Cystic Fibrosis

Question

Hello doctor. I am 12 weeks pregnant and I took the CF test at 99.6% and the following result was obtained:
The tested sample did not detect any pathogenic or likely pathogenic mutation that mediates the classic CF disease. The tested sample is heterozygous for the p.Pro750Leu (c.2249C>T, rs140455771) variant of the CFTR gene (NM_000492.4) which is characterized as having multiple effects by the CFTR2 genotype-clinical phenotype association database.
The clinvar database has conflicting reports regarding the possible pathogenicity of the mutation: 1 entry as pathogenic, 12 as probably pathogenic and 5 as of unknown clinical significance. Based on the current literature, the above variant
appears to be positively associated with congenital absence of the seminiferous tubules.
We were recommended genetic counseling. Our doctor urged us to have our husband do the full test. We received the first results where he had done the ΔF508del and it came out negative. Is there a chance that the mutation I have is pathogenic and the fetus will suffer from CF? Would a mutation on the husband's side have a negative outcome? Thank you

Answer

The p.Pro750Leu, (c.2249C>T) variant has a variety of consequences.
Some patients with this variant, in combination with another variant that causes Cystic Fibrosis (CF), have CF.
Other patients with this variant, in combination with another variant that causes CF, do not have CF.
Because of this variability, it is very important to use CLINICAL CRITERIA ONLY to determine whether a person with this variant has CF.
Because the clinical manifestations of CF can vary over a person's lifetime, people who have this variant plus a variant known to cause CF should have periodic check-ups with their doctor even if they do not currently have clinical signs or symptoms of CF.
From the clinical data it appears that in combination with a pathogenic variant it contributes to the occurrence of a disease related to Cystic Fibrosis (e.g. CBAVD).
Depending on the findings in the husband's tests, an assessment should be made for the current and subsequent pregnancies.
Best regards,
M. Poulou

05.03.2025