Mutations

Question

Hello,
can you tell me what these changes has, by drawing on the answer given here:
http://ecorn-cf.eu/index.php?id=65&L=5&tx_expertadvice_pi1[showitem]=2125&tx_expertadvice_pi1[search]=
My son has two mutations, DeltaF508 and CFTRdup2_18.

Answer

Dear questioner,
There are over 1800 known mutations of the CFTR gene (the cystic fibrosis gene) that are grouped into five or six classes according to the way they affect the synthesis or functioning of the CFTR protein which serves as an ion channel in the cell membrane. Class I-III mutations result in defective synthesis, processing, maturation and regulation of the CFTR protein with an abolished function of the ion channel. Class IV-V mutations result in defective conductance, reduced function/synthesis and increased degradation of the CFTR protein, though still with a residual expression and function of the ion channel.
When a patient has a mutation of a different class in each of his/her two CFTR genes, the less severe mutation affects the functioning of the protein and therefore part of the clinical expression of cystic fibrosis. In general, patients with two mutations from class I-III exhibit a phenotype associated with pancreatic insufficiency and a more severe course of the disease compared to patients with at least one class IV-V mutation. Class IV-VI mutations are usually associated with pancreatic sufficiency and milder lung disease. However, the classification of mutations is not always conclusive and possible.

In your case, one mutation (F508del or DelataF508) belongs to class II; however, but the other mutation has not been reported in the Toronto database neither in the French database in Montpellier.
It is difficult to comment on the pathogenicity of a large duplication before any substantive work has been done. Indeed, if there has been no further study to investigate the position and orientation of the duplicated fragment, it is not possible to "predict" the consequences (duplicating a large portion of gene is not necessarily inserted in the extension of the normal sequence). In the event that it is integrated in the coding sequence of the gene, it would probably be considered involved in the classic CF forms.
To advance the "prediction" of the deleterious effect of this duplication, one should contact the laboratory who identified the mutation and ask them if they have been able to "limit" it (ie specify where the duplicated sequence is inserted, and in which direction it is facing duplicated fragment) or if the boundary is underway.
However, mutation analysis only gives a rough direction but it has to be clearly stated that the individual clinical course and especially the degree of lung involvement cannot be predicted according to the genotype, as many other genetic (modifier genes, etc.) and environmental factors play a role and the severity of disease differs substantially even between patients with the exact same mutations. Therefore, it is very important that the individual patient is seen regularly in a certified CF center and follows his individual treatment program.

Concerning the effect of molecules developed by Vertex, the F508del mutation is involved in clinical trials with the association of two molecules Ivacaftor + Vx-809, currently only in patients carrying two mutations F508del. Other tests and other molecules are under development.
Sincerely,

Dr Sophie Ravilly with the help of Dr. Marie Desgeorges (Banque CFTR France, Montpellier)

18.02.2013