Part Two: New Research Explores a Possible Clue in Some Complex Cases of Moebius Syndrome

Last month, we shared a piece of research that caught our attention because it raised a question we had not seen discussed very much in connection with Moebius syndrome.

The study involved a child with Moebius syndrome who also had several other differences present from birth. Instead of only looking for a change in the child’s genes, researchers also looked at something called a DNA methylation pattern. In simple terms, this is a way of looking at how genes are being controlled or “switched on and off” in the body. What they found was unusual. The child’s pattern looked similar to one already seen in a group of people with several complex developmental conditions.

At the time, we were very careful about what that finding meant. It did not mean researchers had found the cause of Moebius syndrome. It did not mean everyone with Moebius syndrome would have the same pattern. It did not even mean the finding would turn out to be important beyond that one child. It was simply one case, but it was an interesting one because it suggested that, in at least some people with more complex physical differences, the answer may involve more than just the DNA code itself.

That was where the first article left us. Since then, more research has appeared, and it makes that original clue worth looking at again.

The important change is not that researchers have now proven a connection between Moebius syndrome and this pattern. They have not. What has changed is that the pattern itself is beginning to look more real and more repeatable in other people with complex congenital conditions.

To understand why that matters, it helps to think of DNA as the instruction book our bodies use to grow and develop. Genes are part of those instructions, but the body also has ways of controlling when certain instructions are used, how strongly they are used, and when they are turned off. DNA methylation is one of those control systems.

So, a person can have DNA that looks normal in the usual sense, but the way certain genes are being controlled may still be different. That is what makes this type of research interesting. Instead of only asking, “Is there a change in a gene?” researchers can also ask, “Were some genes being used differently during early development?”

The pattern found in the child with Moebius syndrome was similar to one researchers had already identified in people with other complicated developmental conditions, including VACTERL association and oculoauriculovertebral spectrum. These conditions can involve several parts of the body, such as the spine, limbs, heart, ears, or other organs.

In 2024, researchers studied 53 people with these types of complex congenital differences and found a shared DNA methylation pattern in 40 of them. The researchers called this an RCEM episignature. RCEM stands for “recurrent constellations of embryonic malformations,” a term used for groups of congenital differences that repeatedly appear together but often do not have a known single genetic cause.

That was an important first step, but one study is never enough. In science, a finding becomes more meaningful when it can be seen again in a different group of people.

That is now beginning to happen.

In July 2026, another research team released a study involving 38 people with related congenital conditions. Among 21 people diagnosed with VACTERL, 18 showed a strong match to the same RCEM pattern, while the remaining three showed an intermediate match. The researchers described this as an independent validation of the original finding. The study is currently a preprint, which means it has not yet gone through the full peer-review process, so the results still need to be viewed with appropriate caution.

Even with that caution, this is important because researchers are now seeing the same general biological pattern in another group of patients. That makes it less likely that the original RCEM finding was simply a one-time observation.

And that brings us back to Moebius syndrome.

The child we wrote about last month had a DNA methylation pattern that resembled this same RCEM signature. That does not suddenly prove a connection between RCEM and Moebius syndrome, but it does make the original finding more interesting than it was before.

When we first reported it, we were looking at one child whose results resembled a pattern seen in other developmental conditions. Now researchers are continuing to identify that pattern in additional people with complex congenital differences. The question becomes worth asking again: could there be a small group of people with Moebius syndrome, especially those who also have several other physical differences present from birth, who share some of the same developmental processes?

We still do not know the answer, but there is now more reason to study the question.

Another major Moebius syndrome study adds an interesting piece to the picture. In 2025, a research team led by Bryn D. Webb, who serves on the board of the Moebius Syndrome Foundation, examined 149 people who met strict diagnostic criteria for Moebius syndrome. Detailed genetic testing using exome or genome sequencing was performed on 67 of them. The researchers found several possible genetic clues, but they did not identify one repeatedly altered gene that clearly explained Moebius syndrome across the group.

That does not mean genes are unimportant. It simply means the answer may be more complicated than finding one single “Moebius gene.” It is possible that different people can arrive at the same diagnosis through different developmental pathways.

That idea actually fits what we already see in the Moebius community. Two people can both have Moebius syndrome and still have very different physical features. One person may mainly have facial paralysis and difficulty moving the eyes outward, while another may also have limb differences, chest wall differences, hearing problems, feeding difficulties, or other conditions present from birth. They may share the same diagnosis, but the way their bodies developed before birth may not have been exactly the same.

This is why research into gene regulation may matter. Early development depends on an enormous number of instructions happening at the right time and in the right order. If some of those instructions are used differently, even during a relatively short period of development, it could potentially affect how certain parts of the body form. Researchers are now asking whether that type of process could help explain some conditions that have been difficult to understand through ordinary genetic testing alone.

There is still a great deal we do not know. There is no evidence that everyone with Moebius syndrome has this DNA methylation pattern, and there is no evidence that most people do. At this point, researchers cannot even say that it identifies a definite subgroup within Moebius syndrome.

Answering that question would require studying DNA methylation in a much larger group of people with Moebius syndrome. Researchers could then compare those results with each person's physical features and look for patterns. They might find that the RCEM signature appears more often in people who also have differences involving the limbs, chest, ears, spine, heart, kidneys, or other parts of the body. Or they may find no consistent connection at all.

Either result would tell us something useful. It may turn out that the child in the original report was simply an unusual case. It may turn out that a small subgroup exists. Or this line of research may eventually lead scientists somewhere completely different.

That is really why this research is worth following. Researchers have not found the cause of Moebius syndrome, and we should not suggest that they have. What they have found is a clue in one child that now connects to a biological pattern other researchers are continuing to identify in complex developmental conditions.

That makes the original question more interesting than it was when we first wrote about it. It also gives researchers a stronger reason to keep looking. Science does not always move forward because someone suddenly discovers the answer. Sometimes it moves forward because a small clue survives closer examination and becomes important enough to investigate again.

References

Haghshenas S, Karimi K, Stevenson RE, et al. “Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations.” The American Journal of Human Genetics. 2024;111(8):1643–1655. DOI: 10.1016/j.ajhg.2024.07.005.

Postma J, Haghshenas S, Bily TMI, et al. “Validation of the VACTERL Episignature and Evidence for Epigenomic Convergence Across Recurrent Constellations of Embryonic Malformations.” medRxiv. Preprint posted July 2026. DOI: 10.64898/2026.07.10.26357391.

Webb BD, Jurgens JA, Narisu N, Zhang Z, et al. “Systematic phenotype and genotype characterization of Moebius syndrome.” Genetics in Medicine Open. 2025;3:103437. DOI: 10.1016/j.gimo.2025.103437.