Combination of mutations 5Τ/7Τ/9Τ

Question

I have a three year old son (born premature and hospitalized for 2 weeks without respiratory problems). During my pregnancy I and my husband were checked for 36 CF mutations plus for 5T/7T/9T. I was found to be a carrier of 5T and 7T mutations and my husband of 7T and 9T (at intron 8). We were told that if the gene in people with CF were a cassette with the tape torn, in our case most of the tape would just be folded! My son generally looks healthy, but his height and weight is at the lowest growth curves, while I have observed that his sweat is very salty (compared to mine). I would like to know what kind of problems do the possible combinations of the above mutations cause, if the testing we have done so far is adequate, if there is a chance we may be carrying more mutations (I and my husband) and finally if we should choose IVF in case we want a second child. The testing was done with pcr method, what are the chances for error?

Answer

Dear friend!
The CF gene is a very large gene that is related to the production of the CFTR protein.
Since the gene is so large, there are very many CF mutations. Till now more than 1900 mutations have been detected.
It came out that the frequency of the various mutations differs in respect to the population. The most common mutation is the DF508, whose frequency in some populations may rise to 75% of the CF patients. In the greek population its frequency is around 53%.
You have been checked for the 36 most frequent CF mutations and for the polyT region. With this kind of testing the possibility to have a child with CF is reduced to a very great extent but cannot altogether be ruled out.
A person suffers from CF when he/she carries two CF mutations, one on each chromosome.
In some cases a gene can become pathological, only if in the same gene two specific mutations coexist, the so-called complex alleles. In this instance it is very important if the other gene carries a pathological CF mutation. The cases are:
(a) TG13-T5, TG12-T5, TG11-T5 (b) R117H-T5 and R117H-Τ7 and (c) the mutations Ι148Τ and 3199del6.
(a) The mutations TG12-T5 and ΤG13-T5 at the CFTR gene, when they are in heterozygous status with another CF mutation, or in homozygous status, will cause CFTR-related disorders, or congenital vas deferens obstruction, or chronic idiopathic pacreatitis. In some cases they may cause mild CF disease.
(b) When the mutations R117H-Τ5 are located in one chromosome and the other chromosome carries a CF mutation, then the person will suffer from CF with pancreatic sufficiency.
The combination of the mutations R117H-Τ7 in one chromosome with another CF mutation in the second chromosome may lead to mild CF, vas deferens obstruction, or to no disease at all (Castellani 2008).
For the above reasons the 5T mutation is checked for the prevention of CF only in the presence of R117H mutation, while it must be checked in cases of male sterility investigation.
Dear friend you asked about the problems arising from the possible combinations of the mutations 5T/7T you carry and 7T/9T your husband carries. For these combinations no problems exist.
Regarding your comments:
(a) The low height and weight in respect to the age of the child must be evaluated by your pediatrician in respect to height and weight of the parents and general hereditary data.
(b) As far as the sweat is concerned, all sweat is salty, but the sweat of a CF child is as salty as sea water. If you believe that it is so salty, you should contact the CF Center at Aghia Sofia Hospital, in order to do a sweat test.
As I said before, with the prevention we may reduce drastically the chance for a CF child, but this chance cannot be totally eliminated. This chance is reduced further when the number of CF mutations to be checked is larger.
You do not need to proceed with an IVF in your next pregnancy. This is necessary when both parents are confirmed carriers of pathological CF mutations and wish to do a preimplantation genetic testing to see if the zygote carries both CF mutations (i.e. the baby will have CF).
Yours friendly,
Dr. Stavros Doudounakis

24.07.2013