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CFTR-Related Disorders

Includes: Congenital Absence of the Vas Deferens, Cystic Fibrosis

, MD, , MD, , MS, CGC, , MS, MD, and , MD.

Author Information
, MD
Department of Pediatrics
Massachusetts General Hospital
Boston, Massachusetts
, MD
Department of Pediatrics
Case Western Reserve University School of Medicine
Cleveland, Ohio
Genetics Division
Children's Hospital and Regional Medical Center
Seattle, Washington
, MS, MD
Department of Obstetrics and Gynecology
University of Washington School of Medicine
Seattle, Washington
, MD
CFF Genotyping Center
Johns Hopkins University School of Medicine
Baltimore, Maryland

Initial Posting: ; Last Update: February 19, 2008.


Clinical characteristics.

CFTR-related disorders include cystic fibrosis (CF) and congenital absence of the vas deferens (CAVD).

  • Cystic fibrosis affects epithelia of the respiratory tract, exocrine pancreas, intestine, male genital tract, hepatobiliary system, and exocrine sweat glands, resulting in complex multisystem disease. Pulmonary disease is the major cause of morbidity and mortality in CF. Affected individuals have lower airway inflammation and chronic endobronchial infection, progressing to end-stage lung disease characterized by extensive airway damage (bronchiectasis, cysts, and abscesses) and fibrosis of lung parenchyma. Meconium ileus occurs at birth in 15%-20% of newborns with CF. Pancreatic insufficiency with malabsorption occurs in the great majority of individuals with CF. More than 95% of males with CF are infertile as a result of azoospermia caused by absent, atrophic, or fibrotic Wolffian duct structures.
  • CAVD occurs in men without pulmonary or gastrointestinal manifestations of CF. Affected men have azoospermia and are thus infertile.


Most commonly the diagnosis of cystic fibrosis (CF) is established in individuals with one or more characteristic phenotypic features of CF plus evidence of an abnormality in cystic fibrosis transmembrane conductance regulator (CFTR) function based on ONE of the following:

  • Presence of two CFTR pathogenic allelic variants

  • Two abnormal quantitative pilocarpine iontophoresis sweat chloride values (>60 mEq/L)

  • Transepithelial nasal potential difference (NPD) measurements characteristic of CF

The CFTR mutation detection rate varies by test method and ethnic background. In some symptomatic individuals, only one or neither disease-causing mutation is detectable; in some carriers, the disease-causing mutation is not detectable. The diagnosis of CFTR-related CAVD is established in males with azoospermia, low volume of ejaculated semen, absence of vas deferens on clinical or ultrasound examination, and at least one disease-causing mutation in CFTR.


Treatment of manifestations: Treatment/prevention of pulmonary complications using oral, inhaled, or IV antibiotics, bronchodilators, anti-inflammatory agents, mucolytic agents, and chest physiotherapy; lung or heart/lung transplantation in selected patients; topical steroids, antibiotics, and/or surgical intervention for nasal/sinus symptoms; special infant formulas to enhance weight gain; oral pancreatic enzyme replacement with meals in those who are pancreatic insufficient; supplemental feeding, often with an indwelling gastric feeding catheter to increase caloric intake; additional fat-soluble vitamins and zinc; oral ursodiol for biliary sludging/obstruction; management of CF-related diabetes mellitus (CFRD) by an endocrinologist; assisted reproductive technologies (ART) for male infertility.

Prevention of secondary complications: Airway clearance using chest physiotherapy (CPT) and a variety of airway clearance techniques (ACTs); antibiotics to eradicate initial airway infection and prevent chronic airway infection; immunizations.

Surveillance: Regularly scheduled visits to CF care providers to monitor for subtle changes in physical examination, pulmonary function studies, chest radiographs, specific blood and urine tests; cultures of respiratory tract secretions at least four times yearly in patients who are not yet chronically infected with P. aeruginosa; random serum glucose concentration measured annually to screen for CFRD; assessment of bone density starting in adolescence.

Agents/circumstances to avoid: Respiratory irritants (smoke, dust); respiratory infectious agents (especially viruses); dehydration.

Evaluation of relatives at risk: Sweat chloride testing of sibs and mothers of affected individuals to determine if they may have mild or not yet symptomatic forms of CF.

