G542x and another mutation

Question

Hello, I just have a question of my daughters mutations (G542X and c.1210-2A>C). I'm in the states with no answers from anyone here. They said no one else has her two combined but she will eventually have lung disease! She has been diagnosed with cf but has no lung issues at all just gi issues. But also have her on hypertonic saline and albuteral for preventative treatment, how long do we do this to prevent lung problems that are not there? My grandmother also had these gi issues but no one is concerned with her history. Any answers or advice would be great thanks.

Answer

Dear Questioner,

Thank you for your question.

Firstly some background on your daughter mutations:
G542X is a known CF-causing mutation and is one of the five most commonly seen mutations. It is a class 1 mutation and therefore there is no expression of the CFTR protein on the surface of the cell membrane. c.1210-2A>C (c-DNA name, legacy name: 1342-2A->C) is a rarer mutation, for which at this time, unfortunately there is less information on. It has however been described as a “severe splice mutation” (1) and has been documented as a disease causing mutation (2).

Although research has shown that genotype can help predict the severity of disease manifestation, this relates mainly to pancreatic function (3). As you may know, there is no a close relationship between the type of mutation and the degree of lung disease because the pulmonary involvement seems to depend not only on genetics, but also on environmental factors. e.g. level of care, exposure to cigarette smoke; and on the effect of other genes (modifying genes). As a result it is not possible to give an exact prognosis of lung function based on the mutation.

To answer your question relating to preventative treatment;
You do not mention your daughters age, but there exists debate about early intervention and preventative treatment in patients, particularly, infants who are asymptomatic. There is evidence that lung disease starts early and cannot be predicted by the presence or absence of symptoms (4, 5). Therefore some clinicians justify the use of treatments to prevent lung disease. Difficulties arise because clinical trials of treatments are limited in young age groups. Please speak to your CF team if you have any concerns or questions about your daughter’s current treatments as they may be able to offer you further information on treatment justification specifically for your daughter or support in relation to adherence to treatments.

You mentioned your grandmother who had GI symptoms;
As CF is a genetically inherited disease, with 1/25 of individuals being a carrier for the defective gene, it is relatively common that CF will feature in wider family circles. As your grandmother did not have a diagnosis or genotyping, it is not possible to draw comparisons with your daughter. This information, would not however better inform your daughters prognosis or treatment because, as mentioned earlier, there is a weak relationship between the type of mutation and the degree of lung disease.

I hope you find this information useful.

Regards,

Katherine O’Neill


References
1. Dork, T., Fislage, R., Rappen, U. & Tummler, B. Severe splice site mutation preceding exon 9 of the CFTR gene. Hum Mol Genet 2, 1313-1314 (1993).
2. (www.genet.sickkids.on.ca/MutationDetailPage.external?sp=214).

3. Correlation between Genotype and Phenotype in Patients with Cystic Fibrosis
The Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med 1993; 329:1308-1313
Progression of early structural lung disease in young
4. Mott LS, Park J, Murray CP, et al. Thorax (2011). Progression of early structural lung disease in young children with cystic fibrosis assessed using CT.
5. Hoo et al. Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening. Thorax 2012;67:874–881.

13.02.2013

The answer is edited by: Katherine O'Neill