Mutations, do I have CF now?

Question

Dear expert team, could you please explain the following mutations to me?
Result and interpretation:
I have in the exon 21 of the CFTR gene the mutation p.Asn1303lle (c.3908A>T, traditional writing 4040A>T) heterozygously. The clinical meaning of this change is not clearly described. Furthermore, I am a heterzygous carrier of the TG 12-5T-allele in the CFTR gene. Patients with a 5T-allele and 12 TG-repeats in the neighbourhood of it, have, according to Groman et. al (2004), in combination with a second recessive mutation a risk of getting the illness of 78%. The diagnostical meaning of these changes should be judged in combination with the clinical data.

This mutation leads to an incorporation of the aminoacid Isoleucin instead of Asparagin at the position 1303(p.Asn1303lle) and has been described by Ferec et al (cystic Fibrosis Consortium Newsletter 66, 1995) in a Frech CF patient together with a second heterozygous mutation on the other allele.

According to Claustres et al., 2000, the clinical impact remains unclear, as this mutation has been found in patients with a typical CF as well as in patients with a mild or gential form of CF.

The in the intron 8 observed 5-T-allele is juged as a splice mutation and has already been described as illness causing in the literature in the context of a mild or gential form of CF. In intron 8 the 5T/7T-allele is heterozygous.

The direct analysis of the genotype includes the most frequent mutations in mid-Europe in the CFTR gene and covers therefore about 97% of genetic changes in patients with CF:
What happens when the aminoacid Isoleucin is incorporated?
Is this a real CF? A mild form?
I would be pleased if you could comment on this topic.
Thank you

Answer

Hello,
the question if you suffer from CF or not can not be answered according to result of the molecular genetic investigation alone. As obviously already mentioned in the result, the mutation p.ASN1303Ile can be found in patients with a "typical CF", as well as in patients with an atypical form of the illness. This mutation is a so-called missense-mutation, that means formally the codon 1303 of the CFTR-gene is changed and at this site of the CFTR-protein there is then a false aminoacid (Isoleucin instead of Asparagin). How strong the impact of this change on the function of the CFTR-protein is, is not proven. The greater the loss of function, the greater the clinical consequences. In order that it can come to clinical consequences at all, there has to be another mutation on the second CFTR-allele (CF is inherited autosomal-recessive, that means affected patients have inherited one mutation in the CFTR-gene from each parent). In your case, there has been found as a second genetic change a variant in intron 8 of the CFTR-gene, which is associated with atypical forms of CF. However, not all people who carry on one CFTR-gene a typical mutation and on the other CFTR-gene this 12TG/5T varaint, develop any symptoms at all.
I would urgently recommend that you should let the result of the molecular genetic investigation be explained to you in the frame of a genetic counselling. With that one has also take into account, if, according to the investigation of your parents, it could have been shown, that both of the above mentioned changes in the CFTR-gene are located on the two different CFTR-genes, and are not located both on one CFTR-allele. Furhtermore the clinical picture has to be taken into account. For this, it is urgently recommended to present at a CF-center.
According to international valid diagnostic criteria, it can be decided via the CF-center, if you have a CF formally or not. Finally it has to be mentioned that even when fulfilling the formal diagnostic criteria for CF, the clinical expression of the illness is very variable.
Yours sincerely,
Prof. Stuhrmann-Spangenberg

21.04.2010