Orofacial clefts are conditions that affect 1 out of every 700 live births globally, and clefting significantly impacts the health and wellbeing of those affected. Clefts can also be bilateral (affecting both sides) or unilateral (affect the right or left side only). Left-side clefting is significantly more common than right-side clefting with a ratio of 2:1. The magnitude of this ratio strongly suggests that there is an underlying cause for why unilateral clefting is more prevalent on the left side.

For monozygotic (identical) twins, there are a few instances where one twin will have orofacial clefting and the other twin will not. Although they are rare, there are some identical twins where their clefting mirrors each other, with one twin having clefting on the right side and the other on the left side. These clear and physically observable differences are known as differences in phenotype. For these discordant monozygotic twins, genetics alone cannot be the cause of discordant phenotype since they are genetically identical.

Petrin and her team have shown that epigenetic factors, which influence gene expression without altering the genetic code, are likely the root cause of discordancy between the cleft phenotypes in these twins. More specifically, differential DNA methylation is a key epigenetic causal factor in the difference among these identical twins.

The fact that mirror twins are so rare is a unique opportunity for the team to study their DNA and explore the genetic and epigenetic factors that contribute to the causes of cleft and the discordance in laterality. The higher occurrence of clefts in the left side in a well-known fact, but the mechanisms behind it remains underexplored.

The research team was able to identify the mutation that caused mirrored clefts in a pair of twins. But even though the twins have the same mutation, they were born with different clefts. Petrin and her team are investigating the epigenetic factors that influenced the effect of the mutation in each twin, leading one of them to have a left side cleft and the other have a right side cleft.

Thus their preliminary data has suggested that differential methylation also explains differences between mirrored twins.

In their proposed study, Petrin and her team take this initial preliminary data and will validate them with an independent cohort to confirm the role of differential DNA methylation for top candidate genes affecting laterality of clefting.

The study is supported by the University of Iowa College of Dentistry’s Clinical/Dental Education Research Initiative Support Program (CRISP). This program is intended to provide support for faculty who have a specific clinical (or dental education) research question.