Prognosis of mutation classes

Question

Dear experts,
I am always told that the prognosis for CF patients can never be predicted, that it is very different from patient to patient. It would depend on the genes and also on other factors. This is what I know - but as a parent of a CF child one is of course tortured by the insecurity if one will life longer than the own child.
Would you please give your opinion in how far mutation classes are responsible for the severity of the disease?
Concrete: is a patient with 2 class I mutations going to die earlier as a patient with 2 less severe mutations, e.g. class III mutations?
If a CF patient is extremely pancreatic insufficient, does this worsen his prognosis even if he has normal weight due to a high enzyme replacement therapy?
Many thanks for your expertise!

Answer

Hello,
Answer to the first part of the question:
the CF phenotype depends on the CFTR genotype (mutation classes), other genetic factors (one speaks about modifying genes), environment, nutrition, therapy, side effects of the therapy and most probably other until now not known factors. The classification into mutation classes was above all done, in order to be able to work on scientific questions and to be able to conduct epidemiological, statistical studies, in that then it was searched i.a. for genotype- phenotype correlations. Indeed, such studies revealed in case of patients with class I-III mutations more frequently pancreatic insufficiency, meconium ileus, a higher degree of malnutrition, an earlier and stronger involvement of the lung, more frequent impairment of the liver and a higher mortality.
On the other hand, class IV-V mutations are more frequently associated with a lighter involvement of the lung, a lesser extent of pancreatic insufficieny and a decreased mortality. Patients with a compound heterozygousity of class I-III and class IV-V mutations show in general the milder phenotype. This tendency is also seen, if patients are investigated, who turn to shown symptoms only at adult age. They have predominantly class IV-V mutations.
However in the single case, one cannot make a secure prognosis from the type of the mutation. Hereby the genotype is only one factor among others (see above) and therefore e.g. the sweat test or the nasal potential difference are as importnat prognostic factors. These large individual differences are also seen in patients with the same mutation, e.g. a homozygous deltaF508 mutation, who can have nevertheless a very different course of the illness.
Again: genotype-phenotype correlations are useful for epidemiological/ statistical investigations of the population, however should not be taken for making a prognosis of single patients (see also the detailed statement of the consensus conference 2007 in Italy, published: C. Castellani et al. J Cyst Fibros, 2008, 7(3):179-196).

Best regards,
Rainer Koenig

20.10.2014