ArticleAmerican journal of human genetics2016
A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.
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Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers, 6 of them syntheses that pooled it.
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106citing papers in PubMed, 6 pooled it
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Who cites it
106 citing papers in PubMed, 6 syntheses or guidelines pooled it, 174 citations in OpenAlex.
- Genetic heterogeneity and homogeneity among orofacial cleft subtypes: genome-wide association studies in the cleft collective.Human molecular genetics · 2025Pooled it
- Variants in CALD1, ESRP1, and RBFOX1 are associated with orofacial cleft risk.PLoS genetics · 2025Pooled it
- Genome-wide meta-analyses identify five new risk loci for nonsyndromic orofacial clefts in the Chinese Han population.Molecular genetics & genomic medicine · 2023Pooled it
- Genetic markers for non-syndromic orofacial clefts in populations of European ancestry: a meta-analysis.Scientific reports · 2022Pooled it
- Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate.Human genetics · 2017Pooled it
- Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only.Human molecular genetics · 2017Pooled it
- Atlas of cell types and regulatory elements underlying human facial diversity.Nature genetics · 2026Article
- A study of sex-specific genetic effects underlying risk of orofacial clefts also highlights the potential impact of sequencing errors due to short read mis-mapping.medRxiv : the preprint server for health sciences · 2026Article
- Consensus-based detection of aetiologic copy number variants for syndromic orofacial clefts utilising whole exome sequencing of case parent trios.BMC genomic data · 2026Article
- Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.Molecular genetics and genomics : MGG · 2026Article
- Evidence that disruption of Discoidin domain receptor 2 contributes to palate malformations through effects on the extracellular matrix.Human molecular genetics · 2026Article
- Comprehensive analysis ofmedRxiv : the preprint server for health sciences · 2026Article
- Consensus-based Detection of Aetiologic Copy Number Variants For Syndromic Orofacial Clefts Utilising Whole Exome Sequencing of Case Parent Trios.Research square · 2026Article
- Toward Understanding the Role of miRNAs in Cleft Palate Only: Observations from Patient Tissues and In Vitro Assays.International journal of molecular sciences · 2026Article
- Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans.Human molecular genetics · 2025Article
- Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 818 trios.American journal of human genetics · 2025Article
- Loss of the epithelial transcription factor grhl3 leads to variably penetrant developmental phenotypes in zebrafish.Developmental dynamics : an official publication of the American Association of Anatomists · 2025Article
- Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.medRxiv : the preprint server for health sciences · 2025Article
- Etiology of Cleft Lip and/or Cleft Palate in Southeastern Poland Based on Current Observational Study.Journal of clinical medicine · 2025Article
- Identification of functional non-coding variants associated with orofacial cleft.Nature communications · 2025Article
46 more citing papers are in PubMed but not listed here.
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Authors and funding
58 authors at 20 institutions in 17 countries.
Elizabeth J LeslieCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Huan LiuDepartment of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA; State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Jenna C CarlsonCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
John R ShafferCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Eleanor FeingoldCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
George WehbyDepartment of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA 52246, USA.
Cecelia A LaurieDepartment of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA.
Deepti JainDepartment of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA.
Cathy C LaurieDepartment of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA.
Kimberly F DohenyCenter for Inherited Disease Research, Johns Hopkins University, Baltimore, MD 21224, USA.
Toby McHenryCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Judith ResickCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Carla SanchezCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Jennifer JacobsCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Beth EmanueleCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Alexandre R VieiraCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Katherine NeiswangerCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Jennifer StandleyDepartment of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Andrew E CzeizelFoundation for the Community Control of Hereditary Diseases, Budapest 1051, Hungary.
Frederic DeleyiannisDepartment of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO 80045, USA.
Kaare ChristensenDepartment of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense 5230, Denmark.
Ronald G MungerDepartment of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT 84322, USA.
Rolv T LieDepartment of Global Public Health and Primary Care, University of Bergen, Bergen 5020, Norway.
Allen WilcoxEpidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Paul A RomittiDepartment of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52246, USA.
L Leigh FieldDepartment of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
Carmencita D PadillaInstitute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manilla 1000, the Philippines.
