Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 102, Issue 6, Pages 1143-1157Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2018.04.009
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Funding
- Australian National Health & Medical Research Council [AU/1/BA51117]
- Laurel Foundation for Pediatric Craniofacial Research
- NIH [R01-DE014667, R37-DE008559, R24-HD000836, R03-DE024776, UM1-HG006493]
- March of Dimes Basil O'Connor award [FY 98-0718, 6-FY01-616]
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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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