Cystic Fibrosis

Cystic Fibrosis Mutations

Cystic fibrosis is an autosomal recessive, genetic disease that affects more than 31,000 individuals in the United States and approximately 89,00 worldwide. Among people with cystic fibrosis in the United States, approximately 91.4% identify as White, 3.5% as Black, and 5.1% as other. Cystic fibrosis is the most common life-limiting autosomal recessive genetic disorder in Caucasians, with an incidence of 1 in 3000 newborns. 

Cystic fibrosis is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein that functions as a regulated anion channel. CFTR is expressed on the apical membranes of epithelial cells in the trachea, bronchi, liver, pancreas, gastrointestinal tract, and sweat glands. CFTR selectively conducts chloride and facilitates transport of bicarbonate. In general, CFTR mutations result in reduced quantity or function of CFTR protein at the cell surface. Affected cells are impermeable to chloride conductance, leading to increased sweat chloride concentration, highly viscous mucus, and organ damage from ductal inspissation. Symptoms begin in infancy with steatorrhea, poor weight gain, and respiratory symptoms. As people with cystic fibrosis age, other clinical manifestations appear including pancreatic insufficiency with malnutrition, biliary cirrhosis, absence of the vas deferent with azoospermia, chronic sinusitis, and chronic obstructive pulmonary disease. 

CF is an autosomal recessive disease. People with CF inherit a mutation in the CFTR gene from each parent. More than 2,000 sequence variants of the CFTR gene have been identified, of which approximately 700 have been shown to cause disease. The most common disease causing gene variants have been grouped into six classes by the mechanisms they cause CFTR dysfunction. Classes I, II, and III result in minimal to no CFTR and are associated with the highest sweat chloride concentrations, severe lung disease, and pancreatic insufficiency. Classes IV, V, and VI are associated with some residual CFTR function and may have lower sweat chloride concentrations and milder disease. Approximately 85.5% of people in the United States have the F508del mutation which results in the deletion of phenylalanine at position 508 of the protein and the complete loss of function of the anion channel. 

Mutations that result in some residual chloride transport function are often associated with milder disease. More widespread screening of individuals in recent years has led to the realization that the clinical spectrum of disease caused by CFTR mutations is much broader than originally thought. Approximately 2% of adults present with atypical or mono-symptomatic disease including chronic bronchitis, sinusitis with nasal polyposis, male infertility due to obstructive azoospermia, or chronic pancreatitis. 

Diagnostic criteria for cystic fibrosis consist of one or more organ-specific manifestations and elevated sweat chloride concentrations or genetic confirmation of two disease causing variants in the CFTR gene. Sweat chloride testing is the main diagnostic test for cystic fibrosis with high sensitivity (99%) and specificity (95%). An elevated sweat chloride concentration of >60 mEq/L is consistent with the diagnosis. An intermediate sweat chloride concentration between 30 and 59 mEq/L requires further confirmation by genetic testing. Some experts also recommend DNA analysis in individuals with positive sweat testing for prognostic and epidemiological purposes. 

DNA testing is also helpful in optimizing therapy. Small molecule CFTR modulator drugs are available that can improve the health of more than 90% of people with cystic fibrosis. Potentiators, like ivacaftor, increase the probability that the anion channel is open, so chloride and bicarbonate can flow more easily through the cell membrane. Correctors, like lumacaftor, tezacaftor, and elexacaftor, facilitate proper protein folding and enable anion transport to the cell surface. Severe CFTR gene mutations, such as F508del, require treatment with both potentiators and correctors. 

Molecular diagnosis is usually carried out by direct mutation analysis. Most diagnostic laboratories in the United States screen for at least 23 of the most common mutations, using a panel developed for population screening by the American College of Medical Genetics (ACMG).

23 Mutation Panel

Because this panel is limited, some carriers will not be detected. The detection rate of this panel varies with ethnicity.  The following table lists the detection rate of the panel and the remaining carrier risk for an individual who has a negative result. 

Estimated Carrier Risk

In a diverse ethnic population, a panel of 40 mutations that includes CFTR mutations found to be more prevalent in non-European ethnicities is recommended.  

The American College of Medical Genetics (ACMG) and the American College of Obstetrics and Gynecology (ACOG) recommend that all Caucasian couples who are pregnant or are considering pregnancy be offered carrier screening for cystic fibrosis. They also recommended that non-Caucasian couples be made aware of the availability of screening. The rationale for these recommendations is that carrier detection allows for earlier identification of at risk couples who would then have the ability to exercise their reproductive options, including prenatal diagnosis and earlier treatment of affected children.    

Screening may be performed either before pregnancy or during the first trimester. Preconception screening is preferable.  Screening of both partners can be accomplished either concurrently or sequentially.  Concurrent screening of both partners is recommended for Caucasians and Ashkenazi Jews. This provides a more rapid and precise estimate of carrier status and the risk of cystic fibrosis in their offspring.  Sequential screening is the screening of one partner followed by screening of the second partner only in the event of a positive result in the first partner.  Since most individuals test negative, this strategy is less expensive but takes longer.  Also, since the screening tests are not 100% sensitive, there is a higher residual risk when only one partner is tested and found to be negative and the carrier status of the other partner remains unknown.  

Risk of having a Cystic Fibrosis Affected Infant if One or Both Parents Test Negative

Cystic fibrosis can also be detected by newborn screening which includes measurement of immunoreactive trypsinogen from a blood spot. Abnormal levels are confirmed by DNA testing. 

Advances in diagnosis and treatment have improved mean survival from 36.3 years in 2006 to 53.1 years in 2021. 

References

Ong T and Ramsey BW, Cystic Fibrosis: A Review. JAMA 2023;329(21):1859-1871. 

American College Obstetrics and Gynecology, Cystic Fibrosis; Prenatal Screening and Diagnosis, https://www.acog.org/womens-health/faqs/cystic-fibrosis-prenatal-screening-and-diagnosis