DNA Methylation Effects on Van der Woude Syndrome Phenotypic Variability

Amanda Seaberg; Waheed Awotoye; Fang Qian; Ligiane A Machado-Paula; Lindsey Dunlay; Azeez Butali; Jeff Murray; Lina Moreno-Uribe; Aline L Petrin

doi:10.1177/10556656241269495

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DNA Methylation Effects on Van der Woude Syndrome Phenotypic Variability

Journal article

Peer reviewed

DNA Methylation Effects on Van der Woude Syndrome Phenotypic Variability

Amanda Seaberg, Waheed Awotoye, Fang Qian, Ligiane A Machado-Paula, Lindsey Dunlay, Azeez Butali, Jeff Murray, Lina Moreno-Uribe and Aline L Petrin

The Cleft palate-craniofacial journal, Vol.62(10), pp.1641-1650

10/2025

DOI: 10.1177/10556656241269495

PMCID: PMC11802890

PMID: 39109995

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https://pmc.ncbi.nlm.nih.gov/articles/PMC11802890/pdf/nihms-2032253.pdfView

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Abstract

Van der Woude Syndrome (VWS) presents with combinations of lip pits (LP) and cleft lip and/or cleft palate (CL/P, CPO). VWS phenotypic heterogeneity even amongst relatives, suggests that epigenetic factors may act as modifiers. IRF6, causal for 70% of VWS cases, and TP63 interact in a regulatory loop coordinating epithelial proliferation and differentiation in palatogenesis. We hypothesize that differential DNA methylation within IRF6 and TP63 regulatory regions underlie VWS phenotypic discordance.OBJECTIVEVan der Woude Syndrome (VWS) presents with combinations of lip pits (LP) and cleft lip and/or cleft palate (CL/P, CPO). VWS phenotypic heterogeneity even amongst relatives, suggests that epigenetic factors may act as modifiers. IRF6, causal for 70% of VWS cases, and TP63 interact in a regulatory loop coordinating epithelial proliferation and differentiation in palatogenesis. We hypothesize that differential DNA methylation within IRF6 and TP63 regulatory regions underlie VWS phenotypic discordance.DNA methylation of CpG sites in IRF6 and TP63 promoters and in an IRF6 enhancer element was compared amongst blood or saliva DNA samples of 78 unrelated cases. Analyses were done separately for blood and saliva, within each sex and in combination, and to address cleft type (CL/P ± LP vs. CPO ± LP) and phenotypic severity (any cleft + LP vs. any cleft only).METHODSDNA methylation of CpG sites in IRF6 and TP63 promoters and in an IRF6 enhancer element was compared amongst blood or saliva DNA samples of 78 unrelated cases. Analyses were done separately for blood and saliva, within each sex and in combination, and to address cleft type (CL/P ± LP vs. CPO ± LP) and phenotypic severity (any cleft + LP vs. any cleft only).For cleft type, blood samples showed higher IRF6 and TP63 promoter methylation on males with CPO ± LP compared to CL/P ± LP and on individuals with CPO ± LP compared to those with CL/P ± LP, respectively. Saliva samples showed higher IRF6 enhancer methylation on individuals with CPO ± LP compared to CL/P ± LP and contrary to above, lower TP63 promoter methylation on CPO ± LP compared to CL/P ± LP. For phenotypic severity, blood samples showed no differences; however, saliva samples showed higher IRF6 promoter methylation in individuals with any cleft + LP compared to those without lip pits.RESULTSFor cleft type, blood samples showed higher IRF6 and TP63 promoter methylation on males with CPO ± LP compared to CL/P ± LP and on individuals with CPO ± LP compared to those with CL/P ± LP, respectively. Saliva samples showed higher IRF6 enhancer methylation on individuals with CPO ± LP compared to CL/P ± LP and contrary to above, lower TP63 promoter methylation on CPO ± LP compared to CL/P ± LP. For phenotypic severity, blood samples showed no differences; however, saliva samples showed higher IRF6 promoter methylation in individuals with any cleft + LP compared to those without lip pits.We observed differential methylation in IRF6 and TP63 regulatory regions associated with cleft type and phenotypic severity, indicating that epigenetic changes in IRF6 and TP63 can contribute to phenotypic heterogeneity in VWS.CONCLUSIONWe observed differential methylation in IRF6 and TP63 regulatory regions associated with cleft type and phenotypic severity, indicating that epigenetic changes in IRF6 and TP63 can contribute to phenotypic heterogeneity in VWS.

DNA methylation

Van der Woude syndrome

phenotypic variability

epigenetics

cleft lip and palate

lip pits

Details

Title: Subtitle: DNA Methylation Effects on Van der Woude Syndrome Phenotypic Variability
Creators: Amanda Seaberg - University of Iowa
Waheed Awotoye - University of Iowa
Fang Qian - University of Iowa, Dental Research
Ligiane A Machado-Paula - University of Iowa, Dental Research
Lindsey Dunlay - University of Iowa
Azeez Butali - University of Iowa, Dental Research
Jeff Murray - University of Iowa, Neonatology
Lina Moreno-Uribe - University of Iowa, Orthodontics
Aline L Petrin - University of Iowa
Resource Type: Journal article
Publication Details: The Cleft palate-craniofacial journal, Vol.62(10), pp.1641-1650
DOI: 10.1177/10556656241269495
PMID: 39109995
PMCID: PMC11802890
NLM abbreviation: Cleft Palate Craniofac J
ISSN: 1545-1569
eISSN: 1545-1569
Publisher: SAGE PUBLICATIONS INC; THOUSAND OAKS
Grant note: Eunice Kennedy Shriver National Institute of Child Health and Human Development: K01DE027995, R37DE08559, P50HD103556
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institute of Dental and Craniofacial Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, (grant number K01DE027995, R37DE08559 , P50HD103556).
Language: English
Electronic publication date: 08/07/2024
Date published: 10/2025
Academic Unit: Preventive and Community Dentistry; Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research; Otolaryngology
Record Identifier: 9984696758702771

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