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Diseases

Hi. My wife is a carrier of fragile X, with 80 repeats on one X. (There is no history of Fragile X in her family, and our son is not affected.) What are the chances that our children will have fragile X?

Just a side question, her father has green/red color blindness. Could this have any significance? Assuming the Fragile X was inherited from her mother, does this mean our sons would all either have the Fragile X gene or be colorblind?

-A curious adult from Israel

With your wife's premutation (see below), there is a 30-40% risk of your son, and probably your daughter, of having a full mutation. However, while nearly all boys with the full mutation will show signs of the disease, only half of the girls will.

Fragile X is the most common form of inherited mental retardation. About 1 in 4000 males have Fragile X, while only half as many females have it. Fragile X is caused by mutation of a gene on the X chromosome called FMR-1. We don't know exactly what FMR-1 does, but it may be involved in forming the brain.

Males who inherit the mutation are always affected because they only have one X chromosome. (Remember, females have two X chromosomes, males an X and a Y.) In females the outcome is variable. About half of women who inherit the mutation have the disease. Usually it is a milder form than that seen in males. In other cases, the normal X chromosome provides enough FMR-1 protein to prevent brain defects.

So how does someone get Fragile X? Fragile X happens when a certain part of the FMR-1 gene gets too long. There is a part of the gene that normally has between 6 and 54 repeats of the same 3 bases. For most people, the number of repeats stays pretty stable.

Then, for reasons we don't understand, the number of repeats begins to increase. When the number of repeats is above 55, the gene is now said to have a premutation. A premutation is pretty unstable and the number of repeats increases over generations. Once there are 200 or so repeats, the symptoms of the disease kick in.

What happens at 200 repeats is that no FMR-1 protein is made from that copy of the gene. All those repeats act like a skip in a record that blocks the song from finishing. The DNA can't be read through to make the FMR-1 protein.

As you can probably tell, Fragile X inheritance is pretty complicated. The bottom line is that you can only get the full mutation from your mother.

A premutation passed through a father usually expands only a little or not at all. So, his daughters will also have a premutation on one of their X chromosomes. His sons inherit his Y chromosome--no Fragile X risk!

With moms, it is a different story. In female carriers, the repeat sequences can expand when passed down to her children. Can a geneticist say when a premutation will turn into a full mutation? Regrettably, that's not possible with current tests. However, the longer the premutation, the greater the risk of expansion to full mutation size.

Females with the full mutation have a 50% chance of passing that mutation to their children. Since she can't get an X with the mutation from her dad, she can only have one X with the mutation at a time. Each child has a 50% chance of inheriting the X with the mutation. Most of the possible combinations are outlined in the table below.

Father Mother Son Daughter
XY
No disease
XX
No disease
XY
No disease
XX
No disease
XpreY
Carrier
XX
No disease
XY
No disease
XpreX
Carrier
XY
No disease
XpreX
Carrier
XpreY
XY
50% chance of either carrier or Fragile X
XpreX
XX
50% chance of either carrier or Fragile X
XY
No disease
XmutX
50% chance of having Fragile X
XmutY
XY
50% chance of Fragile X
XmutX
XX
50% chance of mutation, 25% chance of Fragile X

(This is oversimplified a bit as the actual percentages are lower. This is because of something called mosaicism which is fairly common with Fragile X. To learn more about mosaicism, go to mosaicism in the GeneTests glossary.)

Now if you really want to get into colorblindness, keep reading! The gene that causes red/green color blindness is located on the X chromosome, like the Fragile X gene. You are right to suggest that your sons will inherit one of your wife's two X chromosomes, with either a Fragile X mutation, or the color blindness gene.

The four possible combinations are diagrammed. Sons (XY) will be either colorblind (ColBl), or inherit an abnormal Fragile X (FraX) gene. Daughters, XX, will be carriers for either the colorblind mutation or Fragile X. While one color blindness gene in a female will have no effect, the Fragile X gene could cause disease.

How is color blindness inherited? It is a recessive trait, meaning that as long as one good copy of the gene is around, color vision is normal. Since males have only one X chromosome, they are always affected by color blindness if they inherit a mutant gene. Females have two Xs so they are rarely affected. It can happen though, if they inherit a mutant gene from both their father (who would be colorblind) and their mother (who is a carrier).

So, while the genes for red-green color blindness and Fragile X are both located on the X chromosome, they are inherited differently. The outcome for color blindness is predictable. An abnormal Fragile X gene is unstable and can change in each generation.