MUTATION

Question

Hello, according to the result of the genetic test we know that our 9 year old son is carrying the mutation C.579 3 A sup.G and c.1521_1523 delCTT or also called p.Phe508del. Could you tell me more about these changes?
Thank you in advance and thank you for this very helpful site.

Answer

Hello,
Based on the information you provide, the genotype of your son expressed according to the traditional nomenclature of mutations is 711+3A>G / F508del . You did not supply information on the phenotype of your son, i.e. the clinical symptoms, the results of the sweat test and fecal elastase assay.
The mutation c.1521_1523delCTT is also called p.Phe508del in the new classification according to whether it refers to the modification of the nucleic acid or the modification of the protein and corresponds to the main mutation called F508del according to the traditional nomenclature.
The so-called c.579+3A>G mutation (according to the new nomenclature) results, in technical terms, in a change of the nucleotide A at intronic position +3 of exon 5, so in intron 5. This mutation is also known as 711+3A>G in the traditional nomenclature. The biological characteristics of this mutation suggests that it would be responsible for a moderate dysfunction of the chloride channel and therefore most often associated with moderate clinical forms.
There is few clinical data associated with your son’s genotype (711+3A>G / F508del) :
- the Data Base Muco-France reports 3 cases associated with a classical CF (1 case), male infertility by congenital bilateral aplasia of the vas deferens - CBAVD (1 case) and pancreatitis (1 case).
- the CFTR2 Data Base (USA) reports 22 cases and states 711+3A>G is a CF-causing mutation when associated with another CF-causing mutation (like F508del) but with a greater frequency of mild forms.
It is important to remind that each individual situation is unique and the sole genotype does not predict the clinical outcome (phenotype) which is determined by many factors, innate (genetic) but also acquired (environmental).
Hope that answers your question.
Sincerely .
Dr. Gilles Rault CRCM Roscoff
With the kind contribution
Marie- Pierre AUDREZET , PhD,
Molecular Genetics , University Hospital of Brest

05.05.2014

30.04.14
For all those who are interested in the molecular findings, that may explain the variable disease expression in case of 711+3A>G Mutation, some information can be found in the guidelines by Castellani et al (Journal of Cystic Fibrosis 7 (2008) 179-196: "Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice").
The 711+3A>G mutation belongs to the so-called splicing mutations. Splicing is a process that is important when the genetic information of the cell (here the CFTR gene) is translated into the protein product (here a chloride channel). The genetic material is transcribed first, and the transcripts have to be processed further by "splicing", and only if the splicing is done correctly, the gene product (chloride channel) is also produced correctly.
"Splicing mutations that still result in a fraction of correctly spliced transcripts, together with aberrantly spliced transcripts, may belong to the CF-causing or CFTR-related disorders associated group...Patients carrying these mutations often have a relatively mild phenotype, yet with variable disease expression, from minimal lung disease, pancreatic sufficiency and male fertility to a relative severe disease in all the involved organs. This variable disease expression is inversely correlated with the quantitiy of correctly spliced transcripts, i.e. lower leverls are associated with a severe disease, while higher levels are associated with a milder phenotype." The percentage of correctly spliced transcripts that has semiquantitatively measured, is around 70% for the 711 + 3A>G mutation. This explains the probability of mild illness courses.
D. d'Alquen