DF508 mutation and mutation of unknown significance

Question

I am 22 weeks pregnant in my second child.
I was to be a carrier of the DF508 mutation, while my husband carries the c3118c>T (L1040f) mutation, of unknown clinical significance. We were not tested when we had our first child, and the geneticians advised us to test our firstborn, who was found to carry both mutations. His clinical picture is excellent, as is his growth. In 2.5 years he has suffered only one bronchiolitis and episodes of laryngitis, without high fever. His sweat test is 47. We were advised not to do an amniocentesis, since, based on the picture of our child, even if the fetus carries both mutations, the symptoms will be very mild.
1) Can the symptoms in the future become severe?
2) Since it is a boy, is sterility a given?
3) What does a borderline sweat test mean? Is it not positive?
Thank you!

Answer

Dear friend,
You are 22 weeks pregnant in your second child. You carry the DF508 mutation and your husband is a carrier of the c.3118C>T mutation.
For the above reasons the geneticians recommended to check you 2.5 years old child, who does not have a history of respiratory infections, except for an episode of bronchiolitis and two episodes of laryngitis. His genotype showed that he carries both mutations and the value of chlorids in his sweat test was 47 mmol/L.
You were advised that an amniocentesis is not necessary, should you wish to terminate the gestation, due to the mild clinical picture of your 2.5 years old child and the borderline value of the sweat test.
Dear friend, the cystic fibrosis gene is a very large gene with many mutations, over 2000. For this reason, there is an international database (CFTR2) and a reference system that was created to give information about the clinical picture and the importance of the mutations. It collects clinical data about the CF mutations from all national report centers (registry), connected to large CF centers in Europe, the Americas, Australia and some countries in Asia.
In their last report (8/12/2017) there are information about the most frequent mutations that have been recorded from 89502 patients. The number of recorded mutations is 374, out of which:

312 mutations cause cystic fibrosis
36 have a variable clinical expression
13 mutations do not cause cystic fibrosis
13 mutations are of unknown clinical importance.
Based on the correlation of the mutations to the CFTR2 data for assisting in the prebirth diagnosis, or in case of a positive neonate screening:

Finding 2 mutations means that there is cystic fibrosis (confirmation through sweat test is necessary)
A mutation of variable clinical importance, when combined with a CF causing mutation, or another mutation of variable clinical importance, may cause typical CF.

A mutation of unknown clinical importance, when combined with a mutation not included in the CFTR2 database, may cause typical CF, or CF of variable expression, or a beging form of the disease.
People who carry one, or more mutations that do not cause CF, will not have CF.
DF508 is the most frequent typical CF mutation worldwide. There are, however, no information about C3118C>T in the CFTR2 database, nor in the scientific literature.

The values of the sweat test are evaluated as follows:
Chloride concentratation under 30 mmol/l = normal
Chloride concentration between 30-60 mmol/l =borderline
Chloride concentration over 60 mmol/l = pathologic.
A concentration of 47 mmol/l ist borderline, a boy will probably be infertile. That does not exclude the possibility to become a parent after using his sperm for IVF procedures.
You were recommended to monitor regularly the development of the disease.

Yours faithfully,
Dr. Stavros Doudounakis

04.05.2018