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Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15116-15121. doi: 10.1073/pnas.1902041116. Epub 2019 Jul 10.

Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.

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Department of Genetics, Yale University School of Medicine, New Haven, CT 06510.
Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY 10016.
Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT 06510.
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065.
School of Pharmacy, University College London, London WC1N 1AX, United Kingdom.
Centre for Biomarker Research, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, United Kingdom.
Craniosynostosis and Positional Plagiocephaly Support, New York, NY 10010.
Department of Radiotherapy, The Maria Skłodowska Curie Memorial Cancer Centre and Institute of Oncology, 44-101 Gliwice, Poland.
Department of Pharmacology, Yale University, New Haven, CT 06510.
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510;


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 (P = 4.0 × 10-8); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 × 10-12). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, 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 KAT6A, and CTNNA1, encoding catenin α-1. These findings establish TFAP2B 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.


TFAP2B; craniofacial syndromes; craniosynostosis; de novo mutation; pleiotropy

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