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Cystic Fibrosis




What is the diagnosis of a severe mutation in trans with the 5t polymorphism. A borderline sweat test and no meconeum ilius was noted.


This is an excellent, but very complex question, with, unfortunately, no precise answer. I will provide a little background.

CF is caused by mutations in BOTH strands of DNA that code for the CF gene, or the gene that codes for CFTR protein, which, if defective or absent, allows CF to occur. Mutations in only one of the two genes usually does not cause CF, as the unaffected gene is able to produce enough protein to help the cells function normally. However, a severe mutation in one gene, with the 5t abnormality in the OTHER DNA strand, can cause no disease, infertility only, or CF disease, usually mild.

What happens is that if the 5t sequence, a series of 5 thymidine molecules, occurs just in front of the part of the DNA that codes for and produces CFTR protein, it can cause the production process to skip that part of the DNA and fail to make good copies of the protein, which then don't function properly. Since the gene on the other DNA strand is abnormal, and the "normal" strand is skipping over the part of the gene that makes CFTR, the cells don't have enough protein to function normally, and the person can have some degree of CF.

To make matters more complicated, it appears that the 5t sequence must be followed by a certain number of other molecules-TG, or thioguanine, in order to cause skipping. If it is followed by 11 or fewer TG molecules, there is usually no effect, or the person (male) is infertile, without CF. If there are 12 or 13 TG molecules after the 5t portion, then there is a risk of, usually mild, CF. This whole issue can also be affected by whether or not there is a usually mild or unimportant mutation on the CFTR gene that follows the 5t abnormality, in which case the CF can be more severe, although this doesn't appear to be the case in the situation that you mention, as there is only the one CF mutation (severe) that you mention.

The borderline sweat test may or may not suggest actual CF, which would likely be a milder version, rather than the most severe, although that can be affected by other factors such as other proteins, many of which we haven't identified, that can help or hurt the cells in compensating for abnormalities in the CF protein.

To specifically answer your question, the abnormalities that you outline may or may not result in clinical, or symptomatic, cystic fibrosis. It would be important, if male, to check for fertility, which if present would argue against CF, lung disease, and pancreas function. Abnormalities in those areas would be helpful in knowing whether or not the person has CF or not.

One article that outlines the role of the 5t abnormality and TG sequences in a very technical way is by Groman, et al., in the American Journal of Human Genetics, vol 74, p176-179, 2004. The title is: "Variation in a Repeat Sequence Determines Whether a Common Variant of the Cystic Fibrosis Transmembrane Conductance Regulator Gene Is Pathogenic or Benign". It would also be helpful for you to talk with a genetic counselor in a nearby hospital, or a counselor from the company that did the genetic testing.

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Response by:

John S Heintz, MD John S Heintz, MD
Former Clinical Assistant Professor of Pediatrics
College of Medicine
The Ohio State University