Therapies under investigation: Antibiotic agents/treatment schedules to delay chronic respiratory tract infection.

Genetic counseling.

CFTR-related disorders are inherited in an autosomal recessive manner. Sibs of a proband with cystic fibrosis and brothers of a proband with CAVD have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. Molecular genetic testing for pathogenic allelic variant(s) in CFTR is used for carrier detection in population screening programs. Prenatal testing is possible for pregnancies at increased risk for CFTR-related disorders if the pathogenic variants in the family are known.


Clinical Diagnosis

Cystic fibrosis (CF). Phenotypic features of CF include but are not limited to the following:

  • Chronic sinopulmonary disease (chronic cough and sputum production, chronic wheeze and air trapping, obstructive lung disease on lung function tests, persistent colonization with pathogens commonly found in individuals with CF, chronic chest radiograph abnormalities, chronic pansinusitis, digital clubbing)
  • Gastrointestinal/nutritional abnormalities (meconium ileus, rectal prolapse, malabsorption/pancreatic insufficiency, steatorrhea, hypoproteinemia, fat-soluble vitamin deficiencies, failure to thrive, distal intestinal obstructive syndrome, recurrent pancreatitis, biliary sludging, elevation of transaminases and gamma-glutamyl transferase, direct hyperbilirubinemia, chronic hepatobiliary disease)
  • Obstructive azoospermia
  • Salt-loss syndromes (acute salt depletion, chronic metabolic alkalosis, hyponatremic hypochloremic dehydration)

The diagnosis of CF is established in individuals with the following:

  • One or more characteristic phenotypic features of CF

  • Evidence of an abnormality in cystic fibrosis transmembrane conductance regulator (CFTR) function based on one of the following:
    • Presence of two disease-causing mutations in CFTR

    • Two abnormal quantitative pilocarpine iontophoresis sweat chloride values (>60 mEq/L)

    • Transepithelial nasal potential difference (NPD) measurements characteristic of CF

The diagnosis of CF may be made in the absence of phenotypic features of CF in the following settings:

Congenital absence of the vas deferens (CAVD). The diagnosis of CFTR-related CAVD is established in males with the following:

  • Azoospermia (absence of sperm in the semen)
  • Absence of the vas deferens on palpation (Rarely, a thin fibrous cord representing a rudimentary vas deferens may be present.)
  • An identifiable mutation in one or both CFTR alleles [Dork et al 1997]

Additional features that may be seen include the following:

  • A low volume of ejaculated semen (<2 mL; normal: 3-5 mL) with a specific chemical profile
  • Evidence of abnormalities of seminal vesicles or vas deferens on rectal ultrasound examination


Cystic Fibrosis

Sweat chloride. The National Committee for Clinical Laboratory Standards has published guidelines for the appropriate performance of the quantitative pilocarpine iontophoresis procedure [Wayne 1994, Legrys 1996]. Centers accredited by the Cystic Fibrosis Foundation are required to adhere to this protocol; alternative sweat test procedures are not acceptable. This test is positive in more than 90% of individuals with CF.

  • A minimum sweat weight of 75 mg must be collected during a 30-minute period to assure a sweat rate of 1 g/M2/min.
  • A chloride concentration greater than 60 mEq/L in sweat on two separate occasions is diagnostic.

Note: Sweat chloride levels higher than 160 mEq/L are not physiologically possible and should be attributed to technical error. (2) False positive sweat chloride results may be associated with other conditions, most notably mucopolysaccharidosis type 1 (Hurler syndrome). (3) False negative sweat chloride results may occur in the setting of acute CF-related salt losses. (4) When CF is suspected in an individual with hyponatremia and hypochloremia, sweat testing should be deferred until electrolyte balance has been restored and fluid status stabilized.

Transepithelial nasal potential difference (NPD). Respiratory epithelia regulate ion transport and alter content of the airway surface fluid by active transport mechanisms. The absence of functional CFTR at the apical surface with resultant alterations in chloride efflux and sodium transport produces an abnormal electrical potential difference across epithelial surfaces. The protocol for NPD measurements in individuals older than age six years is well described, standardized, and safely performed in many specialized CF centers worldwide [Schuler et al 2004, Standaert et al 2004].

