Sweat test 51 - mutation I148T

Question

I have a 16 months old girl with low weight. We have a diagnosis of gastro-esophageal reflux disease since she was 4 months old without vomiting. We did a sweat test in a Thessaloniki hospital with sufficient quantity of sweat and it was borderline with a value of 51. The genetic analysis for 36 mutations (75%) showed heterozygousity for the I148T mutation.The child has never presented any pulmonary problems and her clinical picture in general is very good. We have sent a blood sample to be checked for other mutations and I am really worried. Is it possible for the baby to suffer from CF?

Answer

Dear friend,
Cystic Fibrosis (CF) is a hereditary disease that is caused by mutations of the CF gene (CFTR). In order for a person to suffer from CF he/she must have inherited one mutation from the mother and one from the father, i.e. both inherited copies of gene do not function properly.
If the person carries only one mutation in the CFTR gene, then this person is a carrier of CF, which means that, while one copy of the gene does not function, the other one does, and this suffices for the person not to have CF and the related symptoms.
Researchers have found that the I148T mutation is in essence a “benign polymorphism”, i.e. it is a mutation that does not cause CF, except when it coexists with the 3199del6 mutation.
I148T is therefore a benign polymorphism and only if its found with 3199del6 in coexsistance in the same chromosome due to the 3199del6 mutation this combination represents a CF-causing mutation. However, this combination is only CF-causing, if on the other chromosome also a CF-causing mutation is found.
In your case clinically the baby has a mild to moderate gastroesophageal reflux and a sweat test of 51. You have been checked for 75% of mutations and the polymorphism I148T was found, but not the mutation 3199del6. There is a possibility that another mutation may be found during the checking of the rest 25% . In the case of tracking another mutation, in combination with the polymorphism I148T, but without the mutation 3199del, CF is not caused, and you child will simply be a carrier of CF.
You will need to repeat the sweat test but I am convinced that this time the results will be within normal values.
Concerning the performance of the sweat test, it is important that the test is done in an experienced center using the so-called pilocarpine ionotophoresis to measure the chlorid concentration in the sweat. Only if this standardized procedure is used, the values are suitable to exclude or make the diagnosis of CF; then the following standardized values pertain: under 40mmol/l chloride concentration in the sweat: negative, 40-59mmol/l: borderline, equal or over 60mmol/l: pahtologic.
Yours friendly,
Dr. Stavros Doudounakis

10.09.2012