What is "Mosaicism" anyway?

This is the finding that explains how a person can have VHL when neither of the parents has VHL. And sometimes there are two children with VHL born of parents who test negative for VHL.

This is a puzzle that has only been explained since 1996. To understand how it happens, we need to review some basic genetics.

You know that normally VHL follows a "dominant" pattern of inheritance. Everyone has two copies of the VHL gene. If you have the genetic alteration that causes the condition called VHL, one of your two copies of the VHL gene is in good working order, and the second copy is altered in some way. It could be one small misspelling in the book of instructions for making the VHL protein. It can be quite subtle.

When you make a baby, half of your genetic information goes into each egg or sperm. In other words, you pass to the child one of your two copies of the VHL gene -- either the whole one or the altered one. Your half joins with the DNA of your mate, to make the whole DNA information for the new child. That one cell divides and differentiates to become a baby. Every cell in the body has the same DNA information, put together at conception.

Now for mosaicism. You know what a "mosaic" is, right? A mosaic picture or floor is made up of small bits of glass or tile, assembled to make a pattern or picture. Each piece is different, but they are joined together to make a strong whole.

The concept is that at conception a single cell is formed, and all the VHL genes are normal, from both parents. That cell divides and divides until there are -- let's say either or sixteen cells. At this point, something happens and one copy of one VHL gene in one of the eight cells is altered. This is called a "somatic" event -- after conception. It happens in only one of the eight cells. As those eight cells continue to divide, the cells that are formed by seven cells are normal. The cells that derived from that one altered cell carry the VHL mutation.

Let's say that the cells affected with the VHL alteration go on to become kidney and pancreas. This person is now at risk for VHL tumors of the kidney and pancreas. The blood, however, was derived from the cells that do not have the VHL alteration. When we do a DNA test on this person, it comes out "negative" because we do not find the alteration in the blood cells.

The outstanding question remains, though, whether the gonads (testes or ovaries) carry the VHL alteration or not? Depending on the answer to this question, the eggs or sperm will, or will not, carry the VHL alteration to a new child. Again, there is no easy way to test this. The only way to tell definitively would be to test the children.

If the gonads are affected, then the person who is mosaic for VHL may have one or more children affected with VHL. Each time you make a baby, there is a 50% chance that that child might get the altered gene. The child will get one of the two copies you have to pass. But since there is a chance (let's say one in eight) that the gonads are affected at all, one might say that you have a 6% chance of passing the gene to a child. In fact your chances are either 50% or zero, but at this point there's no way to tell.