<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>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
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
<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
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.