R553x/IVS8-5T-TG12

Question

Hello,

concerning the mutations mentioned above, we have been told repeatedly that this most likely means mild progressions of CF.

But what does that mean? Does my daughter have a normal life expectancy?

She is five years old and does not show any effects in the lungs or other organs. She was diagnosed by chance. She was supposed to get her genetic type for alpha1-antitrypsin insufficiency determined since the laboratory told us she had antitrypsin insufficiency. Since the antitrypsin genetic type was normal in a second test, the blood was examined further, which showed the above mutations.

Many thanks
C.M.

2nd question on this topic:
Hello,

we have been told repeatedly that our daughter has the R553x/IVS8-5T-TG12 mutations and hence a mild form of cystic fibrosis. Do these mutations already mean a higher life expectancy, or can one even reckon with a normal life expectancy? Can these mutations potentially lead to asthma or asthma bronchialis?

Many thanks
C.M.

Answer

Dear questioner,

I would like to answer both your questions together. [This refers to the question titled “Atypical/mild CF.”]

The analysis of your daughter’s CFTR gene has shown that she carries the sequential change R553X on one chromosome and the sequential change IVS8-5T-TG12 on the other.

R553X is a mutation. If your daughter carried such a mutation in both CFTR genes, she would suffer from cystic fibrosis (CF). This is not the case, however. Your daughter is a gene carrier for one mutation in the CFTR gene.

As for the IVS8-5T-TG12 sequential shift, it is not possible to tell clearly whether this is a pathogenic mutation, as this shift is in the gray area between healthy and sick.

What does IVS8-5T-TG12 mean? The CFTR gene consists of 27 coding sections, so-called exons, and in between those lie the non-coding sections, so-called introns. When the CFTR gene is read in order to synthesize the CFTR with mRNA messenger substance, which serves as a matrix for the development of the CFTR protein, the non-coding sections have to be cut out. The signal for the end of an intron is a TG(m)T(n) sequence. m is typically a number between 10 and 14, and n typically a number between 7 and 13.

IVS8-5T-TG12 is your daughter’s TG(m)T(n) signal at the end of intron no. 8. 5T is too short. This causes defects in the development of the CFTR messenger substance. Different amounts of CFTR mRNA messenger substance are produced, which contains all 27 exons (healthy) or else lacks exon no. 9 (inoperable). And now comes the decisive observation: the ratio between healthy and inoperable CFT mRNA messenger substance differs from organ to organ and from person to person.

A big North-American and European study thoroughly examined the symptoms of people with one CF mutation (for instance R553X, as with your daughter) and the IVS8-5T-TG12 sequential shift. Five percent of the people were completely healthy and another five percent showed mild but CF-typical symptoms in the pancreas and the respiratory tracts. 90 percent of the people examined showed mild disturbances of the CFTR function.

Conclusions and recommendations:
1. Your daughter’s 553X and IVS8-5T-TG12 sequential shifts are hereditary risk factors. Compared to the average population, she runs an increased risk of contracting infections of the biliary tract or the pancreas at some point in the course of her life. At the same time, she her risk of viral or bacterial infections of the upper or lower respiratory tracts not healing without any consequences is higher than with the average population.
2. A lower life expectancy compared to the average population due to chronic progressive changes in the liver, lungs, biliary tracts, pancreas or intestines is not to be expected.
3. It is one prerequisite for a normal quality of life and life expectancy to detect CF-like symptoms at an early stage. I therefore urge your daughter to present at a big CF center annually throughout her whole life. As a rule, a visit there will not have any therapeutic consequences. If, however, her lung function decreases, therapeutic measures must be taken immediately in order to prevent irreversible organ damage.
4. Whether the R553X and IVS8-5T-TG12 sequential shifts will impact your daughter’s CFTR function or not can be found out by some exams that have become quite sophisticated technically by now. One of these exams, however, requires for the person to be able to sit still for two hours. You should schedule a whole day for these exams. [The following information is only of regional relevance only and will thus be omitted.]

Kind regards
Dr. Burkhard Tümmler
Hannover Medical School

06.09.2010