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Open AccessArticle

CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer

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New South Wales Health Pathology, Prince of Wales Hospital, Randwick, Sydney 2031, Australia
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Discipline of Child and Adolescent Health, University of Sydney, Sydney 2031, Australia
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Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8011, New Zealand
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Genetics of Learning Disability Service, Waratah, Newcastle 2298, Australia
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The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
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Department of Orthodontics & the Iowa Institute for Oral and Craniofacial Research, University of Iowa, Iowa, IA 52242, USA
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Lidral Orthodontics, Rockford, MI 49341, USA
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Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, MA 02215, USA
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Harvard Medical School, Boston, MA 02115, USA
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Department of Pediatrics, University of Iowa, Iowa, IA 52242, USA
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Departments of Oral & Craniofacial Sciences, School of Dentistry, and Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
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Centre for Clinical Genetics, Sydney Children’s Hospital - Randwick, Sydney 2031, Australia
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Prince of Wales Clinical School, University of New South Wales, Sydney 2031, Australia
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NeuRA, University of New South Wales, Kensington, Sydney 2031, Australia
*
Authors to whom correspondence should be addressed.
Genes 2020, 11(4), 391; https://doi.org/10.3390/genes11040391
Received: 24 January 2020 / Revised: 26 March 2020 / Accepted: 31 March 2020 / Published: 3 April 2020
(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)
Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants. View Full-Text
Keywords: orofacial clefting; cleft lip; cleft palate; gastric cancer; cadherin 1; genotype-phenotype correlation orofacial clefting; cleft lip; cleft palate; gastric cancer; cadherin 1; genotype-phenotype correlation
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Selvanathan, A.; Nixon, C.Y.; Zhu, Y.; Scietti, L.; Forneris, F.; Moreno Uribe, L.M.; Lidral, A.C.; Jezewski, P.A.; Mulliken, J.B.; Murray, J.C.; Buckley, M.F.; Cox, T.C.; Roscioli, T. CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer. Genes 2020, 11, 391.

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