Genetic counselling - Parents carriers of cystic fibrosis mutations

Question

Good morning,
I am in the 1st trimester of my second pregnancy. Both my husband and I carry cystic fibrosis mutations. (Husband in 95% resolution carries the change c.476T>C, while I carry D614G).
Our first child did not inherit any of these (as we knew after trophoblast testing & karyotyping) and is perfectly healthy.
In this pregnancy, recommendation is to receive trophoblast testing again, which I will certainly do.
My question is, what is the genetic counseling if the fetus is at 25% and inherits both changes? As far as we were informed in the 1st pregnancy, there is no recorded case in the literature of the appearance of a typical form of the disease with these combinations.

Thank you,
Christine

Answer

In the literature the p.Asp614Gly (legacy name D614G) variant when combined with a CF-causing variant results in a variety of clinical consequences. This means that some people who have the D614G variant and a CF-causing variant have CF, while others do not. In people with D614G who do not have CF, the D614G variant may contribute to clinical symptoms such as CFTR-related diseases.
The variant c.476T>C (p.Leu159Ser) is characterized as potentially pathogenic and has been reported in the literature in association with a pathogenic variant of the CFTR gene:
1) in people with symptoms of cystic fibrosis with pancreatic sufficiency
2) in people with mild symptoms of the disease and older age of disease onset
3) in male individuals with infertility
4) in asymptomatic individuals
According to the above a person with the combination of p.Asp614Gly and p.Leu159Ser variants may show some mild symptoms of the disease. They are expected to have pancreatic sufficiency and if he is male he is most likely to be infertile.
Prof. Myrto Poupoulu

07.10.2024