The study, “Two novel and correlated CF-causing insertions in the (TG)mTn tract of the CFTR gene,” was published in the journal PLOS One.
CF diagnosis is based on clinical and genetic tests, which include abnormal results in at least two sweat chloride tests and/or having CF-causing mutations, pancreatic insufficiency, or other suggestive symptoms of the disease.
In CF, a faulty cystic fibrosis transmembrane conductance regulator (CFTR) protein leads to the buildup of thick, sticky mucus in the lungs and digestive system. More than 2,000 variations of the CFTR gene have been reported, but there is little information on their functional and clinical impact. Genetic studies are therefore needed not only to better characterize these variants, but also to help select participants for clinical trials or treatment protocols.
Researchers in Italy described two patients — an 18-year-old woman and a 7-year-old boy — carrying novel genetic variants in the CFTR gene.
Both patients had early-onset exocrine pancreatic insufficiency (EPI), which results from a deficiency of exocrine pancreatic enzymes, which results in problems digesting food.
Both also lacked CF features on X-rays, while their throat swabs showed chronic colonization with Staphylococcus aureus and intermittent infection with Pseudomonas aeruginosa — the primary bacterial agent causing chronic lung infections in CF patients — early in childhood (first isolated at age 8 in the woman and at age 3 in the boy).
The girl, born in 2001, was diagnosed at 10 months of age, having experienced gastrointestinal disturbances (she was underweight and had diarrhea) shortly after birth.
Sweat chloride values of 80 and 92 mmol/L confirmed a CF diagnosis. Of note, newborn screening had not been introduced at this time in the region where she was born (south of the Marche region, central Italy).
She also exhibited signs of bronchiectasis in her lungs for the first time in October 2018.
Both patients were started on pancreatic enzyme replacement therapy, which improved their nutritional status.
Genetic analysis confirmed the same deletion — called F508del — in one of the CFTR gene copies (alleles) in both patients. Further analysis revealed each had a second alteration, an amplification of a CFTR region known to modulate the gene’s exon 10.
Genes are composed of exons and introns. Exons contain the information for the production of a protein, while introns do not and are removed during gene expression. The CFTR gene is made up of 27 exons and 26 introns.
The newly found amplifications in the patients both correspond to 306 additional nucleotides (the building blocks of DNA), which led to the insertion of part of intron 10 within intron 9, and the abnormal absence of exon 10 in RNA generated from the mutated allele. The team predicted this would result in a non-functional CFTR protein.
“Molecular and functional features of these alterations are compatible with the definition of novel CF-causing variants of the CFTR gene,” the researchers wrote.
“The discovery of novel rare [disease] variants of CFTR, as well as their experimental functional characterization, are mandatory to ameliorate our diagnostic, prognostic and, in the era of CF personalized medicine, therapeutic ability,” they added.
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