenotype / PNAS Plus / Ras protein / ras Proteins - antagonists & inhibitors / ras Proteins - genetics / ras Proteins - metabolism / Regulators / Risk / Rodents / Sequence Analysis, DNA - methods / Signal Transduction / Skull / Smad6 Protein - genetics / Smad6 Protein - physiology / Studies / Whole Exome Sequencing - methods / Wnt protein