Another question on the answer of Prof. Stuhrmann-Spangenberg about 7T-allele

Question

Dear Prof. Dr. Stuhrmann-Spangenberg

You write as an anwer to a question among other things:
"One should make a comment on the genetic variant R117H: this variant can exist on two genetic backgrounds, one so-called 7-T-allele or a 5-T-allele. The latter would be graded as a CF-mutation, the first only in rare exeptional cases..."

My questions:
Why is 7-T-allele only in rare exeptional cases graded as a CF-mutation? How can this be understood?
I always thought that a change is a mutation or is not a mutation.
How would it be according to the above-mentioned knowledge if somebody shows typical symptoms of CF (with pulmonary involvement, Pseudomonas, Stenotrophomonas, nasal polyposis, pnacreatic insufficiency and increased liver enzymes) and only a 7-T/7-T (7-T-homozygouty) is found in the genetic analysis? The whole gene has been analysed. A 2694 TG is also present.
Would this be graded as such an exeptional case?
Many thanks for your answer,

Answer

Directly before the exon 9 there is a poly-T-tract with a different number of T-nucleotides. 7T and 9T alleles are normal-alleles, the 5T-allele is associated with a reduction of the CFTR-transcription amount and can be graded as a class 5 mutation, that in case of a compund heterozygouty with a typical CF mutation (like e.g. F508del) can lead for example to a CBAVD (congential bilateral absence of the vas deferens). The pathogenicity of the 5T-allele depends on a neighbouring TG-repeat (Groman et al.). R117H again, can occur with 5T or 7T in cis (to be one one allele). R117H-5T is a PS-CF-mutation, R117H-7T is not a CF-mutation (only in very rare exeptional cases). R117H-7T leads in compund heterozygouty with F508del often to a CBAVD.
The question of R117H/7T/5T and 5T/(TG 11,12,13) are discussed in the latest consensus paper of Castellani et. al. If you send me an e-mail, I will be able to send the papers of Groman et al. and Castellani et al. to you.
2694T>G is listed in the CFTR-data base as sequence variation. Probably we have to deal with a polymorphism here.

08.01.2009

After Prof. Stuhrmann-Spangenberg and Prof. Tümmler was asked about this special topic, I tried to summerize the additional information here:

R117H-5T is a PS (pancreas sufficient)-CF-mutation, R117H-7T however is a difficult diagnostic problem that does not allow a clear statement. Dependent on the genetic background there is a wide spectrum of clinical phenotypes.
There have been cases described with a compound heterozygosity
(which means on each of the two gene alleles we find different mutations)
with a PI (pancreas insufficient) CF mutation on one allel and an RH117-7T on the other allel. Among the reported cases were such with no clinical symptoms and others with a picture of the illness that requires some sort of treatment (e.g. mild symptoms with pancreas sufficiency but abnormal lung function). In case that a person carries on both alleles RH117-7T (homozygoty for RH 117-7T) it can not
exactly be predicted what to expect, but it is imaginable to have a similar picture (or even milder) as in cases with a compound heterozygoty for RH-117-7T according to the information above.
In conclusion: if you have the case that you report, meaning a patient with the typical symptoms of CF and so far only a homozygoty for RH117-7T is found, there might be the possibility that there is another CF mutation (probably a very rare one) that has not been detected with the used genetic testing. But in any case, as RH117-7T bears a wide spectrum of clinical phenotypes, it is not totally
excluded to suffer from a form of CF with this constellation, even if it would be most likely to have only a very mild form. Nevertheless it is advisable to present the patient in a CF centre to review the diagnosis and all the diagnostic tools and to initiate a treatment in order to improve lung and digestional function.
Dr. D. d'Alquen