DNA methylation differences in monozygotic twins with Van der Woude syndrome
IntroductionVan der Woude syndrome (VWS) is an autosomal dominant disorder responsible for 2% of all syndromic orofacial clefts (OFCs), with IRF6 being the primary causal gene (70%). Cases may present with lip pits and either cleft lip, cleft lip with cleft palate, or cleft palate, with marked pheno...
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| Format: | Article |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Dental Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fdmed.2023.1120948/full |
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| author | A. L. Petrin E. Zeng M. A. Thomas D. Moretti-Ferreira M. L. Marazita X. J. Xie J. C. Murray L. M. Moreno-Uribe |
| author_facet | A. L. Petrin E. Zeng M. A. Thomas D. Moretti-Ferreira M. L. Marazita X. J. Xie J. C. Murray L. M. Moreno-Uribe |
| author_sort | A. L. Petrin |
| collection | DOAJ |
| description | IntroductionVan der Woude syndrome (VWS) is an autosomal dominant disorder responsible for 2% of all syndromic orofacial clefts (OFCs), with IRF6 being the primary causal gene (70%). Cases may present with lip pits and either cleft lip, cleft lip with cleft palate, or cleft palate, with marked phenotypic discordance even among individuals carrying the same mutation. This suggests that genetic or epigenetic modifiers may play additional roles in the syndrome's etiology and variability in expression. We report the first DNA methylation profiling of two pairs of monozygotic twins with VWS. Our goal is to explore epigenetic contributions to VWS etiology and variable phenotypic expressivity by comparing DNAm profiles in both twin pairs. While the mutations that cause VWS in these twins are known, the additional mechanism behind their phenotypic risk and variability in expression remains unclear.MethodsWe generated whole genome DNAm data for both twin pairs. Differentially methylated positions (DMPs) were selected based on: (1) a coefficient of variation in DNAm levels in unaffected individuals <20%, and (2) intra-twin pair absolute difference in DNAm levels >5% (Δβ > |0.05|). We then divided the DMPs into two subgroups for each twin pair for further analysis: (1) higher methylation levels in twin A (Twin A > Twin B); and (2) higher methylation levels in twin B (Twin B >Twin A).Results and DiscussionGene ontology analysis revealed a list of enriched genes that showed significant differential DNAm, including clef-associated genes. Among the cleft-associated genes, TP63 was the most significant hit (p = 7.82E-12). Both twin pairs presented differential DNAm levels in CpG sites in/near TP63 (Twin 1A > Twin 1B and Twin 2A < Twin 2B). The genes TP63 and IRF6 function in a biological regulatory loop to coordinate epithelial proliferation and differentiation in a process that is critical for palatal fusion. The effects of the causal mutations in IRF6 can be further impacted by epigenetic dysregulation of IRF6 itself or genes in its pathway. Our data show evidence that changes in DNAm are a plausible mechanism that can lead to markedly distinct phenotypes, even among individuals carrying the same mutation. |
| first_indexed | 2024-04-10T09:40:33Z |
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| institution | Directory Open Access Journal |
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| publishDate | 2023-02-01 |
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| series | Frontiers in Dental Medicine |
| spelling | doaj.art-27120ce6a61a46f4ae19cf7197e420bb2024-08-13T11:03:28ZengFrontiers Media S.A.Frontiers in Dental Medicine2673-49152023-02-01410.3389/fdmed.2023.11209481120948DNA methylation differences in monozygotic twins with Van der Woude syndromeA. L. Petrin0E. Zeng1M. A. Thomas2D. Moretti-Ferreira3M. L. Marazita4X. J. Xie5J. C. Murray6L. M. Moreno-Uribe7College of Dentistry and Dental Clinics, University of Iowa, Iowa, IA, United StatesCollege of Dentistry and Dental Clinics, University of Iowa, Iowa, IA, United StatesDepartments of Medical Genetics and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, CanadaDepartment of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, BrazilCenter for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, United StatesCollege of Dentistry and Dental Clinics, University of Iowa, Iowa, IA, United StatesCarver College of Medicine, University of Iowa, Iowa, IA, United StatesCollege of Dentistry and Dental Clinics, University of Iowa, Iowa, IA, United StatesIntroductionVan der Woude syndrome (VWS) is an autosomal dominant disorder responsible for 2% of all syndromic orofacial clefts (OFCs), with IRF6 being the primary causal gene (70%). Cases may present with lip pits and either cleft lip, cleft lip with cleft palate, or cleft palate, with marked phenotypic discordance even among individuals carrying the same mutation. This suggests that genetic or epigenetic modifiers may play additional roles in the syndrome's etiology and variability in expression. We report the first DNA methylation profiling of two pairs of monozygotic twins with VWS. Our goal is to explore epigenetic contributions to VWS etiology and variable phenotypic expressivity by comparing DNAm profiles in both twin pairs. While the mutations that cause VWS in these twins are known, the additional mechanism behind their phenotypic risk and variability in expression remains unclear.MethodsWe generated whole genome DNAm data for both twin pairs. Differentially methylated positions (DMPs) were selected based on: (1) a coefficient of variation in DNAm levels in unaffected individuals <20%, and (2) intra-twin pair absolute difference in DNAm levels >5% (Δβ > |0.05|). We then divided the DMPs into two subgroups for each twin pair for further analysis: (1) higher methylation levels in twin A (Twin A > Twin B); and (2) higher methylation levels in twin B (Twin B >Twin A).Results and DiscussionGene ontology analysis revealed a list of enriched genes that showed significant differential DNAm, including clef-associated genes. Among the cleft-associated genes, TP63 was the most significant hit (p = 7.82E-12). Both twin pairs presented differential DNAm levels in CpG sites in/near TP63 (Twin 1A > Twin 1B and Twin 2A < Twin 2B). The genes TP63 and IRF6 function in a biological regulatory loop to coordinate epithelial proliferation and differentiation in a process that is critical for palatal fusion. The effects of the causal mutations in IRF6 can be further impacted by epigenetic dysregulation of IRF6 itself or genes in its pathway. Our data show evidence that changes in DNAm are a plausible mechanism that can lead to markedly distinct phenotypes, even among individuals carrying the same mutation.https://www.frontiersin.org/articles/10.3389/fdmed.2023.1120948/fullVan der Woude syndromeDNA methylationmonozygotic twinsphenotypic discordancecleft liplip pits |
| spellingShingle | A. L. Petrin E. Zeng M. A. Thomas D. Moretti-Ferreira M. L. Marazita X. J. Xie J. C. Murray L. M. Moreno-Uribe DNA methylation differences in monozygotic twins with Van der Woude syndrome Frontiers in Dental Medicine Van der Woude syndrome DNA methylation monozygotic twins phenotypic discordance cleft lip lip pits |
| title | DNA methylation differences in monozygotic twins with Van der Woude syndrome |
| title_full | DNA methylation differences in monozygotic twins with Van der Woude syndrome |
| title_fullStr | DNA methylation differences in monozygotic twins with Van der Woude syndrome |
| title_full_unstemmed | DNA methylation differences in monozygotic twins with Van der Woude syndrome |
| title_short | DNA methylation differences in monozygotic twins with Van der Woude syndrome |
| title_sort | dna methylation differences in monozygotic twins with van der woude syndrome |
| topic | Van der Woude syndrome DNA methylation monozygotic twins phenotypic discordance cleft lip lip pits |
| url | https://www.frontiersin.org/articles/10.3389/fdmed.2023.1120948/full |
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