Rare mutation

Question

Our son, almost 2 years old, has the mutations F508del and E1104V.
The institute for human genetics told us that a prognosis cannot be given since his constellation was unique. Are you able to tell us something about it? Many thanks.

Answer

Hello,

The information given by the institute of human genetics is correct. The mutation E1104V has neither been described in the scientific literature so far nor is it listed in the mutation data base for CFTR mutations.
Under the condition that one parent is heterozygous for the mutation F508del and the other parent heterozygous for E1104V, your son is “compound”-heterozygous for both of these mutations (“compound”-heterozygous means that the patient inherited from both parents a different mutation in the same gene. Almost half of all CF patients are “compound”-heterozygous for two different CFTR mutations, of which one of both is very often the mutation F508del).
Since the mutation E1104V has not been described so far it cannot be predicted which clinical effects other patients with the genotype F508del/E1104V have shown. But even if this genotype would have been described several times, this would not lead to a reliable prognosis for your son. The reason for this is, that patients with the same genotype can have a very different course what the severity of the disease is concerned (this is called variable expressivity). At the most, an empirical statement can be made for frequent genotypes, like, for example: “the disease is mostly accompanied by a deficiency of pancreas enzymes” (or by no deficiency), or: “the disease is usually diagnosed in the first year of one’s life due to clinical symptoms” (or at a later age).

According to biometrical analysis, the mutation E1104V implies a loss-of-function of the CFTR-protein. Biometrical analysis are not argumentative but can only give a certain evidence for the pathogenicity of the mutation. It can be considered likely that E1104V being “compound”-heterozygous with F508del actually leads to CF. However, a reliable prognosis about the severity of the disease cannot be made at all.

Finally, for your son it can only be deduced that a cystic fibrosis could be explained by the detected genotype.

Best regards,
Prof. Stuhrmann-Spangenberg

01.08.2011