Individuals with CF have the following:

  • A raised (more negative) baseline NPD reflecting enhanced sodium absorption across a relatively chloride-impermeable membrane
  • A greater change in NPD during perfusion of the nasal mucosa with amiloride, an inhibitor of sodium channel activity
  • Minimal change in NPD in response to perfusion with amiloride/low chloride/beta-agonist, as a measure of cAMP-mediated chloride transport via CFTR

Newborn screening. Newborn screening using immunoreactive trypsinogen (IRT) assays performed on blood spots has been implemented in most of the United States [National Newborn Screening Status Report (pdf)]. Trypsinogen is synthesized in the pancreas; in CF, its release into the circulation appears to be enhanced by abnormal pancreatic duct secretions. Thus, IRT levels are elevated in cystic fibrosis. The benefits of newborn screening across various populations have been reviewed [Wagener et al 2004, Grosse et al 2006].


Semen analysis. Additional findings of the semen of men with CAVD include the following [Holsclaw et al 1971]:

  • Low pH (pH <7; normal: pH >8)
  • Elevated citric acid concentration (>2000 mg/100 mL; normal: 400-1500 mg/100 mL)
  • Elevated acid phosphatase concentration (760-1140 mµ/mL; normal: 140-290 mµ/mL)
  • Low fructose concentration (30-80 mg/100 mL; normal: 250-720 mg/100 mL)
  • Failure to coagulate

Molecular Genetic Testing

Gene. CFTR is the only gene known to be associated with the CFTR-related disorders, CF and CAVD.

Clinical uses

  • Diagnosis in symptomatic individuals
    • With CF
    • With CAVD
  • Carrier testing
    • In at-risk relatives and their reproductive partners
    • In population screening programs for CF
  • Prenatal diagnosis
    • For pregnancies at increased risk for CF
    • For pregnancies in which fetal echogenic bowel has been identified
  • Preimplantation genetic diagnosis for pregnancies at increased risk for CF

Clinical testing

  • Targeted mutation analysis

    Mutation panels. Several panels are available. In 2004, the American College of Medical Genetics (ACMG) decreased the recommended mutation panel from 25 to 23 mutations [Watson et al 2004]. The mutation detection rate for the 23-mutation panel (Table 8) varies with ethnic background (Table 1) [Richards et al 2002].

    5T/TG tract analysis
    • The poly T tract, a string of thymidine bases located in intron 8 of the CFTR gene, can be associated with CFTR-related disorders depending on its size. The three common variants of the poly T tract are 5T, 7T, and 9T. Both 7T and 9T are considered polymorphic variants and 5T is considered a variably penetrant mutation. The 5T variant is thought to decrease the efficiency of intron 8 splicing. Poly T testing is appropriate as a reflex test when an R117H mutation is detected or an adult male is being evaluated for CAVD.
    • The TG tract lies just 5' of the poly T tract. It consists of a short string of TG repeats that commonly number 11, 12, or 13. A longer TG tract (12 or 13) in conjunction with a shorter poly T tract (5T) has the strongest adverse effect on proper intron 8 splicing [Cuppens et al 1998, Groman et al 2004].
    • Males with CAVD or suspected CAVD, individuals with non-classic CF, or adult carriers of 5T who wish to further refine their reproductive risks are all appropriate for 5T/TG tract typing.
  • Deletion analysis. MLPA (multiplex ligation-dependent probe amplification) can detect deletions not identified by sequence analysis. Mutation detection rate is not known.
  • Sequence analysis. Sequencing of all exons, intron/exon borders, promoter regions and specific intronic regions detects more than 98% of CFTR mutations [Strom et al 2003].

Table 1.

