Forms of mutations

Question

My son has been diagnosed to suffer from CF additionally due to a meconium ileus and at the same time a pathological result of the newborn screening and a subsequent sweat test.
After a detailed analysis of the genetic testing we got the result of the kind of mutation: DF508/del.13/14a.
As I have read that the forms of mutations are divided into 5 classes according to severity, I would like to know now, if in case of this kind of mutation still functioning proteins are produced in the cell (class 5) respectively if it is a class 2 mutation, i.e. the protein is not able to mature in den endoplasmatic reticulum.
Is there an influence on the severity of the course of CF due to a heterozygous respectively a homozygous form of the mutation?
Best regards,
N. R.

Answer

Dear N. R.
I answer your question in 3 parts:
first of all I will address the 2 mutations, then the connection between the severity and the homozygous forms of mutations.

1. CF-mutation F508del
In case of F508del, it is a classical CF-mutation of type II. The mutation is well known: 70% of CF-genes carry this mutation, 50% of CF-patients are homozygous for this mutation. F508del is a class 2 mutation.

2. CF-mutation "del.13/14a"
Now to "del.13/14a": presumably its a matter of a deletion (therefore del) of a great part of the CF-gene (presumably exon 13 and 14a, therefore "13/14a"). I write "presumably" as the name "del.13/14a" cannot be found either in the international CF-gene mutation database (there are at the moment at least nearly 2000 variants of the CF-gene listed there) nor it is an official mutation name (del13/14a is a colloquial description, for deletions there are unfortunately no easily understandable international valid rules of name-giving). I would not like to guess here: please try to contact the human genetic specialist in charge, that first of all it is doubtlessly clear, if in your son indeed the exons 13 and 14a of the CFTR-gene are deleted. In case this tradition pertains, "del13/14a" is a so-called "out-of-frame-deletion", as a consequence a mutation class 1, from which no functional protein can derive.

3. Grade of severity and mutation combination
In general a mutation genotype "class 1/ class 2" leads to a typical CF, that e.g. is always accompanied by pancreatic insufficiency. Furthermore however, the following is true: dependent on the inherited mutations one can draw conclusions on the average course of the illness in a group of patients with the same CFTR-mutations, however the validity for the individual course of a single patient is NOT given thereby. In a recent statement of an internationally composed CF-expert group it says word for word: "...broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not acurately predict individual outcome. The use of CFTR-genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended...."(for the sake of completeness the source: Journal of Cystic Fibrosis 7(3):179-196; 2008). The reasons for this lack of predictive value for the single human being are all influence factors on the course of CF, that play a role besides the CFTR-mutation genotype (environmental factors, other inherited factors, especially important: physician and therapeutic management of the illness) - according to the recent estimate these "non-CFTR-factors" have a greater significance as the sole CFTR-mutation genotype.

Best regards,
Frauke Stanke

18.06.2013