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

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)
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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 languageEnglish
Pages (from-to)1900-1921
Number of pages22
JournalHuman Molecular Genetics
Issue number11
Early online date20 Mar 2020
Publication statusPublished - 21 Jul 2020


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