Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P. Copyright © 2018 American Society of Human Genetics. All rights reserved.

Citation

Liza L Cox, Timothy C Cox, Lina M Moreno Uribe, Ying Zhu, Chika T Richter, Nichole Nidey, Jennifer M Standley, Mei Deng, Elizabeth Blue, Jessica X Chong, Yueqin Yang, Russ P Carstens, Deepti Anand, Salil A Lachke, Joshua D Smith, Michael O Dorschner, Bruce Bedell, Edwin Kirk, Anne V Hing, Hanka Venselaar, Luz C Valencia-Ramirez, Michael J Bamshad, Ian A Glass, Jonathan A Cooper, Eric Haan, Deborah A Nickerson, Hans van Bokhoven, Huiqing Zhou, Katy N Krahn, Michael F Buckley, Jeffrey C Murray, Andrew C Lidral, Tony Roscioli. Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate. American journal of human genetics. 2018 Jun 07;102(6):1143-1157

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PMID: 29805042

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