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DF508 and T7, T9 polymorphism


my daughter is 7 months old and she has been diagnosed with CF when she was 2 1/2 months based on her clinical symptoms and sweat test result over 100. She is severely pancreatic insufficient with no lung implications so far.
We performed genetic testing for her and it seems they detected delF508 and T7 and T9 polymorphism in her dna.

I am a carrier for delF508 and no mutation has been detected for my husband.

We would like to search for the other mutation as well as were told that T7 and T9 polymorphism don't mean anything in connection to her disease. Is this correct? I have been searching for info in relation to polymorphisms and it seems that they actually mean something in connection to a second cf mutation, but unfortunately I haven't been able to understand the medical terminology, therefore how they influence eachother and whether it has an impact on the disease.

Could you kindly explain the relationship between delF508 and the above mentioned polymorphisms? Should we search for another mutation? Can it be that only one mutation and these polimorphisms caused her desease?

Thank you,
Ana Toma
Dear Ana Toma,
There are over 1800 known mutations of the CFTR gene (the cystic fibrosis gene) that are grouped into 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-VI 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-VI 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, the most frequent CF mutation deltaF508 has been found in you and your daughter. This mutation impairs the maturation of the chloride channel protein, and is a class II mutation. This means, if it is in combination with another class I-III mutation, the classical picture of CF (pancreatic insufficiency, lung disease, sweat test values over 100mmol/l chloride concentration) occurs. However, when combined with a chromosome without any genetic CFTR mutation (like in your own case), the person with one copy of deltaF508 is a healthy carrier (being able to transmit the mutation to his offspring, however).
Your daughter seems to show the typical clinical picture of CF. A genetic analysis had been done and in addition to the deltaF508, 7T and 9T polymorphisms have been found. Those T tracts in the CFTR gene are called polymorphic tracts, as they can be found in variable length; three to four common alleles may be detected: T5, T7 and T9 and much rarer T3. T7 and T9 are the “normal “ variants, not resulting in CF at all. T3 and T5 are the variants, that could lead together with a certain length of a so-called TG repeat to disease symptoms, mostly however, even not to the classical clinical picture but only to mild courses. However, your daughter has the normal length of the T tract with T7 and T9, so this has nothing to do with her CF (probably you read about other polymorphisms, there are many, many others in other places of the CFTR gene, with different clinical impact, however, here we talk about the specific T polymorphism).
Please find even more about this under the following link to a former question:

So in case of your daughter, I assume that a standard genetic test has been performed. As I mentioned above, over 1800 mutations are known, the standard test kits test for about 23-60 of the most frequent mutations, reaching a test sensitivity of 70-90%. As your daughter shows the full clinical picture, it is very likely, that she has inherited another CF-causing mutation from the father, which could not be detected with the standard kit so far. The next step could be a full genetic sequencing, with that, much more mutations can be found, however, there is no genetic test with 100% security.
However, even if you will be successful in finding the second mutation with genetic sequencing, 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.
Yours sincerely,
Dr. Daniela d’Alquen (coordinator of the Central English Archive of ECORN-CF)
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"