Genmutationcombi F508/R117H symptom free

Question

My husband (age 46) has a very mild disease of CF (F508/IVS-5t) so that most of his life he has been without any symptoms. He only has absence of the vas deferens. Now they have found out that I carry the R117H mutation. Since we would like to have children we want to know about possible risks. When surfing the net I found out that the worst possible combination (F508/R117H) does not necessarily lead to a sick child but that just as my husband such a person could go through life without any symptoms. The explanation would be that R117H is not always associated with symptoms. Is this correct ?

Answer

Dear questioner,

Your husband carries F508del and the T5 on his other CFTR gene. You carry R117 and a normal (NL) CFTR gene.

In case you get pregnant for every single pregnancies one of the four following combinations will occur and every combination has a 25% chance to happen.
1. F508del / NL
2. T5 / NL
3. R117H / T5
4. R117H / F508del

Situation 1 and 2 (50%) do not lead to CF.

For combination 3 and 4 it’s harder to give a simple answer. The consequences of the R117H mutation are very variable. They can lead to CF but they can also lead to a totally healthy individual. To make it even more complicated the mutation R117H can be linked to T5 or T7. This should thus be tested in yourself. R117H-T7 is much more common than R1117-H T5.

The possible combinations of 3 and 4 will thus be:
3a. R117H-T5 / T5
4a. R117H-T5 / F508del
of
3b. R117H-T7 / T5
4b. R117H-T7 / F508del

Only combination 4a has a really greater probability of causing CF, allthough usually a mild form of it.

As to combination 4b: in a French study where newborns were systematically screened it was established that 8 individuals with this exact combination R117H-T7/F508del had no symptoms of CF up till the age of 9 years when the study was reported. Thus most likely less than 1 in 8 individuals with the combination R117H-T7/F508del mutation will not get any symptoms of CF during the childhood years. Other genes and environmental factors are at the basis of this variability. These are at present insufficiently knowledge to predict whether a specific individual carrying R117H-T7/F508del will or will not have symptoms. But we should state again that in that case CF patients with these mutations have a mild form of the disease.

For situations 3a and 3b its even harder than for situation 4. The chance of having CF would be even smaller and if it would occur one would expect that it would be a mild form of CF, even milder than people carrying the combination 4.

To conclude, with every pregnancy there would be 50% chance that the child would be healthy and 50% chance of the disease, allthough usually mild. Individuals carrying F508del and R117H mutation can have a mild form of CF, especially if this R117H is linked to T5. You do see that this is really complex matter and therefore we suggest you get in contact with a CF centre where there is a lot of experience with genetics and diagnosis and treatment of CF.
H. Cuppens

13.10.2009

13.10.09
Please find even more information about that topic under the term "genetics" ("Probability of outbreak" and "Another question on the answer of Prof. Stuhrmann-Spangenberg about 7T-allele").
D. d'Alquen

23.12.09
After discussion with several experts on this topic we want to add the following comment:
A larger recent French study confirms previous findings. The R117H mutations is often found without it causing clinical symptoms; hence the difficulty of including this mutation in a newborn screening panel. On the countrary, if a subject with symptoms suggestive of CF is being investigated and the R117H mutation turns up plus a second CFTR mutation in trans, this mutation explains the clinical picture in the patient.

Prof. Kris de Boeck