Harmful cystic fibrosis mutations mapped

Philippa Brice

27 August 2013

A team of US researchers has probed the genetic complexity of mutations underlying cystic fibrosis (CF), a recessive genetic (heritable) disease of variable severity.


There are approaching two thousand different documented mutations within the CFTR gene, which is relatively large; many, but not all, are associated with overt (phenotypic) CF. Some mutations are very common (notably the ΔF508 deletion) butmany others are rare. Some are known to be associated with particular aspects of CF, such as lung disease or digestive tract involvement, or with different disease severity. However, uncertainty over the clinical significance of many of the rarer mutations complicates medical advice, especially when these mutations are identified following newborn screening or pre-conception carrier screening.


New research published in the journal Nature Genetics has analysed genotypic and phenotypic data from nearly 40,000 clinically diagnosed CF patients from 24 countries in Europe and North America, in order to map which mutations are associated with symptomatic disease, and of what severity.


The researchers began with the more common mutations among the CF patients and found 159 CFTR gene variants (representing over 96% of all variants), which were then assessed for clinical severity and functional impact. 127 (80%) were consistent with disease by both criteria. To evaluate the remaining 32 variants, researchers analysed more than 2,000 fathers of the CF patients. Impaired CFTR gene function results in male infertility, so the version of the gene not passed to their offspring with CF must be non-penetrant for the disease. Twelve of the variants were concluded to be neutral in effect on the basis of this analysis, leaving just 20 variants of unknown effect.


Comment: This study increased the number of gene variants associated with clinically apparent CF from 23 to 127, leaving just 0.21% of all the CF patients sampled without at least one confirmed pathogenic CFTR variant. This is a substantial addition to existing knowledge that should enhance the accuracy of genetic testing for disease prediction among corresponding populations – a significant clinical benefit. This is particularly so in countries where pre-conceptual genetic screening is common; the practice is rare in the UK at present. The authors also hope it may help the development of new treatments directed at genetic subgroups of CF patients, a form of personalised medicine.

More broadly, the study addresses a potential approach to the problem of rare genetic variants of unknown medical significance, an issue likely to grow alongside the development of genomic medicine and clinical whole genome sequencing. It would seem that linking high-quality genetic and phenotypic data can provide a resource for research to distinguish neutral and pathogenic mutations within the same gene. This is one potential benefit for patients, families and future generations in the area of rare diseases that could be realised by the UK 100,000 Genomes Project being led by Genomics England – provided that robust and appropriate systems are put in place for recording, storing and interrogating linked genomic and clinical patient data.