G542X

Question

My child has cystic fibrosis with the p.G542X and c.4375-2A> C mutations.
Are both mutated alleles expressed in cells or does one dominate the other mutation?
Please, what is the clinical expression of this combination in the medical database if available?
Thank you in advance for your reply.

Answer

Hello,
Both mutated alleles related to the CFTR genotype are expressed independently from each other in the cells of the organism.
Depending on the nature and the position of a mutation in the gene, the amount of CFTR protein which can be synthetized and then migrate into the cell membrane to ensure its function as a chloride channel, can be more or less large and consequently can more or less attenuate the symptoms and the course of the disease (the phenotype).
The genotype of your child therefore combines G542X and 4375 -2A > C mutations (or p.G542X and c.4375 -2A > CC according to the nomenclature of the Human Genome Variation Society - HGVS ).
The G542X mutation is identified as a class I mutation, also called "nonsense mutation” or "stop mutation". This means that it induces a premature termination of protein synthesis, which is recognized as abnormal, then destroyed in the cell and is thus not functional.
We do not have clinical data associated with the 4375 -2A > C mutation except the only data of the International Consortium of CFTR mutations (www.genet.sickkids.on.ca/) indicating its identification in a patient with a typical CF.
However, the position of this mutation suggests that it probably acts as a stop mutation causing a premature termination of the synthesis of CFTR protein. Note however that some stop mutations may be partially functional if the arrest occurs close to the end of synthesis and if the almost complete mutated protein is not recognized as abnormal and thus is not destroyed and eventually transported into the cell membrane.
In addition, genotype-phenotype correlations should be used with caution when it comes to make a prognosis for a given patient. Certainly, statistical analyzes involving thousands of patients have led to correlations between certain combinations of mutations (genotypes) and clinical outcome (phenotype), but the sole CFTR genotype cannot predict clinical outcome and therefore prognosis of a individual patient. The phenotype of a given individual is indeed the result of an infinite number of possible combinations of genetic factors on the one hand and environmental factors on the other.
In summary, the status of each patient is unique and prognostic extrapolation from single genotype is abusive. I can only recommend you continue to make your child monitored by the multidisciplinary team of you CF center who is capable the best to discuss with you the treatment decision that requires your child's situation.
I also remind the importance of gathering information for the National CF Registry (connected to the European one). This information is essential to improve knowledge of the disease and organize clinical trials in order to develop personalized treatments, particularly depending on the nature of the CFTR genotype.
Hope to have answered your questions , I wish you and all your loved ones a joyous festive season.
Sincerely .
Dr. Gilles Rault
CRCM Roscoff
with the kind support of:
Marie- Pierre AUDREZET, PhD,
Molecular Genetics, University Hospital of Brest, France

07.01.2014