Combination of two mutations

Question

Dear expert team,

I am a carrier of the F508del mutation, my husband is a carrier of the 5-T variant in the CFTR gene. My brother has CF. Our son was born two-and-a-half years ago in the 36th week. Apart from being very small and lightweight due to premature birth, he does not show any signs of CF. We have therefore been advised against diagnostics so far, and we were also told that a manifest CF would be very unlikely for our son with this combination of mutations, and that my husband’s mutation is a very mild one.

Now my question:
Is CF really unlikely for our son with our combination of mutations? And what does “mild mutation” mean for my husband?

Many thanks for your advice.

Answer

Dear questioner,

I am happy to answer both your questions, although in reverse order. You will therefore first get a very long answer to question no. 2 (for which I apologize in advance – but the consequences of the 5T variant which are so important to you cannot be answered in a satisfactory manner in just one sentence).

Concerning question 2: What does “mild mutation” CFTR-5T mean?
I assume your husband was tested with the standard test kit for mutations in the CFTR gene – this kit usually scans for several common variants of the gene. You are writing that your husband is a carrier of the 5T variant; I therefore assume that he carries CFTR-5T on one of the two chromosomes and that nothing else was found.

Answer 2A – molecular biology of the CFTR-5T variant:
From the perspective of a molecular biologist, the name “5T variant” or “CFTR-5T” describes the following: The actual protein CFTR is read from the carrier molecule “mRNA,” which contains more information than is necessary for putting together the actual protein building blocks. These information fragments exist in pieces, roughly like this: informationforproteinCFTRnumber1-connector- informationforproteinCFTRnumber2-etc. For the CFTR protein, there is a total of 27 such information fragments. In one of these connectors, there is also a number of T (where T stands for thymidine) building blocks located directly one after another, which can be 7T (i.e., TTTTTTT) or 5T (i.e. TTTTT) long in humans. The number of T building blocks determines how well the cell can process the information of the carrier molecule: the smaller the number of T blocks, the lower the amount of functioning CFTR that can be produced from the genetic material of the chromosome – figuring out the connectors correctly becomes more difficult for the cell if the connectors contain fewer Ts.

Answer 2 B – which symptoms do carriers of the 5T variant have?
Carriers of a 5T variant do not get CF, because the 5T CFTR produces enough functioning CFTR together with the other chromosome to prevent the disease. The phrase “5T is a mild mutation” refers to several other symptoms, such as the predisposition to produce fewer sperms, without further reasons to see a doctor. Moreover, the 5T variant is seen as a risk variant for mild diseases of the upper and lower respiratory tracts (i.e. everything from troublesome sinus polyps to slightly limited lung function). Which symptoms a carrier of the 5T variant can develop depends on additional factors that cannot be inferred from the label “CFTR-5T.”

Answer 2C – 5T does not equal 5T:
Directly next to the T building blocks mentioned above, there is another motif which recurs in the genetic material, the so-called TG repeat. These are repetitions of the T and G building blocks, i.e. TGTGTGTG… etc. The TGs appear 13, 12 or 11 times. For the cell, this means that the longer the TG repeat, the smaller the amount of functioning CFTR is built by the genetic material from this chromosome. According to the official classification of the European CF Society, by now a distinction is being made between the different 5T CFTR chromosomes: the 2008 Consensus Report (J Cyst Fibros. 2008 May ; 7(3): 179–196) categorizes the T5TG13 variant into the group of mutations that can cause mild symptoms in several organ systems; on the other hand, the T5TG12 CFTR variant is linked to atypical clinical pictures. T5TG11, again on the other hand, does not have any clinical consequences. As long as the person carries a second, healthy chromosome, this categorization is only of academic interest: F508del shows distinctively more functional limitations than the worst T5 variant T5TG13. Nevertheless, carriers of F508del are not sick, as you know yourself.

Summary for question 2:
CFTR-5T produces less functioning CFTR protein than the normal gene for CFTR on the chromosome. This CFTR variant does not cause classic CF. Whether the carrier of the 5T variant will stand out at an andrologyst’s or pulmonologist’s practice due to clinical symptoms depends on further factors such as the TG repeat and cannot be predicted.

Now on to question 1: Is a “manifest CF” unlikely for your son with the combination of parental genetic dispositions CFTR-5T and wild-type CFTR(=healthy) (this is your husband’s genotype) as well as CFTR-F508del and wild-type CFTR(=healthy) (this is your genotype)?
If your son ONLY inherited CFTR-F508del from you, he is as hale and hearty as you yourself – if ONLY inherited CFTR-5T from your husband, he is as hale and hearty as your husband. However, in case he inherited BOTH CFTR-5T AND CFTR F508del, there is a possibility that he will show symptoms – although a classic CF is highly unlikely. I therefore support your paediatrician, who says that with this combination “a manifest CF is very unlikely.” However: the so-called mild, atypical progressions often become manifest only at the adult stage, say at 30 or even above 40 years of age. Specialized doctors such as human geneticists or doctors at a CF clinic would be the right people to talk to for yourself and later also for your son.

Kind regards,
Dr. Frauke Stanke.

22.03.2012