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Description
Cleft lip and palate are among the most common birth differences worldwide, touching not only a child’s appearance but also their ability to eat, speak, and grow with confidence. For families, the
diagnosis often brings emotional strain and financial challenges, while for health systems, it requires lifelong surgical and supportive care. Researchers have long recognized that both genetic and environmental factors contribute to clefting, yet the reasons why one child develops a cleft while another does not remain only partly understood. The puzzle becomes especially compelling when it involves twins. Dizygotic, or “fraternal,” twins share the same prenatal environment but only about half of their genetic material, similar to ordinary siblings. In some cases, one twin may be born with a cleft while the other is completely unaffected. This striking difference provides a powerful opportunity to explore how inherited variation interacts with shared and unique
environmental influences in shaping craniofacial development. Against this backdrop, the present study aims to investigate the genetic and epigenetic mechanisms that may explain why only one
fraternal twin develops a cleft. The research will focus on identifying differences in DNA sequence, copy number, or gene regulation, as well as epigenetic changes that could underlie this discordance.
In doing so, the study seeks to reveal how shared and individual factors combine to influence developmental outcomes and to generate knowledge that can improve counseling, prevention, and treatment strategies for families. The study will take a multi-layered approach. Blood and buccal samples from discordant twin pairs will be analyzed using whole-genome sequencing to detect rare sequence or structural variants. Chromosomal analysis will identify copy number changes, while genome-wide DNA methylation profiling will reveal epigenetic differences. Small RNA
profiling will also be incorporated to capture emerging regulators such as tRNA fragments. Complementing these molecular methods, detailed craniofacial imaging and dental assessments will be carried out to uncover subtle traits in the “unaffected” twin, offering a fuller picture of the spectrum of cleft expression. It is expected that the study will reveal meaningful differences between affected and unaffected twins, whether in methylation of developmental pathways such
as TGF-β, Wnt, or Notch signaling, or in small-RNA activity. Subclinical features in the unaffected twin may also be detected, highlighting that clefting may exist on a continuum rather than as an all-or-none condition. Together, these insights will highlight candidate genes, pathways, and regulatory mechanisms that shape susceptibility to clefting and explain how siblings in the same womb can experience such different outcomes. In conclusion, this project seeks to use the natural
contrast provided by dizygotic twins to uncover the hidden genetic and epigenetic layers of craniofacial development. Beyond advancing scientific understanding, it carries practical significance: improving genetic counseling, guiding earlier detection, and informing preventive
strategies. By revealing why one twin is affected while the other is spared, the study contributes to the broader goal of easing the burden of clefts for children, families, and communities.
Keywords: Dizygotic twins, cleft lip and palate, DNA methylation, somatic mosaicism, epigenetics, craniofacial development