Mutations in and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.

TitleMutations in and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.
Publication TypeJournal Article
Year of Publication2019
AuthorsTimberlake, AT, Jin, SChih, Nelson-Williams, C, Wu, R, Furey, CG, Islam, B, Haider, S, Loring, E, Galm, A, Steinbacher, DM, Larysz, D, Staffenberg, DA, Flores, RL, Rodriguez, ED, Boggon, TJ, Persing, JA, Lifton, RP
Corporate AuthorsYale Center for Genome Analysis
JournalProc Natl Acad Sci U S A
Date Published2019 Jul 23

Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation ( = 4.0 × 10); additionally, a rare damaging mutation in , which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in , a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant ( = 8.2 × 10). Three probands had rare damaging mutations in , , or , which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier , and , encoding catenin α-1. These findings establish as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID31292255
PubMed Central IDPMC6660739
Grant ListS10 OD018521 / OD / NIH HHS / United States
T32 GM007205 / GM / NIGMS NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States