Cystic Fibrosis

Question

Good evening, I am in the 15th week of pregnancy and I a test for CF. The results showed that the nucleotide change c.330C>A (p.Asp110Glu) of the CFTR gene was detected in a heterozygous state. In the ClinVar database, it is characterized as unknown clinical significance, but also as pathogenic in terms of its association with the manifestation of Cystic Fibrosis and disorders related to the CFTR gene. In the CFTR-France database, it is characterized as a pathogenic change, while in the CFTR2 database it is described as a change with varying effects, some carriers of which in combination with a pathogenic mutation show symptoms of Cystic Fibrosis, while others do not. These were reported in my results. Now we are expecting my husband's. I would like you to tell me if this mutation that was detected in me gives a greater chance that, in the event that the husband also has a mutation, the child will be either a carrier or an affected person?

Answer

The c.330C>A (p.Asp110Glu) variant in the CFTR gene is a rare genetic variant of the CFTR gene, which has different evaluations in different databases:
• In ClinVar: it is classified as of unknown significance (VUS) but in some cases also pathogenic.
• In CFTR-France: it is recorded as pathogenic.
• In CFTR2: it is classified as a variant with variable effects, i.e. in combination with a classic pathogenic mutation it may or may not cause Cystic Fibrosis or related disorders.
You are heterozygous (carrier) — this means that you do not have Cystic Fibrosis, but you have one copy of the gene with this variant. The risk to the child depends solely on whether your husband is also a carrier of a pathogenic mutation in CFTR.
Scenarios depending on the husband's results:
1. If the husband is NOT a carrier:
• The child can inherit either the normal gene or the mutant one from you.
• If he gets the mutant one, he will be a simple carrier (like you) — he will not have the disease. In this case there is no risk of Cystic Fibrosis.
2. If the husband is a carrier of a pathogenic mutation:
• Then the child has a 25% chance of inheriting both of your mutations - it does not have to be the same mutation.
• In the case of your variant, because it is not an absolutely "clear" classic mutation, but has been characterized as having "various effects", if the child gets your variant and a pathogenic one from the father, there is a possibility of either:
o showing a mild form of the disease,
o or being a carrier without obvious symptoms,
o or manifesting related disorders (e.g. infertility, mild respiratory problems) — this depends on the combination of the two mutations.
So, if the husband is a carrier, genetic counseling should be done and the need for amniocentesis or other prenatal testing for the fetus should be discussed.

Answer to your question:
The c.330C>A (p.Asp110Glu) variant does not increase the risk by itself. The risk depends entirely on whether the husband is also a carrier of a pathogenic mutation. If the husband is a carrier, then there is indeed a chance that the child will be affected or a carrier — depending on what he inherits.
If he is not a carrier, the child is not at risk of developing Cystic Fibrosis — he has a chance of being a carrier, just like you.
Best regards,
M Poulou

25.04.2025