Monday, 26 August 2013

Which CFTR mutations actually cause CF?

A recent study sheds new light on which of the 1,900 plus known mutations of the CFTR gene actually cause cystic fibrosis (CF) and which do not. The study is called "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene" and it was published on 25 August 2013 in Nature Genetics. The results have important implications for family planning and drug development although this work is ongoing and part of a bigger project aiming to characterize all known CFTR mutations. Researchers analysed genetic information from nearly 40,000 CF patients to find out which of the 1,900 mutations cause CF and which are benign. Their findings increased the number of known CF-causing mutations from 22 to 127. Prior to this, more than 25% of couples in which both partners were found to carry a mutation on the CFTR gene could have no way of telling whether their mutations could actually cause CF in their offspring. As a result of this study, that is reduced to 9%. The work provides some interesting clues for drug development too. By looking at the differences in severity of disease caused by changes in CFTR associated with different genotypes, the researchers have a better idea of the potential efficacy of drugs which achieve the same changes in CFTR.

I emailed some questions to Dr. Patrick Sosnay, co-author of the study and assistant professor of pulmonary and critical care at Johns Hopkins University. 

How did you do this study?

"We collected CF patients and parents from around the world (mostly N. America and Europe) and looked at the mutations they had. We then looked at each of these mutations to tell for sure if they caused CF. We looked at the clinical outcomes of patients that had those mutations (assuming the higher their sweat chloride, the more likely the mutation was truly a CF causing mutation); we looked at how the mutation behaved in experiments (the less it behaved like the non-mutated or "wild-type" CFTR, the more likely it was truly a CF causing mutation), and we looked at how often it was seen in people with CF, vs. carriers, vs. the general population."

What is the relevance of the results?

"We have better defined the range that can be seen with the 159 most seen CF mutations. Some always cause CF, some cause CF some of the time, and some we do not think cause CF. Obviously, because it is a recessive disease a patient has to have mutations on both copies of CFTR they inherit."

What are the implications of this data for family planning?

"This will help genetic counselling in that we will have a better idea what the most likely consequence of a mutation is. People having genetic testing done before this study were more likely to get back a CF mutation that we did not know how to interpret. They would be told – you have a mutation in CFTR, we do not know if it causes CF or not. There are still many mutations out there that are uncharacterized, but we have chipped away at some of the more common ones."

What are the implications of this data for drug development?

"This information will be used by scientists studying therapies to group mutations according to their functional consequences. We also hope to learn more about what contribution CFTR genotype makes to making CF mild or severe."

Is this project continuing and what is the ultimate goal?

"This work is continuing. For every mutation that has ever been seen in CFTR, we want to be able to say: does it cause CF, if so what drugs could be used against it?"

Here is a link to the study in Nature GeneticsDefining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene