Rare CF mutations

Question

What percentage of the UK population carries a rare mutation for cystic fibrosis (excluding the 50 most commonly found mutations)?

Answer

Dear Questioner, thank you for your question.

It may be difficult to fully address your question, specifically with regard to the UK alone as most research addresses the prevalence of CF genetics based on the worldwide population or the European population as a whole.

More than 1500 CFTR mutations have been identified worldwide and in routine practice it is only possible to check for approximately 100 of these. The screening of CFTR mutations is used in the diagnosis of CF. The presence of two mutations known to cause CF indicates that the individual has CF. The finding of only one mutation or no mutations does not exclude the diagnosis.
Worldwide, fewer than 20 mutations occur more frequently than 0.1%. The most common mutation is F508del (formerly called ΔF508), which accounts for approximately two-thirds of alleles in patients with CF worldwide. This mutation is found in all populations with varying frequency.

On the European continent, 10 mutations account for 79% of alleles. The birth prevalence of CF in the UK is 1:2400 and the 3 most common mutations are: F508del, G551D and R117H

Coming now to your concrete question—only a rough calculation can be made as frequencies can vary from country to country in a certain extent depending on the ethnic background of the population. On a European level around 3.3% (1/30) of the population are carriers of a mutation for cystic fibrosis, in the UK this carrier frequency it rather 1/25, that means around 4% of the population are carriers of a CF mutation. If you do a commercial assay including around the most frequent 30-40 CF-causing mutations, the detection rate would be estimated to be minimally 70% and optimally 90% (this also depends on the ethnic background and can therefore not be exactly determined).
If you would perform this test to the whole population, you would only detect 70-90% out of the 4% gene carriers. That means, after you did this test, there remain still 0.4%-1,2% (depending on the detection rate 70%-90%) of the population carrying a "rare" CF-mutation that could not be detected by your standard kit. The lab report should give you a residual risk depending on your ethic origin.

References:
•Boyle MP. Adult cystic fibrosis. JAMA. 2007;298(15):1787-1793.
•Castellani C, Cuppens H, Macek M Jr, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008;7(3):179-196
•Castellani et al. Benchmarks for Cystic Fibrosis carrier screening: A European consensus document. J Cyst Fibros. 2010, 9:165-178:
•O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891-1904.
•www.cftrscience.com/epidemiology.php


Yours Sincerely

Katherine O’Neill Physiotherapist
Prof Stuart Elborn Consultant Physician
Daniela d'Alquen Pediatrician

24.01.2013

The answer is edited by: Prof Stuart Elborn