Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome

Reham Alharatani; Athina Ververi; Ana Beleza-Meireles; Weizhen Ji; Emily Mis; Quinten T. Patterson; John N. Griffin; Nabina Bhujel; Caitlin A. Chang; Abhijit Dixit; Monica Konstantino; Christopher Healy; Sumayyah Hannan; Natsuko Neo; Alex Cash; Dong Li; Elizabeth Bhoj; Elaine H. Zackai; Ruth Cleaver; Diana Baralle; Meriel McEntagart; Ruth Newbury-Ecob; Richard Scott; Jane A. Hurst; Ping Yee Billie Au; Marie Therese Hosey; Mustafa Khokha; Denise K. Marciano; Saquib A. Lakhani; Karen J. Liu

doi:10.1093/hmg/ddaa050

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome

Reham Alharatani, Athina Ververi, Ana Beleza-Meireles, Weizhen Ji, Emily Mis, Quinten T. Patterson, John N. Griffin, Nabina Bhujel, Caitlin A. Chang, Abhijit Dixit, Monica Konstantino, Christopher Healy, Sumayyah Hannan, Natsuko Neo, Alex Cash, Dong Li, Elizabeth Bhoj, Elaine H. Zackai, Ruth Cleaver, Diana BaralleMeriel McEntagart, Ruth Newbury-Ecob, Richard Scott, Jane A. Hurst, Ping Yee Billie Au, Marie Therese Hosey, Mustafa Khokha, Denise K. Marciano, Saquib A. Lakhani, Karen J. Liu

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Abstract

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

Original language	English
Pages (from-to)	1900-1921
Number of pages	22
Journal	Human Molecular Genetics
Volume	29
Issue number	11
Early online date	20 Mar 2020
DOIs	https://doi.org/10.1093/hmg/ddaa050
Publication status	Published - 21 Jul 2020

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Novel truncating mutations in_ALHARATANI_Acc16Mar2020Epub20Mar2020_GOLD VoR(CC BY)Final published version, 3.11 MBLicence: CC BY

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Alharatani, R., Ververi, A., Beleza-Meireles, A., Ji, W., Mis, E., Patterson, Q. T., Griffin, J. N., Bhujel, N., Chang, C. A., Dixit, A., Konstantino, M., Healy, C., Hannan, S., Neo, N., Cash, A., Li, D., Bhoj, E., Zackai, E. H., Cleaver, R., ... Liu, K. J. (2020). Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome. Human Molecular Genetics, 29(11), 1900-1921. https://doi.org/10.1093/hmg/ddaa050

@article{ac24470a7d1e462ab8ccc1ed79f5b19c,

title = "Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome",

abstract = "CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.",

author = "Reham Alharatani and Athina Ververi and Ana Beleza-Meireles and Weizhen Ji and Emily Mis and Patterson, {Quinten T.} and Griffin, {John N.} and Nabina Bhujel and Chang, {Caitlin A.} and Abhijit Dixit and Monica Konstantino and Christopher Healy and Sumayyah Hannan and Natsuko Neo and Alex Cash and Dong Li and Elizabeth Bhoj and Zackai, {Elaine H.} and Ruth Cleaver and Diana Baralle and Meriel McEntagart and Ruth Newbury-Ecob and Richard Scott and Hurst, {Jane A.} and Au, {Ping Yee Billie} and Hosey, {Marie Therese} and Mustafa Khokha and Marciano, {Denise K.} and Lakhani, {Saquib A.} and Liu, {Karen J.}",

year = "2020",

month = jul,

day = "21",

doi = "10.1093/hmg/ddaa050",

language = "English",

volume = "29",

pages = "1900--1921",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

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Alharatani, R, Ververi, A, Beleza-Meireles, A, Ji, W, Mis, E, Patterson, QT, Griffin, JN, Bhujel, N, Chang, CA, Dixit, A, Konstantino, M, Healy, C, Hannan, S, Neo, N, Cash, A, Li, D, Bhoj, E, Zackai, EH, Cleaver, R, Baralle, D, McEntagart, M, Newbury-Ecob, R, Scott, R, Hurst, JA, Au, PYB, Hosey, MT, Khokha, M, Marciano, DK, Lakhani, SA & Liu, KJ 2020, 'Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome', Human Molecular Genetics, vol. 29, no. 11, pp. 1900-1921. https://doi.org/10.1093/hmg/ddaa050

TY - JOUR

T1 - Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome

AU - Alharatani, Reham

AU - Ververi, Athina

AU - Beleza-Meireles, Ana

AU - Ji, Weizhen

AU - Mis, Emily

AU - Patterson, Quinten T.

AU - Griffin, John N.

AU - Bhujel, Nabina

AU - Chang, Caitlin A.

AU - Dixit, Abhijit

AU - Konstantino, Monica

AU - Healy, Christopher

AU - Hannan, Sumayyah

AU - Neo, Natsuko

AU - Cash, Alex

AU - Li, Dong

AU - Bhoj, Elizabeth

AU - Zackai, Elaine H.

AU - Cleaver, Ruth

AU - Baralle, Diana

AU - McEntagart, Meriel

AU - Newbury-Ecob, Ruth

AU - Scott, Richard

AU - Hurst, Jane A.

AU - Au, Ping Yee Billie

AU - Hosey, Marie Therese

AU - Khokha, Mustafa

AU - Marciano, Denise K.

AU - Lakhani, Saquib A.

AU - Liu, Karen J.

PY - 2020/7/21

Y1 - 2020/7/21

N2 - CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

AB - CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

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U2 - 10.1093/hmg/ddaa050

DO - 10.1093/hmg/ddaa050

M3 - Article

C2 - 32196547

AN - SCOPUS:85087037861

SN - 0964-6906

VL - 29

SP - 1900

EP - 1921

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 11

ER -

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome

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