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

TitleMutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.
Publication TypeJournal Article
Year of Publication2018
AuthorsCox, LL, Cox, TC, Uribe, LMMoreno, Zhu, Y, Richter, CT, Nidey, N, Standley, JM, Deng, M, Blue, E, Chong, JX, Yang, Y, Carstens, RP, Anand, D, Lachke, SA, Smith, JD, Dorschner, MO, Bedell, B, Kirk, E, Hing, AV, Venselaar, H, Valencia-Ramirez, LC, Bamshad, MJ, Glass, IA, Cooper, JA, Haan, E, Nickerson, DA, van Bokhoven, H, Zhou, H, Krahn, KN, Buckley, MF, Murray, JC, Lidral, AC, Roscioli, T
JournalAm J Hum Genet
Date Published2018 06 07
KeywordsAlleles, Amino Acid Sequence, Animals, Biotinylation, Cadherins, Catenins, Cleft Lip, Cleft Palate, Epithelium, Female, Gene Deletion, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Male, Mice, Mutation, Palate, Pedigree, Syndrome, Whole Exome Sequencing

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID29805042
PubMed Central IDPMC5992119
Grant ListR37 DE008559 / DE / NIDCR NIH HHS / United States
R01 DE014667 / DE / NIDCR NIH HHS / United States
R24 HD000836 / HD / NICHD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R03 DE024776 / DE / NIDCR NIH HHS / United States