CF mutation combination A120T and E826K

Question

I am 14 weeks pregnant, I am heterozygous for c.358G>A exon 4 (A120T) of varying clinical significance and my husband is heterozygous for C2476G>A exon 13 (E826K) of unknown clinical significance. Will the fetus have CF? Or will it simply be a carrier? Is trophoblast screening, amniocentesis or NIPT required? Thank you

Answer

Your results:
• You: c.358G>A (p.Ala120Thr / A120T) — of variable clinical significance.
• Husband: c.2476G>A (p.Glu826Lys / E826K) — of unknown clinical significance.
Both variants:
• are not among the classic pathogenic mutations associated with typical CF.
• are of uncertain or unknown clinical significance and when combined, are not considered to be at high risk for typical CF.
Will the fetus be affected?
If both parents are carriers of the specific variants, the possible scenarios are:
1. The fetus is a simple carrier (like you or your husband) (50% probability)
2. The fetus is not a carrier of any mutation (25% probability)
3. Either inherits both variants (one from each parent – ​​25% probability) — in this case, due to the mild and ambiguous nature of these variants, the child is not expected to suffer from the typical form of Cystic Fibrosis.
In practice, such combinations are in most cases associated with:
• no symptoms at all,
• or in a few cases, with mild forms of the disease, e.g. some respiratory sensitivity or possible infertility in boys (CBAVD), without manifesting serious disease.

Is trophoblast screening / amniocentesis or NIPT necessary?
1. NIPT (non-invasive test):
Does not test for Cystic Fibrosis, only for chromosomal abnormalities such as Trisomy 21, 18, 13, etc. – Not a suitable test for Cystic Fibrosis
2. Trophoblast / Amniocentesis:
Can give a clear answer as to whether the fetus has inherited both variants. The decision to test with trophoblast or amniocentesis depends on your own desire, as these variants are not considered classic pathogenic variants of the disease.
Best regards,
M. Poulou

25.04.2025