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.
Highlights
Genetic variation in CTNND1, which encodes for the armadillo-‐repeat protein p120-‐catenin61 (p120), is associated with human birth defects, most notably non-‐syndromic cleft palate and blepharocheilodontic (BCD) syndrome, which involves eyelid, lip and tooth anomalies [MIM: 617681]1-‐3
We propose that CTNND1 variants have a wider developmental role than previously described, and that variations in this gene underlie cleft palate and BCD but may be expanded to a broader velocardiofacial-‐like syndrome
This work expands upon the spectrum of abnormalities associated with CTNND1 variants
Summary
12 1Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial. 18 5Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of. 22 7Pediatric Genomics Discovery Program, Departments of Genetics and Pediatrics, Yale University. 24 8South Thames Cleft Unit, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK. 28 12Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 29 13Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, USA. 30 14Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. 34 17Clinical Genetics, University Hospital Bristol NHS Foundation Trust, Bristol, UK. CTNND1; p120-‐catenin; craniofacial, cardiac; blepharocheilodontic syndrome; cleft lip 42 and palate; hypodontia; neural; larynx; Xenopus; mouse
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