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Genotype-Phenotype Study Defines Disease-Causing Versions of Cystic Fibrosis Gene

NEW YORK (GenomeWeb News) – With the help of genotypic and phenotypic data for tens of thousands of individuals with cystic fibrosis, a Johns Hopkins University-led team has hammered out a list of more than 125 variants that can contribute to the disease.

As they reported online yesterday in Nature Genetics, the researchers sifted through a multitude of possible mutations in the cystic fibrosis transmembrane conductance regulator gene CFTR, using information from almost 40,000 CF patients to try to determine which changes are harmless and which are apt to have clinical or functional effects.

Their analysis produced a set of 127 CFTR alleles that appear capable of causing CF, along with several dozen variants with either neutral or still-uncertain effects. The collection is expected to prove useful for understanding CF biology and targeting treatments to match mutant alleles present in CFTR, when possible. It should also help in screening newborns for CF and determining the carrier status of individuals with variant versions of the gene.

"Since not all mutations cause disease, sequencing the DNA in both copies of your CFTR gene and finding an abnormality in one wouldn't tell us if you are a carrier for CF unless we knew if that abnormality causes CF," senior author Garry Cutting, a pediatrics researcher with JHU's McKusick-Nathans Institute of Genetic Medicine, said in a statement.

"Until this new work, more than a quarter of couples in which both partners were found to carry a CFTR mutation were left wondering if their mutations were going to affect their offspring," Cutting said. "Now it's down to 9 percent."

Researchers have long known that affected individuals inherit CF recessively when both of his or her parents each pass on a mutated copy of the CFTR gene. But the clinical significance of many alternative alleles in the gene remains murky, even though this list of variants continues to grow.

"Almost 2,000 variants have been reported in the CFTR coding and flanking sequences," authors of the new study noted, "but the disease liability of only a few dozen variants has been ascertained."

In the hopes of untangling some of this clinical uncertainty, the team turned to data from CF registries and clinics across North America and Europe for an effort known as the Clinical and Functional Translation of CFTR — or CFTR2 — project, ultimately bringing together genotype and phenotype information for 39,696 individuals with the disease.

For the first phase of the CFTR2 project, researchers focused on CFTR variants found with at least 0.01 percent frequency in the individuals, which whittled the list of potential CF risk variants in the group down from 1,044 variants to 159 variants.

"Together, these 159 variants accounted for 96.4 percent of the identified cystic fibrosis alleles in CFTR2," they noted. "Our efforts focused on the evaluation of the disease liability of these 159 variants to maximize clinical sensitivity for cystic fibrosis genetic testing."

Of those, 127 variants met the investigators' criteria for producing both functional changes in CFTR as well as clinical effects, such as changes in sweat chloride concentrations, a marker for CF severity.

That set of variants represents an estimated 95.4 percent of the disease-causing alleles present in the patients considered, they reported. It also brings the list of CF culprits up dramatically from the 23 risk alleles known prior to the study.

Among the other 32 variants were a dozen variants with apparently neutral effects and 20 variants with yet-undetermined clinical and functional consequences, according to a disease penetrance analysis done with data for more than 2,000 fathers with CF-affected children.

"The indeterminate variants as well as over 1,600 CFTR variants that are unclassified remain a diagnostic dilemma," the study's authors wrote, noting that machine learning methods may bolster the ability to predict variants' functional effects computationally.

In the meantime, the group is optimistic that the existing set of CF-causing alleles will have applications in understanding, detecting, and perhaps even treating the disease. Vertex Pharmaceuticals already offers a drug called Kalydeco (ivacaftor) that targets a CFTR mutation found in around 4 percent of CF sufferers, prompting interest in other targeted treatments.

"It's our hope that the functional data we have provided for these other mutations can be used to find additional drugs for specific CF mutations," Cutting said in a statement.