Summary of Molecular Genetic Testing Used in CFTR-Related Disorders

Test MethodMutations DetectedMutation Detection Frequency by Population Group
Targeted mutation analysisCFTR mutations using the original 25-mutation panel 1 Ashkenazi Jewish97% 2
Non-Hispanic white88.3% 3
African American69% 2
Hispanic American57% 2
Asian AmericanUnknown
Deletion analysisCFTR exonic and whole-gene deletionsAll populationsUnknown
Sequence analysisCFTR sequence variants 4All populations98.7% 5

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

1. The original 25-mutation panel recommended by the American College of Medical Genetics [Grody et al 2001] included the 23 mutations listed in Table 8, 1078delT, and I148T. The 23-mutation panel recommended in 2004 is expected to have a similar mutation detection rate [Watson et al 2004]. Other panels may have significantly different mutation detection rates.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Using an assay to sequence all the coding sequences, splice donor and acceptance sites, the promotor region, and two intronic sequences [Strom et al 2003]

Interpretation of test results used in diagnosis of individuals suspected of having CF

  • The number of abnormal alleles detected (two, one, or none) (Table 2) depends on the mutation detection rate (Table 1).

Table 2.

Expected Percentage of Abnormal Alleles Detected in Individuals with CF Based on the Detection Frequency of the Test Method Used

Mutation Detection Frequency of Test MethodPercentage of Individuals with CF for which a Given Number of Abnormal Alleles is Identified
Two Abnormal Alleles One Abnormal AlleleNo Abnormal Allele

Calculated using Hardy-Weinberg Rule

Interpretation of test results used in diagnosis of individuals suspected of having CAVD. The percentage of mutant CFTR alleles and 5T variant alleles detected in males with CAVD is summarized in Table 3.

Table 3.

Percentage of Abnormal Alleles Detected in Males with CAVD

Number of Mutant CFTR Alleles%
Other than 5T5T

Interpretation of results of CF carrier testing. It is recommended that in population screening programs cystic fibrosis carrier testing be performed using the ACMG 23-mutation panel (Table 8).

  • 5T and TG tract typing should not be included in a routine carrier screen.
    • If an individual has the R117H mutation, reflex testing for the variants 5T/7T/9T is recommended.
    • If the individual has the 5T allele, family studies are recommended to determine if the 5T allele is in cis configuration or trans configuration with the R117H allele.
  • The 5T/TG tract analysis is not able to provide a specific risk figure for developing symptoms or having a child who develops symptoms of non-classic CF or CAVD; it is able to assign risk as "increased" or "decreased."
    • A person with ΔF508 (Phe508del) and 5T/11TG is less likely to develop non-classic CF, but it is still possible.
    • An individual with ΔF508 and 5T/12TG or ΔF508 and 5T/13TG is more likely, though not certain, to develop CAVD or non-classic CF [Groman et al 2004].

Testing Strategy

Cystic fibrosis. In most circumstances, the following strategy is indicated:

  • Quantitative pilocarpine iontophoresis for sweat chloride concentrations (remains the primary test for the diagnosis of CF, accurately diagnosing >90% of cases)
  • Molecular genetic testing of CFTR for diagnostic purposes if sweat chloride testing is unavailable or uninformative (CFTR molecular genetic testing for prognostic and epidemiologic purposes is appropriate for individuals diagnosed with CF based on sweat chloride testing.)
  • Transepithelial nasal potential difference (NPD) measurements to confirm the diagnosis of CF in symptomatic individuals with borderline or nondiagnostic sweat tests in whom only one or no CFTR disease-causing mutation has been detected

In the following special circumstances, CFTR molecular genetic testing is the initial diagnostic test:

  • Prenatal testing in a high-risk fetus
  • Prenatal diagnosis in low-risk fetus with echogenic bowel
  • Newborn screening
  • Symptomatic infants (i.e., those with meconium ileus) who are too young to produce adequate volumes of sweat
  • Testing of symptomatic sibs of an affected individual in whom both CFTR mutations have been identified

CAVD. The diagnosis of CAVD is generally made in three steps:


Evaluation of infertility. A male with severe oligospermia (<5 million), azoospermia, or very low volume of semen (<2 mL) proceeds to Step 2.


Clinical evaluation by a urologist. If absence of the vas deferens is diagnosed by palpation, the workup proceeds to Step 3. (Imaging may be used but is not usually necessary if the clinical examination is consistent.)


