An international group of experts has updated the guidelines for the definite diagnosis of cystic fibrosis (CF), which will help clinicians make a correct diagnoses and offer personalized therapies to their patients.
The article with the updated guidelines, “Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnoses,” was published in The Journal of Pediatrics. Two supplemental articles on the data used to create the new guidelines and their implications were also published in the same journal.
Cystic fibrosis is a genetic disease characterized by persistent lung infections and difficulty in breathing due to a build-up of mucus in the lungs. Healthy lungs produce mucus that is transported to the throat by the waving movements of ciliated cells in the respiratory tract, which help to remove small particles that have been inhaled, including bacteria or viruses.
In CF patients, however, a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene causes the mucus to thicken, preventing its clearance. There are now over 2,000 identified mutations in the CFTR gene, but not all of them will cause CF.
“We’ve more precisely defined what cystic fibrosis is. That precision was a result of the genetic research we did and from studying the many mutations associated with cystic fibrosis,” Patrick Sosnay, MD, assistant professor of medicine at Johns Hopkins University School of Medicine and the study’s author, said in a news release.
To better quantify and describe these genetic mutations, Sosnay and 31 other leading CF specialists compiled data from patients in Europe, North and South America, Australia, Asia, and the Middle East.
The global project, named CFTR2 (the Clinical and Functional TRanslation of CFTR), provides information for patients, researchers, and the general public about specific variants or mutations in the CFTR gene. Since its launch in 2008, the project has characterized about 300 out of the 2,000 identified mutations.
According to the newly updated guidelines, the latest classification that should be used to aid in the diagnosis of cystic fibrosis include: CF-causing mutations, mutations of varying clinical consequence, and non-CF-causing or uncharacterized mutations.
Mutations are categorized according to whether they meet the criteria for definite CF, as well as the likelihood of someone carrying the mutation to develop the disease.
This is a substantial update from the 23-mutation panel recommended by the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists, which has been in use since 2004.
“The stakes in categorizing a mutation are particularly high. For example, claiming that a mutation 100 percent causes cystic fibrosis may affect people’s reproductive decisions if they believe their child will have the mutation,” Sosnay said.
Sosnay considers that offering patients all information currently available on cystic fibrosis may lead to a better understanding of the wide spectrum of CFTR-related diseases — and to better treatment decisions.
“Therapies exist for individuals with certain mutations. The compilation and availability of all this data can lead to more personalized medicine if people know what mutation(s) they have and seek appropriate care,” Sosnay added.
The new guidelines also standardized diagnostic criteria for those who are diagnosed with CF outside of newborn screening, a standard blood test that is performed in infants right after they are born. This test is not performed in all countries, and even in the U.S., where it’s been in use since the 1980s, there is a high chance of false negative results.
Because more than 30 percent of all CF diagnoses in the U.S. in 2014 were not the result of newborn screening, experts consider it is still necessary to screen individuals beyond screening at birth.
The majority of individuals with cystic fibrosis can be readily diagnosed through a sweat test and CFTR genetic analysis. Elevated levels of chloride in sweat — above 40 millimoles per liter — was, until now, the limit considered to provide direct evidence that the CFTR protein is not working, and deem a “possible” case of CF.
A normal range for chloride sweat concentration is 10 to 20 millimoles per liter, with 60 millimoles per liter constituting a definite case of CF.
With the new guidelines, people with levels of sweat chloride between 30 and 40 millimoles per liter will be considered for reassessment as possibly having cystic fibrosis or a related disease.
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