How a hidden gene twist caused a rare disorder

Imagine searching for an answer to your family's health puzzle for over 40 years. That is what happened to a family affected by craniofrontonasal syndrome, or CFNS, a rare condition that changes the way faces and skulls grow. Recently, scientists finally uncovered the cause: a hidden twist in the DNA near an important gene, offering hope and new information for families and doctors alike (original research article).

What is craniofrontonasal syndrome?

Craniofrontonasal syndrome, or CFNS, is a rare disorder that affects how the bones of the head and face form. People with CFNS often have wide-set eyes, a broad nose with a split tip, cleft lips or other facial differences, and sometimes other body changes. Strangely, girls with CFNS tend to have more severe symptoms than boys, which is the opposite of what usually happens with conditions linked to the X chromosome.

Why do girls have more severe symptoms?

Genes are like instruction books in our cells. Boys have one X chromosome, while girls have two. In CFNS, a gene called EFNB1 is involved. Because girls have two X chromosomes, each cell randomly turns one off, so their bodies end up with a mix of cells using either the healthy or the changed gene. This patchwork, or “mosaic,” of cell types can cause more noticeable problems, a phenomenon called "cellular interference." This concept is a bit like how some rare diseases, such as VEXAS syndrome, arise from a mix of changed and normal cells, as explained in this SlothMD article on VEXAS syndrome.

The long search for answers

For decades, doctors knew that changes in the EFNB1 gene caused CFNS. But when they tested this family, they could not find any changes in that gene. This left them searching for answers. It turns out that about 20% of people with CFNS do not show the expected changes in standard genetic tests (more on genetic testing challenges).

The hidden inversion: a DNA twist

To solve the puzzle, scientists used advanced whole genome sequencing—a powerful tool in health AI and modern medicine. They found a large section of DNA, called an inversion, that had flipped direction about 106,000 letters downstream from the EFNB1 gene. This twist did not break the gene itself but landed in a region that helps control how much the gene is used. The inversion also caused two tiny deletions.

To check if this DNA twist was really the cause, the team made special stem cells from the family's skin cells. They discovered that when the X chromosome with the inversion was active, EFNB1 was much more active than normal. This unbalanced activity can disrupt how cells stick together and talk to each other, leading to the unique features of CFNS (read more about mosaicism in stem cells).

How does gene regulation work?

Genes often rely on distant switches, called enhancers and insulators, to control when and how they turn on. The inversion in this family broke up these normal controls, like messing up a light switch that is far from the lamp itself. Recent studies show that changes in these switches, even without touching the gene, can have powerful effects (see DNA regulatory elements). In fact, flipping the direction of DNA can rearrange the way the genome folds, changing how genes are read (see research on genome folding).

Why does this matter for families?

Finding this DNA inversion ended a 43-year diagnostic mystery for the family. Now they understand the cause of CFNS in their family, which helps with planning for future children and managing health. It also shows the value of looking at the whole genome, not just the obvious genes, when solving rare disease puzzles. This approach is similar to how health AI tools like SlothMD are helping people discover new ways to stay healthy—for example, by understanding how muscle power affects aging, as described in this SlothMD article on muscle power.

The future of genetic diagnosis

This discovery highlights the importance of advanced genetic testing in rare diseases. Understanding the big picture of how our DNA works, including hidden twists and turns, can lead to better treatments and answers for families around the world. More research is needed, but with tools like health AI and genome sequencing, scientists are closer than ever to solving even the toughest health mysteries (see how inversions are being discovered in rare diseases).