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

Abstract

<p class="first" id="d4251851e570">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 ( <i>CTNND1</i>, <i>PLEKHA7</i>, <i>PLEKHA5</i>) and an epithelial splicing regulator ( <i>ESRP2</i>), in addition to the known CL/P-associated gene, <i>CDH1</i>, 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 <i>CTNND1</i> and <i>ESRP2</i> variants, and recapitulation of the CL/P spectrum in <i>Ctnnd1</i> 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 <i>de novo</i> single gene variants explain a substantial proportion of NS-CL/P. </p>