Mutation

Question

Mutation c.-8G>C (rs1800501) homozygous

Dear expert team,
this above mentioned mutation is in the genetic result report of my daughter, who is 4.5 years old and suffers constantly from birth on of obstrucitve bronchitis. She has already had 3 pneumonias and partly, if the mucous congestion of the airways increases, also slight impairment of the digestion. Her sweat test values were at 31 and 33. Now we are sent to a nasal potential difference (NPD) investiagtion as we have been told that there are humans with this mutation who do not show any symptoms at all.
Could you tell me something about this mutation? Does homozygous mean that my husband and I have bequeasted the same mutation? In how far does the mutation have to do with CF? Would it be an atypical form?
Many thanks in advance.

Answer

Dear questioner,
I will answer this complex question in two parts:
1. the genetic result and
2. all other things (i.e. sweat test, symptoms, NPD-diagnostic, atypical CF)

ad 1.: the human genetic specialist has told you that your daughter carries on both chromosomes a variant named c.-8G>C (rs1800501). You have correctly concluded from this, that your daughter has inherited this variant from you as well as from your husband. However: according to the latest knowledge there is no hint, that this variant is causing CF. Admittedly: in the literature, there are up to now no cases documented, in that a patient carries this variant homozygously (therefore as your daughter on both chromosomes).
It is however important: even if the human geneticist does not find an unambigous CF mutation, the patient can carry a disease causing mutation, as on the one hand it is actually not searched everywhere in the disease causing CFTR gene (for this the CFTR gene is much too big) and on the other hand there are very many sequence variations, that cannot be judged about their meaning (for this, many CFTR variants are too rare, therefore it is not possible to tell, if they are disease causing or not). Therefore: the result of the human geneticist does not help further in finding a diagnosis in your case.
ad 2.: Your daughter has doubtlessly symptoms of a recurrent illness of the airways, that led to the initiation of CF diagnostics. As the genetic investigation can not rule out the illness of CF, it makes sense, now to initiate a NPD measurement, as hereby it is measured, if CFTR is "functioning" (that means chloride can be transported regularly via the nasal mucosa). This functional test is totally independent of the genetic investigation. The physician can decide with the help of the NPD measurement, how the therpeutical focus has to be made in the future: with regard to an impaired function of the CFTR or with regard to CFTR-independent causes of the symptoms. Also in case of a diagnosis like atypical CF or CFTR-related disorder (that means a CFTR-caused non-CF illness), the patient will profit from the clinical knowledge, that the doctors have concerning their experience with CF - therefore in a CF-center, you have in any case arrived at the right partner.
Best regards,
Frauke Stanke

28.07.2014