Cystic Fibrosis Related Disorders

Question

I am 21 weeks pregnant. I was found to carry the DF508 CF mutation and my husband the c.220C>T (p.R74W). Does this combination cause mild or severe CF symptoms? Do you recommend an amniocentesis? We have two conflicting opinions. Thank you.

Answer

Dear friend,
You are 21 weeks pregnant and you were found to carry the DF508 CF mutation, while your husband is a carrier of the R74W mutation.
The CF gene is a large gene, which is located in the long leg of chromosome 7. It produces a protein, the CFTR protein, which is comprised of 1480 aminoacids and which can be found on the surface of the epithelial glands of exocrine glands. Its basic function is the normal functioning of chloride channels.
Up till now there have been more than 2000 CF mutations detected, the majority of which are pathological. This means that the production, or the function of the CFTR protein is affected. In the Greek population the most common mutation is the DF508, with a rate of 53,4%. 64 mutations have been found at a rate over 0.1%, and another 64 have been detected at a rate less than 0.1%, namely in one person.
For this reason a global database, the CFTR2, has been established. It collects data from national registries and CF centers from all over the world for the clinical significance of the common CF mutations from 89052 patients. After the last data collection at 8/12/2017 the clinical importance of 374 mutation has been established.
312 mutations cause CF
36 mutations have variable clinical manifestations
13 mutations do not cause CF
13 mutations are of unknown clinical significance.

Based on these data the R74W mutation does not cause CF.
Therefore, if you get pregnant, the baby will have a 25% chance to carry in heterozygote state the DF508 mutation, a 25% chance to carry in heterozygote state the R74W mutation, a 25% chance to carry no mutation at all, and, finally, a 25% chance to carry both mutations (R74W and DF508). In this last case the baby will not have CF, but it may present CFTR related disease. CFTR -RD is a clinical entity that is associated with the dysfunction of the CFTR protein, but does not fulfill the diagnostic criteria of CF (Bombieri 2011).
The main clinical manifestations are congenital bilateral absence of the vas deferens (CBAVD) in boys, recurrent of chronic pancreatitis and diffuse bronchiectasis in the adults.
In the international literature there are reports relating them to CBVAD (Clausters 2004, Terlizzi 2016). Regarding your question about amniocentesis, in order to find out the status of the fetus, and proceed accordingly, there are broader ethical and philosophical considerations, so you need to discuss the issue extensively and get a lot of information, in order for you to decide about future actions.
Yours friendly,
Dr. Stavros Doudounakis

22.06.2018