Mutations in the epithelial cadherin-p120-catenin complex cause Mendelian non-syndromic cleft lip with or without cleft palate
Date
2018
Authors
Cox, L.
Cox, T.
Moreno Uribe, L.
Zhu, Y.
Richter, C.
Nidey, N.
Standley, J.
Deng, M.
Blue, E.
Chong, J.
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Journal article
Citation
American Journal of Human Genetics, 2018; 102(6):1143-1157
Statement of Responsibility
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, and Tony Roscioli
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Abstract
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.
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© 2018 American Society of Human Genetics.