Molecular genetic testing for CFTR mutations

Clinical Characteristics

Clinical Description

Cystic Fibrosis

Cystic fibrosis (CF) affects the epithelia in several organs resulting in a complex, multisystem disease that includes the exocrine pancreas, intestine, respiratory tract, male genital tract, hepatobiliary system, and exocrine sweat glands. Disease expression varies by severity of CFTR mutations [De Braekeleer et al 1997], genetic modifiers [Drumm et al 2005, Blackman et al 2006, Vanscoy et al 2007], and environmental factors [Goss et al 2004]. The range extends from early childhood death as a result of progressive obstructive lung disease with bronchiectasis, to pancreatic insufficiency with gradually progressive obstructive lung disease during adolescence and increasing frequency of hospitalization for pulmonary disease in early adulthood, to recurrent sinusitis and bronchitis or male infertility in young adulthood.

The great majority of individuals with CF are pancreatic insufficient. Individuals with CF and pancreatic sufficiency (<10%) have a milder clinical course with greater median survival (i.e., 56 years [1995 CFF Patient Registry]) than those with pancreatic insufficiency.

The overall median survival is 36.5 years (95% confidence intervals, 33.7-40.0 years) [Cystic Fibrosis Foundation 2006]. A gender difference is present in CF, with greater median survival in males than in females [CFF Patient Registry 1999].

Respiratory. Pulmonary disease remains the major cause of morbidity and mortality in CF [Cystic Fibrosis Foundation 2006]. Affected individuals have lower airway inflammation and chronic endobronchial infection. Failure of lung defenses leads to bacterial endobronchitis (most commonly Staphylococcus aureus and Pseudomonas aeruginosa) with resulting airway obstruction and intense neutrophilic inflammation.

Early manifestations are chronic cough, intermittent sputum production, and exertional dyspnea. As the lung disease progresses as a result of chronic endobronchitis, structural injury to the airways occurs with resulting bronchiectasis. End-stage lung disease is characterized by extensive damage to the airways (cysts/abscesses) and accompanying fibrosis of lung parenchyma adjacent to airways.

Gastrointestinal. Meconium ileus occurs in 15%-20% of newborns diagnosed with CF.

Pancreatic insufficiency with malabsorption occurs in the great majority of individuals with CF. Exocrine pancreatic insufficiency is caused by inspissation of secretions within the pancreatic ducts and ultimately interstitial fibrosis. The clinical manifestations are steatorrhea and poor growth related to fat malabsorption and hemolytic anemia, defective coagulation, or skin rashes related to deficiencies of fat-soluble vitamins and zinc. Acute or chronic recurrent pancreatitis can be a presenting manifestation of CF, and is much more common among those with pancreatic sufficiency (10% prevalence) than those with pancreatic insufficiency (0.5% prevalence) [De Boeck et al 2005].

Cystic fibrosis-related diabetes mellitus (CFRDM) may present in adolescence. It is diagnosed in 7% of those age 11 to 17 years [Cystic Fibrosis Foundation 2006]. The prevalence increases in adulthood. The etiology is a combination of reduced insulin secretion (secondary to fibrosis of the pancreas and reduced number of islet cells) and peripheral insulin resistance [Lanng 1996, Hardin et al 1997].

Hepatobiliary disease, with elevation of serum concentration of liver enzymes in school-age children, infrequently progresses to biliary cirrhosis in adolescents and adults. Prevalence of liver disease varies based on definition, with the overall rate reported as 6.1% in the 2003 CFF Patient Registry. As liver disease progresses, portal hypertension and varices develop. Liver disease is second to pulmonary disease (plus organ transplantation complications) as a cause of mortality in CF (1.7% of deaths) [Cystic Fibrosis Foundation 2003].

Fertility. More than 95% of males with CF are infertile as a result of azoospermia caused by altered vas deferens, which may be absent, atrophic, or fibrotic. The body and tail of the epididymis and seminal vesicles may be abnormally dilated or absent.

Women with CF are fertile, although a few females have abnormal cervical mucus that may contribute to infertility. The rate of live births among females with CF age 13-45 years is 1.9 per 100 [Cystic Fibrosis Foundation 2003].

Pregnancy. The survival of individuals with CF has improved considerably over the past few decades. Currently, the average median survival is approximately 37 years and pregnancy in women with CF has become an important issue.

Early reports of such pregnancies were discouraging. Historically, the predictors of poor pregnancy outcome for mother and/or fetus have been a forced vital capacity (FVC) of less than 50% of the predicted value and poor nutritional status. In fact, an FVC of less than 50% of the predicted value was an absolute contraindication to pregnancy.

