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newborn with Del f508 and 5T-TG12

My baby boy was screened in California and tested positive for Del F508 and 5T-TG12
variant. His initial sweat test was 20 at 5 weeks of age. Therefore, he is not classified as CF but will be monitored throughout his life. I understand his mutations can put him into a healthy or mildly sick group depending on the amount of working mRNA.

1. Are there any tests that can determine whether his combinations will affect his CFTR function? At what age?

2. At what age can we find out whether he is infertile?

3. Do all people with this combination have symptoms or some are completely healthy? How many have only infertility, and how many show lung issues?

4. What is MILD cf? How does it express? I understand this combination probably won't cause pancreatic problems, but mostly lung issues. Is that correct?
Dear questionner thank you for your question.

You are correct in your understanding that the combination of mutations present, affects the amount of working mRNA. This will influence how much a person will be affected.

In response to your questions outlined in 1, 3 and 4:

As your baby boy’s mutations have now been identified, this information will help to inform clinicians about his CFTR function.
The impact that any given CF mutation has on severity of disease is often determined by the combination of CF mutations, rather than any one mutation in isolation.[1]
Worldwide, Del F508 is the most prevalent CF causing mutation. 5T-TG12 variant mutation may or may not act as a CF-causing mutation depending on the combination. There is some research to show that your son’s particular mutation combination may act as a disease-causing mutations, resulting in elevated sweat chloride and clinical symptoms of CF. These symptoms may be variable or milder than those caused by other disease-causing mutations, and there is an increased risk for male infertility (2). The CFTR2 database describes the clinical characteristics of 51 patients with Del F508 and 5T mutation combination (this also includes patients with other types of 5T mutation variants e.g. TG11, TG12, and TG13). The average lung function as measured by spirometry was within the normal range (compared to non-CF) and 75% were pancreatic sufficient (2).

Mild CF is a term used to describe patients who present with sweat test results within the normal range and where diagnosis of CF requires detection of one disease causing mutation on each CFTR gene. When two mutations are detected, at least one is by previous experience classified as ‘‘mild’’. Most of these patients have exocrine pancreatic sufficiency and milder lung disease (3). It is important to keep in mind that there is a high variability in phenotype (i.e. how a person’s presents) within identical CFTR genotypes.[4] As definite modifier genes remains to be identified we support consensus statements advising that clinicians should not use genotype alone to predict clinical outcomes at the time of diagnosis.[5]

There are other types of tests to assess CFTR function, including a test called Nasal potential difference. This test measures epithelial ion fluxes at the mucosal surface of the nasal passages (the upper airway). This test can be carried out in infants and can help to resolve any diagnostic dilemmas by assessing CFTR related dysfunction (3).
However these tests are not available at all centres. And as your CF team now have your son’s mutations to inform them about his likely CFTR function, they may gain more information about your son’s progress by monitoring his clinical status that is; by measuring lung function, monitoring his weight and checking for symptoms.

In relation to your questions about your son’s fertility:

Infertility in men with CF is primarily due to obstruction or absence of the vas deferens. Reports have confirmed at least 97% of men with CF have absence of the vasa deferentia (6). The prevalence of infertility in patients with the 5T variant mutation has been variable (7). The clinical assessment of male fertility is initially made later in life when your son is in adulthood. This will involve seeing a specialist, through your CF team, for an assessment and semen analysis.

I hope you have found this information helpful.

Best Wishes
Katherine O'Neill


1.Comer, D.M., et al., Clinical phenotype of cystic fibrosis patients with the G551D mutation. QJM, 2009. 102(11): p. 793-8.
3. De Boeck, K., Wilschanski, M., Castellani, C., Taylor, C., Cuppens, H., Dodge, J. & Sinaasappel, M. 2006, "Cystic fibrosis: terminology and diagnostic algorithms", Thorax, vol. 61, no. 7, pp. 627-635.
4.Loubieres, Y., et al., Association between genetically determined pancreatic status and lung disease in adult cystic fibrosis patients. Chest, 2002. 121(1): p. 73-80.
5.Castellani, C., et al., Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros, 2008. 7(3): p. 179-96.
6. Lyon, A. & Bilton, D. 2002, "Fertility issues in cystic fibrosis", Paediatric Respiratory Reviews, vol. 3, no. 3, pp. 236-240.
7. Kerem, E., Rave-Harel, N., Augarten, A., Madgar, I., Nissim-Rafinia, M., Yahav, Y., Goshen, R., Bentur, L., Rivlin, J., Aviram, M., Genem, A., Chiba-Falek, O., Kraemer, M.R., Simon, A., Branski, D. & Kerem, B. 1997; 1997, "A cystic fibrosis transmembrane conductance regulator splice variant with partial penetrance associated with variable cystic fibrosis presentations.", Am J Respir Crit Care Med, vol. 155, no. 6, pp. 1914-1920.
The answer is edited by: Katherine O'Neill