Mutation ΔF508 and c.650A>G

Question

Good evening.
I am 18 weeks pregnant and have tested positive for the Δf508 mutation for cystic fibrosis. My husband tested positive for the c.650A>G mutation today
We immediately informed my gynecologist who suggested that we do an amniocentesis.
What are the chances that the baby will be born with cystic fibrosis due to the mutations we carry? Do you think amniocentesis is necessary? I would like to avoid it due to the possibility of miscarriage later.
Thank you in advance for your answer.

Réponse

Mutations carried by parents:
• Mother: Δf508 (F508del – p.(Phe508del) classic pathogenic mutation, the most common cause of cystic fibrosis).
• Father: c.650A>G (p.Glu217Gly).
This mutation has been described in several studies, but it is not one of the classic pathogenic variants of the disease. The literature often characterizes it as a variant of uncertain significance or of variable clinical consequences, which in combination with a typical mutation such as Δf508 may lead to mild symptoms or in some cases to Cystic Fibrosis.
Probabilities for the baby:
If the fetus inherits Δf508 from you and c.650A>G from the husband, then we cannot predict with absolute certainty the clinical outcome. In some cases, such combinations cause mild cystic fibrosis or atypical symptoms. In other cases, they are almost asymptomatic. Rarely, typical symptoms of the disease may appear.
At 18 weeks of pregnancy, amniocentesis is the only safe test to determine whether the fetus has inherited both mutations.
Is amniocentesis necessary?
Medically: It is not "mandatory", it is optional and is always the parents' choice as long as they have been informed about the purpose of the test and the risks. Your doctor must inform you and you can decide whether you want to proceed with the test. If you do not proceed with amniocentesis, the diagnosis can only be made after birth (with a sweat test and molecular testing).
It is important to know:
• c.650A>G is often associated with a mild or non-classical form of CF.
• The combination with Δf508 in many cases does not lead to a severe clinical picture.
• Some individuals with this combination live without serious symptoms or show mild manifestations in the course of their lives (e.g. respiratory sensitivity, infertility in boys, mild digestive problems).
The risk for classic Cystic Fibrosis seems lower due to the nature of the husband's mutation, but it cannot be completely ruled out without knowing whether the child inherited both.
The decision to have amniocentesis is a personal one and must balance:
• the medical benefit (knowledge),
• with the small risk of the procedure.
Best regards,
M. Poulou

25.04.2025