Genetics IVS8T5 homozygous

Question

My son has CF. His grandfather was 83 years old and homozygous with IVS8T5! Did he thus have CF with this? How frequently does IVS8T5 occur in homozygous form?

Kind regards.

Answer

Dear questioner,

Many thanks for your questions, which I will be happy to answer consecutively.

A. I think your son’s grandfather did not have cystic fibrosis – I take this from your saying that he was 83 years old. Symptoms of CF usually show much earlier and even with rarer, mild forms people are mostly diagnosed in the fourth or fifth decade of life. I found two fitting case examples in the literature. The first case (Thorax 2005;60:974-975) describes a male IVS8T5 homozygous patient whom the doctors were able to diagnose at age 54. This patient had been suffering from respiratory tract infections since childhood and had severe pneumonia at age 45. A second case (AmJRespirCritCareMed 2000;162:1919-1924) describes a female IVS8T5 homozygous patient who was diagnosed at age 48 – here, too, repeated respiratory tract infections since early childhood led to the suspicion of CF. This then means that people who are IVS8T5 homozygous can have CF (rarely), show an atypical course of the disease that is also called “CFTRopathy” or "CFTR related disease" (a bit more common), or be clinically unsuspicious (this is true for most IVS8T5 homozygous people). This is due to the great variability of the IVS85T variant, whose causes will be explained in more detail below.

B. The frequency of homozygosity IVS8T5 in the population can be estimated: assuming that the IVS8T5 predisposition occurs in 5-10% of the genes, this yields a frequency of 0.25-1% for the IVS8T5 homozygous constellation, i.e. at least one in 400 people, and at most one in 100 people.

Now on to the longer answer – unfortunately, the IVS8T5 variant can not be explained in one sentence.

1. What does “IVS8T5” mean?

From the perspective of a molecular biologist, the name “IVS8T5” describes the following:
The actual CFTR protein is read from the “mRNA” messenger molecule, which contains more information than necessary e.g. for creating the actual protein components. These fragments of information are available in pieces, roughly like this: “information for CFTR protein no. 1”—“connector”—“information for CFTR protein no. 2”—etc. There are a total of 27 such information fragments for the CFTR protein. In one of these connectors (more precisely: in connector no. 8, hence IVS8), there is a number of T components located one right after another (T stands for thymidine), which can be 7T (i.e. TTTTTTT) or 5T (i.e. TTTTT) long in humans. The number of T components determines how well the cell can process information provided by the messenger molecule: the fewer Ts, the less functional CFTR is produced from the gene – processing the connectors is more difficult for the cell if there are fewer Ts sitting there.

2. Which symptoms do carriers of the IVS8T5 variant have?

IVS8T5 is associated with symptoms that concern individual organs separately (as opposed to CF, which concerns several organs simultaneously). One example of this is the disposition to have no sperm in the ejaculate because of a so-called "congenital bilateral absence of the vas deferens" without any other reasons that would necessitate consulting a doctor". Furthermore, the IVS8T5 variant is considered a risk variant for mild diseases of the upper and lower respiratory tracts (i.e. everything from bothersome nasal polyps to slightly limited lung function). Which symptoms a carrier of the IVS8T5 variant can develop depends on further factors that are not indicated by the name “IVS8T5.”

3. IVS8T5 is not the same as IVS8T5:

Right next to the T components mentioned above lies a further self-repeating motif in the genetic material, the so-called TG repeat. This is a repetition of the T and G components, i.e. TGTGTGTG… etc. The TGs occur 13, 12, or 11 times. Here, the following applies for each cell: the longer the TG repeat, the less functional CFTR is produced by this gene. The official classification of the European CF Society distinguishes different 5T-CFTR genes: The 2008 consensus report (J Cyst Fibros. 2008 May ; 7(3): 179–196) classifies the T5TG13 variant along with those mutations that can cause milder symptoms in several organs; the CFTR T5TG12 variant, on the other hand, is associated with atypical clinical pictures. T5TG11, in contrast, does not have any clinical consequences. As for the example of the female IVS8T5 homozygous patient mentioned above who was diagnosed only at the age of 48, TGTG12 were found on both chromosomes.

Conclusion:
CFTR-IVS85T produces less functional CFTR protein than a regular CFTR gene. This CFTR variant does not cause classic CF. Whether a carrier of a 5T variant or a person homozygous for two IVS8T5 chromosomes will conspicuous in an andrology or pulmonology practice due to clinical symptoms depends on further factors such as the TG repeat and can not be predicted.
Sincerely,
Dr. Frauke Stanke

25.10.2012