Journal article
Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate
American journal of human genetics, Vol.102(6), pp.1143-1157
06/07/2018
DOI: 10.1016/j.ajhg.2018.04.009
PMCID: PMC5992119
PMID: 29805042
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.
Details
- Title: Subtitle
- Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate
- Creators
- Liza L Cox - Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USATimothy C Cox - Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Anatomy & Developmental Biology, Monash University, Clayton, VIC 3800, Australia. Electronic address: tccox@uw.eduLina M Moreno Uribe - Department of Orthodontics & the Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA 52242, USAYing Zhu - New South Wales Health Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia; Genetics of Learning Disability Service, Waratah, NSW 2298, AustraliaChika T Richter - Department of Orthodontics & the Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA 52242, USANichole Nidey - Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USAJennifer M Standley - Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USAMei Deng - Birth Defects Research Laboratory, University of Washington, Seattle, WA 98195, USAElizabeth Blue - Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USAJessica X Chong - Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USAYueqin Yang - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USARuss P Carstens - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADeepti Anand - Department of Biological Sciences, University of Delaware, Newark, DE 19716, USASalil A Lachke - Department of Biological Sciences, University of Delaware, Newark, DE 19716, USAJoshua D Smith - Department of Genome Sciences, University of Washington, Seattle, WA 98195, USAMichael O Dorschner - Northwest Clinical Genomics Laboratory, Center for Precision Diagnostics, University of Washington, Seattle, WA 98195, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USABruce Bedell - Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USAEdwin Kirk - New South Wales Health Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Sydney, NSW 2031, AustraliaAnne V Hing - Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Seattle Craniofacial Center, Seattle Children's Hospital, Seattle, WA 98105, USAHanka Venselaar - Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, the NetherlandsLuz C Valencia-Ramirez - Fundación Clínica Noel, Medellin 050021, ColombiaMichael J Bamshad - Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USAIan A Glass - Birth Defects Research Laboratory, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USAJonathan A Cooper - Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAEric Haan - South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), North Adelaide, SA 5006, Australia; School of Medicine, University of Adelaide, Adelaide, SA 5000, AustraliaDeborah A Nickerson - Department of Genome Sciences, University of Washington, Seattle, WA 98195, USAHans van Bokhoven - Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, the Netherlands; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, the NetherlandsHuiqing Zhou - Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, the Netherlands; Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525 GA, the NetherlandsKaty N Krahn - UVA Center for Advanced Medical Analytics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USAMichael F Buckley - New South Wales Health Pathology, Prince of Wales Hospital, Randwick, NSW 2031, AustraliaJeffrey C Murray - Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USAAndrew C Lidral - Lidral Orthodontics, Rockford, MI 49341, USATony Roscioli - Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Sydney, NSW 2031, Australia; Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2031, Australia; Neuroscience Research Australia, Sydney, NSW 2031, Australia. Electronic address: tony.roscioli@health.nsw.gov.au
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.102(6), pp.1143-1157
- DOI
- 10.1016/j.ajhg.2018.04.009
- PMID
- 29805042
- PMCID
- PMC5992119
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- United States
- Grant note
- R37 DE008559 / NIDCR NIH HHS R01 DE014667 / NIDCR NIH HHS R24 HD000836 / NICHD NIH HHS UM1 HG006493 / NHGRI NIH HHS R03 DE024776 / NIDCR NIH HHS
- Language
- English
- Date published
- 06/07/2018
- Academic Unit
- Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Addiction Medicine; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984066096902771
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