Eva Maria C Cutiongco-de la PazInstitute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manilla 1000, the Philippines; Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manilla 1000, the Philippines; Philippine Genome Center, University of the Philippines, Manilla 1101, the Philippines.
Andrew C LidralDepartment of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
Luz Consuelo Valencia-RamirezFundación Clínica Noel, Medellin 050012, Colombia.
Ana Maria Lopez-PalacioDepartment of Basic Integrated Studies, College of Dentistry, University of Antioquia, Medellin 050001, Colombia.
Dora Rivera ValenciaPopulation Genetics and Mutacarcinogenesis Group, University of Antioquia, Medellin 050001, Colombia.
Mauricio Arcos-BurgosGenomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology & Environment, The Australian National University, Canberra, ACT 0200, Australia.
Eduardo E CastillaCEMIC: Center for Medical Education and Clinical Research, Buenos Aires 1431, Argentina; Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil; ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro 21941-617, Brazil.
Juan C MerebECLAMC (Latin American Collaborative Study of Congenital Malformations) at Hospital de Area, El Bolson 8430, Argentina.
Fernando A PolettaCEMIC: Center for Medical Education and Clinical Research, Buenos Aires 1431, Argentina; Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil; ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro 21941-617, Brazil.
Iêda M OrioliECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro 21941-617, Brazil; Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil.
Flavia M CarvalhoCEMIC: Center for Medical Education and Clinical Research, Buenos Aires 1431, Argentina; Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil.
Jacqueline T HechtDepartment of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Susan H BlantonDr. John T. Macdonald Foundation Department of Human Genetics, Hussman Institute for Human Genomics, Mailman School of Medicine, University of Miami, Miami, FL 33124, USA.
Carmen J BuxóSchool of Dental Medicine, University of Puerto Rico, San Juan 00936, Puerto Rico.
Azeez ButaliDepartment of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
Peter A MosseyDepartment of Orthodontics, University of Dundee, Dundee DD1 4HN, Scotland.
Wasiu L AdeyemoDepartment of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, P.M.B. 12003, Nigeria.
Olutayo JamesDepartment of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, P.M.B. 12003, Nigeria.
Ramat O BraimahDepartment of Oral and Maxillofacial Surgery, Obafemi Awolowo University Ile-Ife, Ife-Ife, P.M.B. 13, Nigeria.
Babatunde S AregbesolaDepartment of Oral and Maxillofacial Surgery, Obafemi Awolowo University Ile-Ife, Ife-Ife, P.M.B. 13, Nigeria.
Mekonen A EsheteSurgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia.
Milliard DeribewSurgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia.
Mine KoruyucuDepartment of Pedodontics, Istanbul University, Istanbul 34116, Turkey.
Figen SeymenDepartment of Pedodontics, Istanbul University, Istanbul 34116, Turkey.
Lian MaSchool of Stomatology, Peking University, Beijing 100081, China.
Javier Enríquez de SalamancaHospital Infantil Universitario Niño Jesús, Unidad de Cirugía Plástica, Madrid 28009, Spain.
Seth M WeinbergCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Lina MorenoDepartment of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
Robert A CornellDepartment of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
Jeffrey C MurrayDepartment of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Mary L MarazitaCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: marazita@pitt.edu.
