Mutation 855del22

Question

Hello,
Only one question: do you know the mutation 855del22? It’s unknown on the web. My two children have a mild and obviously very rare form of CF, with pancreatic sufficiency: 855 del 22 or c.723_743+1del. It corresponds to the loss of 22 nucleotides at the exon 6a, named 855del22. We found this mutation in my daughter who is 16 years old, in my son and in my husband. I’m carrier of the 3849+10kbC>T (c.3747+10kbC>1) mutation. I learned from the french CF association “Vaincre La Mucoviscidose” that there is a more well known mutation - 852del22 mutation - in italian patients (I specify that my husband is of italian descent: from south, around Bari). Thank you in advance for your answer. Cordially.

Answer

Hello,

More than 1800 CFTR mutations have been identified to date. They are divided into five classes according to their impact on:
- the CFTR protein synthesis (class 1),
- its maturation and on its transfer to the cell membrane (class 2),
- or its functioning, once in place in the membrane (alteration of the regulation of the chloride channel: Class 3; alteration of its ability to transfer the chlorine: Class 4, alteration of the stability of the protein: class 5).

Only the mutation F508del (class 2) is common: it’s found in approximately 80% of the patients in France. Other mutations are rare, found in less than 2% of the patients in France, or even exceptional. The 855del22 mutation (also called c.723_743+1del in the new nomenclature) is one of them. This mutation is found in less than 10 of the 6000 patients recorded in the 2010 annual French CF Registry survey. This mutation causes the loss of a piece of the CFTR gene. This characteristic causes defective synthesis of CFTR protein, typical of the class 1 mutations. It is the same for the 852del22 mutation that you quote as carried by patients in Italy but which is not identified in any patient in France.

The 3849+10kb C/T mutation is a class 5 mutation. It results in an "incomplete splicing": the resulting change in the 3D shape of CFTR protein alters the transfer of chlorine through the membrane. This mutated CFTR protein is however well established and partially functioning which explains the mild expression of the disease, regardless of the class of the second mutation carried by the patient.

Thanks to your question, we analyzed the clinical characteristics of 45 patients (registered in the French CF Registry) carriers of a 3849+10kb C/T mutation associated to a F508del (classe 2). This analysis shows that:
- 34 of them have no exocrine pancreatic insufficiency;
- Body Mass Index Score average is the same as that of the general population;
- FEV1 predicted expressed as a percentage depends on the age of patients, but is on average at 80%, which is the lower limit of a normal value.

Most often, these patients have a mild form of the disease as seems the case with your children. Regular medical follow-up in a specialized care centre remains advisable even if it may be adapted to each individual situation.

Hope that answers your question.
Gilles RAULT, MD

14.05.2012