Journal article
DNA methylation differences in monozygotic twins with Van der Woude syndrome
Frontiers in dental medicine, Vol.4, 1120948
02/17/2023
DOI: 10.3389/fdmed.2023.1120948
PMCID: PMC10019782
PMID: 36936396
Abstract
Van der Woude Syndrome (VWS) is an autosomal dominant disorder responsible for 2% of all syndromic orofacial clefts (OFCs) with
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 2 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.
We 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% (delta beta > | 0.05|). We then divided the DMPs in 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).
Gene ontology analysis revealed a list of enriched genes that showed significant differential DNAm, including clef-associated genes. Among the cleft-associated genes,
was the most significant hit (p=7.82E-12). Both twin pairs presented differential DNAm levels in CpG sites in/near
(Twin 1A > Twin 1B and Twin 2A < Twin 2B). The genes
and
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
can be further impacted by epigenetic dysregulation of
itself, or genes in its pathway. Our data shows evidence that changes in DNAm is a plausible mechanism that can lead to markedly distinct phenotypes, even among individuals carrying the same mutation.
Details
- Title: Subtitle
- DNA methylation differences in monozygotic twins with Van der Woude syndrome
- Creators
- Aline L Petrin (Corresponding Author)Erliang Zeng (Author) - College of Dentistry and Dental Clinics, University of Iowa, Iowa, IA, United StatesM A Thomas (Contributor) - Departments of Medical Genetics and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, CanadaDanilo Moretti-Ferreira (Author) - Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, BrazilMary L Marazita (Author) - Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, United StatesXian Jin Xie (Author) - College of Dentistry and Dental Clinics, University of Iowa, Iowa, IA, United StatesJeffrey C Murray (Author) - Carver College of Medicine, University of Iowa, Iowa, IA, United StatesLina M Moreno Uribe (Author) - College of Dentistry and Dental Clinics, University of Iowa, Iowa, IA, United States
- Resource Type
- Journal article
- Publication Details
- Frontiers in dental medicine, Vol.4, 1120948
- DOI
- 10.3389/fdmed.2023.1120948
- PMID
- 36936396
- PMCID
- PMC10019782
- NLM abbreviation
- Front Dent Med
- eISSN
- 2673-4915
- Grant note
- DOI: 10.13039/100000072, name: National Institute of Dental and Craniofacial Research, award: K01DE027995, ALP and R01DE08559, JCM
- Language
- English
- Date published
- 02/17/2023
- Academic Unit
- Preventive and Community Dentistry; Roy J. Carver Department of Biomedical Engineering; Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984382559402771
Metrics
56 Record Views