Mutation

Question

Hello

My daughter has CF and is almost 4 years old. She is clearly pancreatic insufficient and has a rather moderate pulmonary impairment, (say Staphylococcus colonization, and started Pulmozyme 6 months ago) with mutations deltaF508 /1898 +1 G> A. I failed to get information from my CF Center about this mutation. I'd like to know what's its class and its exact function (CFTR production or not etc...) and whether other similar cases have been described.
Thank you.

Answer

Hello,

To date, of the 1853 CF gene mutations recorded in the data base run by the International consortium (Cystic Fibrosis Mutation Database: www.genet.sickkids.on.ca), 508delF mutation is the only one very frequent since it is found in at least one copy in more than 80% of patients in France.
Besides this main mutation, about 5 other mutations, varying according to regions or countries, are found in less than 5% of patients in France. Though most mutations are very rare and found in fewer than 1 in 1000. This is the case of mutation 1898+1 G-> A present in 5 patients reported to the French CF Registry. The eldest one is 10 years old ; 3 of them are called "heterozygous composite” F508del/1898+1G->A. This mutation is mainly found in Northern Europe, foremost in the United Kingdom. The publications reporting this mutation date for more than 10 years and are mainly focused on molecular genetic aspects. It is described as splicing mutation resulting in a lack of synthesis or a synthesis of non-functional protein that sorts it out within the class I mutations. The clinical data in these publications are poor and rare: one publication reported an 18 male CF patient with the homozygous genotype 1898+1G- >A/1898+1G->A). The patient was born with meconium ileus, has a positive sweat test, an exocrine pancreatic insufficiency, a severe liver damage and a slight respiratory impairment (normal Pulmonary function tests, slight bronchiolar thickening and lung pulmonary inflation on the chest X Ray). Let me draw your attention on the fact that many factors may determine the clinical course of a given patient, either genetic linked to CF genotype and modifier genes or environmental. The value of genotype for presuming clinical course is extremely limited as evidenced by very different evolutions that can be observed among siblings carrying the same mutations. So I can not emphasize enough the importance of regular follow up of your daughter by your CF center team. Feel free to ask questions: indicator values of her state of health (including body mass index and FEV1); opportunities to participate in therapeutic education sessions; which treatments are most appropriate given her condition; existence of clinical trials that might be proposed to you (her), especially those that involve patients with a class I mutation.
I hope I have answered your question and begg you to apologise for my delayed answer.
Gilles RAULT, MD (with aknowlegments to Claude Férec, Virginie Scotet Gil Bellis and Sophie Ravilly for their kind cooperation)

08.02.2011