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

Andrew T. Timberlake, Sheng Chih Jin, Carol Nelson-Williams, Robin Wu, Charuta G. Furey, Barira Islam, Shozeb Haider, Erin Loring, Amy Galm, Derek M. Steinbacher, Dawid Larysz, David A. Staffenberg, Roberto L. Flores, Eduardo D. Rodriguez, Titus J. Boggon, John A. Persing, Richard P. Lifton

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)15116-15121
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number30
Early online date10 Jul 2019
DOIs
Publication statusPublished - 23 Jul 2019

Fingerprint

Craniosynostoses
Wnt Signaling Pathway
Mutation
Genes
Exome
Cranial Sutures
Catenins
Neural Crest
Chromatin
Cell Movement
Cell Differentiation
Transcription Factors
Parents

Cite this

Timberlake, Andrew T. ; Jin, Sheng Chih ; Nelson-Williams, Carol ; Wu, Robin ; Furey, Charuta G. ; Islam, Barira ; Haider, Shozeb ; Loring, Erin ; Galm, Amy ; Steinbacher, Derek M. ; Larysz, Dawid ; Staffenberg, David A. ; Flores, Roberto L. ; Rodriguez, Eduardo D. ; Boggon, Titus J. ; Persing, John A. ; Lifton, Richard P. / Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 30. pp. 15116-15121.
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abstract = "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.",
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author = "Timberlake, {Andrew T.} and Jin, {Sheng Chih} and Carol Nelson-Williams and Robin Wu and Furey, {Charuta G.} and Barira Islam and Shozeb Haider and Erin Loring and Amy Galm and Steinbacher, {Derek M.} and Dawid Larysz and Staffenberg, {David A.} and Flores, {Roberto L.} and Rodriguez, {Eduardo D.} and Boggon, {Titus J.} and Persing, {John A.} and Lifton, {Richard P.}",
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Timberlake, AT, Jin, SC, 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 2019, 'Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 30, pp. 15116-15121. https://doi.org/10.1073/pnas.1902041116

Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis. / Timberlake, Andrew T.; Jin, Sheng Chih; Nelson-Williams, Carol; Wu, Robin; Furey, Charuta G.; Islam, Barira; Haider, Shozeb; Loring, Erin; Galm, Amy; Steinbacher, Derek M.; Larysz, Dawid; Staffenberg, David A.; Flores, Roberto L.; Rodriguez, Eduardo D.; Boggon, Titus J.; Persing, John A.; Lifton, Richard P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 30, 23.07.2019, p. 15116-15121.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis

AU - Timberlake, Andrew T.

AU - Jin, Sheng Chih

AU - Nelson-Williams, Carol

AU - Wu, Robin

AU - Furey, Charuta G.

AU - Islam, Barira

AU - Haider, Shozeb

AU - Loring, Erin

AU - Galm, Amy

AU - Steinbacher, Derek M.

AU - Larysz, Dawid

AU - Staffenberg, David A.

AU - Flores, Roberto L.

AU - Rodriguez, Eduardo D.

AU - Boggon, Titus J.

AU - Persing, John A.

AU - Lifton, Richard P.

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N2 - 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.

AB - 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.

KW - Craniofacial syndromes

KW - Craniosynostosis

KW - De novo mutation

KW - Pleiotropy

KW - TFAP2B

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U2 - 10.1073/pnas.1902041116

DO - 10.1073/pnas.1902041116

M3 - Article

VL - 116

SP - 15116

EP - 15121

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

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

SN - 0027-8424

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