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

Media type: E-Article
Title: De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis
Contributor: Timberlake, Andrew T.; Furey, Charuta G.; Choi, Jungmin; Nelson-Williams, Carol; Loring, Erin; Galm, Amy; Kahle, Kristopher T.; Steinbacher, Derek M.; Larysz, Dawid; Persing, John A.; Lifton, Richard P.; Bilguvar, Kaya; Mane, Shrikant; Tikhonova, Irina; Castaldi, Christopher; Knight, James
imprint: Proceedings of the National Academy of Sciences, 2017
Published in: Proceedings of the National Academy of Sciences
Language: English
DOI: 10.1073/pnas.1709255114
ISSN: 0027-8424; 1091-6490
Origination:
Footnote:
Description: <jats:title>Significance</jats:title> <jats:p> Craniosynostosis is a common congenital malformation resulting from premature fusion of the bones that comprise the cranial vault, requiring surgery in infancy to prevent adverse neurologic outcomes. Eighty-five percent of cases are non-syndromic and of unknown cause. By exome sequencing of families with non-syndromic midline craniosynostosis, we show that 5% of cases have de novo damaging mutations in negative regulators of the Wnt, bone morphogenetic protein (BMP), and Ras/ERK signaling pathways, developmental cascades that converge on common nuclear targets to promote bone formation. Another 5% have transmitted mutations in these pathways. Common variants near <jats:italic>BMP2</jats:italic> show genetic interaction with these rare mutations. The results provide insight into pathophysiology and have immediate implications for the diagnosis and genetic counseling of families with craniosynostosis. </jats:p>
Access State: Open Access

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