CF mutations

Question

After genetic testing for CF my wife was found to be a carrier of the c.3635G>T mutation. According to the results the aitiopathology of the mutation is not defined and the mutation is considered to be of unknown clinical significance. I was tested as well and found to carry the c579+3A>G mutation. Both tests were for 99.9% of CF mutations. What is your opinion about the chances for a healthy fetus?

Answer

Dear friend,
Your wife is a heterozygote of the mutation c.3634G>T, for which there are no clinical information. You were found to carry the 570+3A>G CF mutation. All this was due to typical genetic testing.
The CF gene is a a large gene that is found on the long leg of chromosome 7. It regulates the production of the CFTR protein, which is comprised of 1400 aminoacids. This protein if found on the surface of epithelial cells of exocrine glands. The main function of this protein is to control the chlorine channels.
Uptodate there have been over 2000 mutations reported, the majority of which are considered pathological, i.e. the affect the production, or the function of the CFTR protein. In the greek population the most common mutation, the DF508, has been found in 53.4% of CF cases. There are 64 other CF mutations that are reported in over 0.1% of patients, and nearly as many others that are reported in less than 0.1% of patients, i.e. in one patient only.
For these reasons a world wide database has been created, the CFTR2, in which CF patients from all other the world (national registries, CF centers) are recorded, and clinical data of the most common CF mutations from 89509 patients are gathered.
During the last recording of 8/12/2017 the clinical significance of 374 mutations was noted.
312 mutations cause CF
36 present a variable clinical manifestation of CF
13 do not cause CF
13 are of unkown clinical significance.

The fetus has a 25% chance to carry no CF mutation at all, a 25% chance to carry the c.3634G>T mutation, in which case it will be healthy like your wife, a 25% chance to carry the 579+3A>G mutation (your mutation), in which case it will be healthy, and a 25% chance to carry both mutations. In this last case, the American association of CF, in its consesus about the diagnosis of the disease and the use of genetic testing for verifyning the diagnosis, recommends:
(A) The existance of two mutations that cause CF in different chromosomes means that the person will suffer from CF.
(B) A mutation of variable clinical importance, in combination with a Cf causing mutation, or in combination with a CF mutation of variable clinical importance, may cause CF.
(C) Mutations of unknown clinical importance, whn combined with a CF causing mutation, may cause CF, or manifestation of CF of variable clinical severity, or they may be begign.
(D) A person with one, or more, mutations that do not cause CF is not probable to manifest CF (Sonesy 2017).

You belong in category C. I am at your disposal for further information at tel. number: 2132037304 (10.00-14.00).
Yours friendly,
Dr. Stavros Doudounakis

09.09.2018