However, with increasingly improved pulmonary treatment, aggressive management of infections with a greater variety of antibiotics, and improved nutrition, pregnancies today are well tolerated, especially in women with mild to moderate disease [Edenborough et al 2000, Gilljam et al 2000, Gillet et al 2002, Cheng et al 2006]. In these women, the risk factors for deteriorating health and early death after pregnancy are the same as for the non-pregnant adult population. In a recent study, Goss et al [2003] adjusted for FEV(1) percent predicted, weight, height, and pulmonary exacerbation rate per year and found that pregnancy was not associated with an increased risk of death. In fact, pregnancy did not appear to be harmful even in a subset of women with diabetes mellitus or with FEV(1) less than 40% of predicted. Important predictors of pregnancy outcome for the fetus are the severity of maternal pulmonary impairment and nutritional status, in that deterioration during pregnancy may precipitate preterm delivery.

The risk for congenital anomalies in the fetus is not increased over background.

Breastfeeding is possible.

Congenital Absence of the Vas Deferens (CAVD)

Men without clinically apparent pulmonary or gastrointestinal manifestations of CF may have CAVD. Hypoplasia or aplasia of the vas deferens and seminal vesicles may occur either bilaterally or unilaterally. CAVD does not pose a health risk per se to the affected male. Testicular development and function and spermatogenesis are usually normal.

CAVD is generally identified during evaluation of infertility or as an incidental finding at the time of a surgical procedure, such as orchidopexy.

Genotype-Phenotype Correlations


Cystic fibrosis. The best correlation between genotype and phenotype is seen in the context of pancreatic function. The most common mutations have been classified as pancreatic sufficient or pancreatic insufficient. Individuals with pancreatic sufficiency usually have either one or two PS alleles, indicating that PS alleles are dominant with respect to pancreatic phenotype.

In contrast, genotype-phenotype correlation is generally poor for pulmonary disease in CF. Pulmonary disease among individuals with identical genotypes varies widely, a finding that may be accounted for in part by genetic modifiers or environmental factors [see Cutting 2005, Drumm et al 2005, Braun et al 2006].

  • Compound heterozygotes with the ΔF508/A455E mutations have better pulmonary function than individuals who are homozygous for ΔF508 [De Braekeleer et al 1997].
  • The severity of lung disease in individuals with one or two R117H mutations depends on the presence of a variation in the poly T tract of intron 8 [Massie et al 2001]. Individuals with a CFTR disease-causing mutation plus the 5T variant in cis configuration with the R117H mutation usually develop the lung disease of CF, but those individuals with R117H and the 7T variant or the 9T variant have a highly variable phenotype that can range from no symptoms to mild lung disease [Kiesewetter et al 1993, Chmiel et al 1999].
  • Because A455E and R117H mutations are associated with pancreatic sufficiency, the less severe lung disease seen in individuals with these mutations could be the consequence of better nutritional status.

CAVD. CAVD usually results from the combination of one severe CF mutation on one chromosome with either a mild CF mutation or the 5T allele on the other chromosome (Table 3). However, some overlap exists between the CAVD phenotype and a very mild CF phenotype, with some fraction of individuals with CAVD also reporting respiratory or pancreatic problems [Dork et al 1997, Gilljam et al 2004]. Moreover, the 5T allele may be associated with lung disease in adult females with CF-like symptoms [Noone et al 2000]. Thus, caution must be exercised in attempting to use genotype to predict the future course of individuals initially diagnosed with CAVD only.

At-risk individuals. Genotype-phenotype correlations are most relevant for genetic counseling of two carriers who have not had an affected child but who have been detected either through evaluation of at-risk family members or screening programs. The considerations in predicting the phenotype of potential offspring are the same as described above for probands with CF or CAVD.

  • In general, prediction of severity of pancreatic disease on the basis of genotype is most reliable, while prediction of the severity of respiratory disease is less reliable.
  • Prediction of the risk of CAVD from genotype is reasonably reliable, but couples should be aware that mild respiratory and/or pancreatic disease can also occur in individuals with genotypes usually associated with CAVD. The mechanism of partial penetrance of the 5T allele for CAVD appears to be variation in the length of the adjacent TG tract (estimated at 60% in one study) [Groman et al 2004] (see Table 4).

