p.F508del

Question

Hello,
We just received the two mutations of our daughter. The p.F508del and c.3140-26A> G (3272-26A> G)
Please, what will be the common impacts of these changes even though I know it varies from one individual to another?
Thank you in advance for your help and feedback.

Answer

Hello,
Indeed, the mere knowledge of mutations in the cystic fibrosis gene (CFTR gene) cannot predict the progression of symptoms for a given individual. This development varies from one individual to another and depends on many factors: genetic factors (CFTR gene mutations, modifiers genes) and environmental factors (pollution, lifestyle, access to health care ...).
However, knowledge progresses through analysis of databases that collect genetic and clinical information of thousands of patients. This is the case of the database CFTR2 that is freely available but is in English.
In summary, it states that the 3272-26A> G mutation is a so-called "causing CF" mutation, meaning it causes CF when combined with another mutation "causing CF” fibrosis." In other words, the discovery of two “causing CF” mutations combined in a patient enables the diagnosis of CF. This is the case with your daughter.
There are to date more than 1,800 known mutations in the CFTR gene. Each individual has two copies of the CFTR gene, one inherited from the mother the other from the father. So there are millions of possible combinations of two mutations.
The 3272-26A>G mutation is present in only 186 patients in the database CFTR2 and in 139 of them it is combined with the F508del mutation. Those patients who have the same genotype that your daughter:
- Have an average sweat test value of 94 mmol/l, the same as the average of all patients (the test is said to be positive when greater than 60 mmol/L);
- Have pancreatic insufficiency requiring pancreatic enzymes taken by mouth present for 1 in 2 (46%), while present in more than 4 in 5 (87 %) for the all CF patients;
- Have respiratory disease (FEV value) which is not significantly different from that of other patients.
I remind you that the situation of each patient is unique and prognostic extrapolation from a single genotype is abusive. I can only recommend that you continue to monitor your child's health by a multidisciplinary team of a specialized CF center able to discuss with you the treatment decisions demanded by the situation of your child.
Hope that answers meet your expectations.
Sincerely.

Gilles RAULT
Roscoff CF Center

10.09.2014

10.09.14
For extenden information about this particular mutation, there is a paragraph in the guidelines by Castellani et al in the Journal of Cystic Fibrosis 7 (2008) 179-196: "Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice":
"Splicing mutations [remark: splicing means a certain processing of the genetic information on its way from the DNA of the chromosomes to its translation in a produced protein] that still result in a fraction of correctly spliced transcripts, together with aberrantly spliced transcripts, may belong to the CF-causing or the CFTR-related disorder group (e.g. ...3272-26A>G...)Patients carrying these mutations often have a relatively mild phenotype, yet with varibale disease expression, from minimal lung disease, pancreatic sufficiency and male infertility to a relative severe disaese in all the involved organs. This variable disease expression is inversely correlated with the quantity of correctly spliced transcripts, i.e. lower levels are associated with a milder phenotype."
D. d'Alquen