DNA methylation differences in monozygotic twins with Van der Woude syndrome

Area of Science:

• Genetics
• Epigenetics
• Developmental Biology

Background:

• Van der Woude Syndrome (VWS) is an autosomal dominant disorder causing orofacial clefts (OFCs), primarily linked to IRF6 gene mutations.
• Phenotypic variability in VWS, even among individuals with identical mutations, suggests the involvement of genetic or epigenetic modifiers.
• Understanding these modifiers is crucial for explaining the range of VWS presentations, from lip pits to cleft palate.

Purpose of the Study:

• To investigate the role of DNA methylation in the etiology and variable expressivity of Van der Woude Syndrome.
• To compare DNA methylation profiles in monozygotic twin pairs discordant for VWS to identify epigenetic contributions.
• To explore potential epigenetic mechanisms underlying phenotypic differences in VWS.

Main Methods:

• Whole genome DNA methylation (DNAm) data generation for two pairs of monozygotic twins with VWS.
• Identification of differentially methylated positions (DMPs) based on methylation level variation and intra-twin pair differences.
• Gene ontology analysis to identify enriched genes with significant differential DNAm, focusing on cleft-associated genes.

Main Results:

• Differential DNA methylation was observed in both twin pairs, particularly in CpG sites near the TP63 gene.
• TP63 was identified as a significantly enriched gene associated with differential DNAm (p=7.82E-12).
• DNAm differences were noted in TP63 in both twin pairs, with varying directions of methylation changes (Twin 1A > Twin 1B and Twin 2A < Twin 2B).

Conclusions:

• Epigenetic dysregulation, specifically changes in DNA methylation, is a plausible mechanism contributing to the variable phenotypes observed in Van der Woude Syndrome.
• The interplay between the causal IRF6 gene and epigenetic modifications of genes like TP63 may influence disease severity and presentation.
• These findings highlight the importance of epigenetic factors in understanding the complex etiology of VWS and orofacial clefts.