Cystic Fibrosis (CF) is an inherited condition caused by a defect in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which regulates the movement of salt and water across cell membranes. A malfunction in the CFTR protein leads to the production of abnormally thick and sticky mucus, primarily affecting the lungs, pancreas, and other organs. This dense mucus blocks airways, traps bacteria leading to chronic infections, and prevents digestive enzymes from reaching the intestine. Screening aims for early identification, allowing for prompt specialized treatment that significantly improves nutritional status and long-term health outcomes.
Universal Newborn Screening
Screening for cystic fibrosis is a mandated public health measure performed on nearly all newborns shortly after birth. The initial step involves collecting a few drops of blood, typically from a heel prick, dried onto a filter paper card. This specimen is first analyzed for Immunoreactive Trypsinogen (IRT), a pancreatic enzyme precursor.
Infants with CF often have elevated IRT levels because enzyme precursors are unable to drain properly from blocked pancreatic ducts, causing them to leak into the bloodstream. Since an elevated IRT alone can be a temporary finding, a positive result triggers a second tier of screening. This reflex testing involves a limited DNA analysis on the same dried blood spot to check for a panel of the most common CFTR gene mutations.
This two-tiered approach, called IRT/DNA screening, significantly improves accuracy by reducing false-positive results. If the IRT is elevated and one or two CFTR mutations are detected, the infant is classified as “screen positive” and referred immediately for definitive diagnostic testing.
Diagnostic Confirmation Testing
When newborn screening is positive or when a child or adult exhibits suggestive symptoms, the gold standard for definitive diagnosis is the Sweat Chloride Test. This test measures the concentration of chloride in sweat, which is characteristically high in people with CF due to the defective CFTR protein’s inability to reabsorb chloride back into the cells.
The procedure uses quantitative pilocarpine iontophoresis to stimulate sweat production. Pilocarpine is applied to the skin, and a mild electrical current activates the sweat glands. The resulting sweat is collected over about 30 minutes onto a specialized material and then analyzed to determine the chloride concentration.
Results are interpreted using established concentration cutoffs. A sweat chloride concentration of 60 millimoles per liter (mmol/L) or greater is consistent with a diagnosis of cystic fibrosis. Results below 30 mmol/L indicate the condition is unlikely. Intermediate values (30 to 59 mmol/L) are considered borderline and necessitate a repeat test or further genetic testing.
Carrier Screening for Prospective Parents
A separate form of screening is available for adults planning a pregnancy to determine their risk of having a child with cystic fibrosis. Carrier screening is performed on a blood or saliva sample to check an individual’s DNA for a single defective copy of the CFTR gene. Since CF is inherited in an autosomal recessive pattern, a person must inherit a defective copy from both parents to develop the disease.
A person with only one altered copy is a carrier, typically showing no symptoms, but can pass the mutation to their children. Standard screening panels detect the most common CFTR mutations, such as the F508del variant. While the detection rate is high, a negative result does not eliminate risk entirely, as there are more than 2,000 known mutations.
If both prospective parents are identified as carriers, there is a 25 percent chance with each pregnancy that their child will have cystic fibrosis. This information is used for reproductive planning and risk assessment, and results are often discussed with a genetic counselor.
Advanced Genetic Analysis
In cases where newborn screening or the sweat test is inconclusive, or when an individual shows atypical symptoms, specialized genetic analysis offers a more detailed examination of the CFTR gene. This advanced molecular testing moves beyond common mutation panels to provide a comprehensive look at the gene’s entire structure.
Techniques such as next-generation sequencing (NGS) are employed to sequence the full coding regions and exon-intron boundaries of the CFTR gene. This deep sequencing can identify rare mutations, Variants of Uncertain Significance (VUS), and large deletions or duplications that might be missed by conventional methods.
This detailed genetic information is useful for confirming a diagnosis in complex cases, for individuals with milder forms of the disease, or for guiding the use of modern CFTR modulator therapies which target specific genetic defects.