University of Pittsburgh · USUniversity of Iowa · USCentro de Educación Médica e Investigaciones Clínicas Norberto Quirno · ARUniversity of Washington · USAddis Ababa University · ETIstanbul University · TRObafemi Awolowo University · NGUniversidad de Antioquia · COUniversity of Lagos · NGUniversity of the Philippines Manila · PHAustralian National University · AUDr. John T. Macdonald Foundation · USHospital Infantil Universitario Niño Jesús · ESJohns Hopkins University · USNational Center for Epidemiology · HUNational Institute of Environmental Health Sciences · USPeking University · CNThe University of Texas Health Science Center at Houston · USUniversidade Federal do Rio de Janeiro · BRUniversity of Bergen · NO
Funding
Hispanics in Research Capability: SoHP & SOM Partnership (HIREC)S21MD001830 · NIMHD · UNIVERSITY OF PUERTO RICO MED SCIENCES · PI ELIAS BONETA, AUGUSTO R, ESTAPE, ESTELA S · 2005 to 2010
$30.0MTECHNOLOGIES AND RESOURCES FOR CORE LABORATORIESU54MD007587 · NIMHD · UNIVERSITY OF PUERTO RICO MED SCIENCES · PI LUCIANO, CARLOS A., NOBOA, CARIAMARIE · 2012 to 2018
$23.2MExtending the Phenotype of Nonsyndromic Orofacial CleftsR01DE016148 · NIDCR · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI MARAZITA, MARY L., WEINBERG, SETH M · 2004 to 2018
$19.7MMOLECULAR STUDIES IN NONSYNDROMIC CLEFT LIP AND PALATER01DE011931 · NIDCR · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI BLANTON, SUSAN HALLORAN, HECHT, JACQUELINE T · 1999 to 2017
$7.6MHispanic Clinical and Translational Research Education and Career Development ProgramR25MD007607 · NIMHD · UNIVERSITY OF PUERTO RICO MED SCIENCES · PI Karen G. Martinez Gonzalez, Barbara Segarra-Vazquez · 2012 to 2026
$7.4MMolecular Genetic Epidemiology of Cleft Lip and PalateR37DE008559 · NIDCR · UNIVERSITY OF IOWA · PI MURRAY, JEFFREY C · 2004 to 2013
$6.8MWATER PRECAUTIONS AND TYMPANOSTOMY TUBESM01RR000084 · NCRR · CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS · PI PERLMUTTER, DAVID H · 1985 to 2006
$5.6MEpidemiologic Study Of Reproductive Outcomes And Environmental ExposuresZIAES044003 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI WILCOX, ALLEN J · 2009 to 2020
$4.7MDissecting the transcriptional network governing differentiation of peridermR01DE023575 · NIDCR · UNIVERSITY OF WASHINGTON · PI CORNELL, ROBERT AARON, SCHUTTE, BRIAN C · 2013 to 2023
$4.3MIowa CBDRP: Birth Defects Study To Evaluate Pregnancy exposureSU01DD001035 · DD · UNIVERSITY OF IOWA · PI ROMITTI, PAUL A · 2013 to 2017
$3.5MEnvironmental And Genetic Causes Of Birth DefectsZIAES049027 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI WILCOX, ALLEN J · 2009 to 2020
$2.6MGenetic instrumental variable studies of maternal risk behaviors for oral cleftsR01DE020895 · NIDCR · UNIVERSITY OF IOWA · PI WEHBY, GEORGE L · 2010 to 2014
$2.5MNCBDD CDC HHS U01 DD001035NCRR NIH HHS M01 RR000084NHGRI NIH HHS X01-HG007845NHLBI NIH HHS HHSN268201200008CNHLBI NIH HHS HHSN268201200008INIDCR NIH HHS K99 DE024571NIDCR NIH HHS K99 DE025060NIDCR NIH HHS R00 DE022378NIDCR NIH HHS R01 DE009886NIDCR NIH HHS R01 DE011931NIDCR NIH HHS R01 DE011948NIDCR NIH HHS R01 DE016148NIDCR NIH HHS R01-DE016148NIDCR NIH HHS R01 DE020895NIDCR NIH HHS R01-DE020895NIDCR NIH HHS R01 DE023575NIDCR NIH HHS R21 DE016930NIDCR NIH HHS R37 DE008559NIDCR NIH HHS U01 DE018993NIDCR NIH HHS U01-DE018993NIDCR NIH HHS U01 DE024425NIMHD NIH HHS U54 MD007587
Abstract
Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.
Indexed as
Polymorphism, Single NucleotideAnimalsCase-Control StudiesCleft PalateDisease Models, AnimalDNA-Binding ProteinsEthnicityGenetic LociGenome-Wide Association StudyGenotyping TechniquesHumansMutation, MissenseRisk FactorsTranscription FactorsZebrafishDNA-Binding ProteinsGRHL3 protein, humanTranscription Factors
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