Why Research Matters: New Clues About Cleft Development

Why Does Cleft Lip and Palate Occur?

It may seem like a simple question, but the answer is complex. Scientists know that both genetic and environmental factors can play a role in cleft, but there is still much to learn about how these factors interact—and why cleft occurs in one child but not another.

Understanding why cleft occurs is more than a scientific question. It is part of a larger effort to understand cleft, explore new solutions and expand access to the comprehensive care people born with cleft conditions need.

For more than 16 years, Operation Smile’s International Family Study (IFS) has supported research to better understand the factors associated with cleft. The study brings together families, researchers and health care professionals from countries around the world, including communities that have historically been underrepresented in genetic research.

By studying families with different ancestral backgrounds and contexts, researchers can explore questions that may not be answered through research involving a limited group of populations. The findings can help build knowledge about cleft and inform future research and solutions.

Families in Madagascar Provide Genetic Clues

In 2023, IFS researchers studied genetic samples from families in Madagascar. Their research identified several genes that could play a role in cleft development and raised a new question: Could different genes work together to influence whether cleft occurs?

To explore that question, researchers from Operation Smile, the University of Southern California, Children’s Hospital Los Angeles and Nagoya City University studied five of the genes identified through the earlier research.

They used frog models as a way to study how these genes may influence facial development. While frogs and humans are very different, some biological processes involved in early development are shared. Laboratory models can help researchers study questions that cannot be tested directly in people.

When researchers changed the activity of each gene individually, the frogs did not develop clefts. But when they changed the activity of two genes—SEPTIN9 and MSX1—at the same time, the frogs developed clefts.

When researchers introduced normal versions of both genes, the cleft formations were no longer present.

New Pieces in a Complex Puzzle

The findings add to evidence that nonsyndromic clefting (when someone is born with a cleft and no other related conditions or genetic syndromes) may involve the combined effects of multiple genetic factors, rather than changes in a single gene.

Think of it as putting together pieces of a puzzle. One genetic change may not tell the whole story. Researchers need to understand how different genes interact and how genetic factors may work alongside other influences involved in development.

This study provides evidence that SEPTIN9 and MSX1 can work together to influence facial development. It does not explain all the reasons cleft occurs, and it does not mean these are the only genes involved.

Instead, it gives researchers another piece of information to build on as they study the complex biology behind cleft.

Why Global Representation Matters for Cleft Research

The study also points to an important question about who gets represented in genetic research.

Research has historically included some populations more heavily than others. When researchers study a wider range of communities and ancestral backgrounds, they may identify genetic variations and biological pathways that could otherwise remain undiscovered.

That is why global representation matters.

The International Family Study works with families in countries and communities that have historically been underrepresented in genetic research. While about 80% of global research is conducted in high-income countries, IFS exclusively focuses on low-and-middle-income countries. The findings from families in Madagascar are one example of how research involving diverse populations can lead to new questions and scientific insights. The discoveries about SEPTIN9 and MSX1 were possible because families in Madagascar participated in the research.

Turning Knowledge into Possibilities

For Operation Smile, research is part of the work of looking beyond what we know today.

Every person born with cleft has their own experience, needs and journey to care. Understanding more about cleft conditions can help researchers ask better questions, explore new possibilities and build knowledge that may inform future solutions.

Through the International Family Study, families around the world have opportunities to contribute to research that helps scientists investigate the genetic and environmental factors associated with cleft. What begins with families and communities can lead to new research, collaborations and insights that extend far beyond a single study or country.

This work is connected to Operation Smile’s broader effort to expand access to comprehensive cleft care and strengthen local health systems. Research alone cannot close gaps in access to care, but it can inform and improve support for patients, their families and health care teams around the world.

What Comes Next?

There is still much to learn about why cleft occurs.

The latest findings give researchers a foundation for investigating other combinations of genetic variants and better understanding the biological pathways involved in facial development.

For the families who participate in the International Family Study, their contributions are helping researchers ask new questions and expand what is known about cleft.

And for people born with cleft and their families, every question answered creates an opportunity to learn more, explore new solutions and continue working toward a future where everyone who needs cleft care can access it.