Table 4.

Genotype-Phenotype Correlations

CFTR Genotype 1 Range of Phenotypes 2
First AlleleSecond Allele
(or Homozygous)
Classic (e.g., ΔF508)ClassicClassic >> non-classic
Mild (e.g., A455E)Classic or mildNon-classic > classic
R117H/5TClassic or mildNon-classic > classic
R117H/7TClassic or mildAsymptomatic female or CAVD > non-classic
5T/TG13 or TG12Classic or mildCAVD or non-classic CF >> asymptomatic carrier
5T/TG11Classic or mildAsymptomatic > CAVD
7T or 9TClassic or mildAsymptomatic
7T or 9T7T or 9TAsymptomatic

1. Patterns reflect dominant effect of "milder" alleles in compound heterozygotes. Classic alleles generally refer to Class I-III mutations; mild alleles refer to Class IV-V mutations exclusive of R117H and 5T alleles (see Table 10).


Outdated or alternative nomenclature for cystic fibrosis appears in the literature very infrequently.

  • In Europe, CF is sometimes referred to as mucoviscidosis.
  • "Atypical CF" is still used to denote mild CF or CF-like illness. Use of this confusing term is strongly discouraged; it should be replaced with classic CF versus non-classic CF.


CF is the most common life-limiting autosomal recessive disorder in persons of northern European heritage; the disease incidence is 1:3200 live births in this population group [Rosenstein & Cutting 1998]. Approximately 30,000 affected persons live in the US.

CF occurs with lower frequency in other ethnic and racial populations (1:15,000 African-Americans, and 1:31,000 Asian Americans) [Rosenstein & Cutting 1998].

In persons of northern European heritage the heterozygote frequency is one in 22-28 (see Table 5).

Table 5.

Carrier Frequency for Mutant CFTR Alleles

Population GroupApproximate Carrier FrequencyReference
Ashkenazi Jewish1:29Kerem et al [1997]
North American of northern European heritage1:28Hamosh et al [1998]
African American1:61Hamosh et al [1998]

Differential Diagnosis

Disorders in the differential diagnosis of cystic fibrosis (CF) include the following:

  • Dysphagia with chronic descending tracheal aspiration and gastroesophageal reflux (GER) with or without ascending tracheal aspiration
    • Similarities. Chronic cough in infancy; may be associated with failure to thrive; either of these conditions may present as secondary complications in individuals with CF lung disease during infancy, or in the case of GER, later in childhood.
    • Differences. Chronic aspiration is typically associated with focal densities in the lower lobe of the right lung; cough is often temporally associated with feedings; steatorrhea is not associated with primary dysphagia and primary GER.
  • Immunologic abnormalities (especially severe combined immunodeficiency)
    • Similarities. May present with recurrent respiratory infections and chronic diarrhea in infancy
    • Differences. These individuals are also prone to non-respiratory infections (e.g., otitis media, cellulitis) not specifically associated with CF.
  • Airway anomalies
    • Similarities. Chronic cough and wheezing during infancy
    • Differences. GI or nutritional manifestations that are typically present in individuals with CF with respiratory symptoms during infancy are not associated with these anomalies.
    • Similarities. Cough and sputum production during infancy; Pseudomonas aeruginosa or other opportunistic bacterial pathogens may be cultured from airway secretions; chronic sinus disease; may progress to chronic bronchiectasis.
    • Differences. Situs inversus occurs in about 50% of persons with PCD; steatorrhea and failure to thrive are not associated with PCD; associated with mutations in multiple genes encoding different structural components of cilia.
  • Shwachman-Diamond syndrome (congenital lipomatosis of pancreas; Shwachman-Bodian syndrome; Shwachman-Bodian-Diamond syndrome)
    • Similarities. Pancreatic insufficiency, steatorrhea, and failure to thrive; respiratory symptoms may occur during infancy as a result of hypoplasia of the chest wall.
    • Differences. Chronic neutropenia, anemia, thrombocytopenia, or pancytopenia; additional hematologic abnormalities (myelodysplasia) with increased risk of leukemic transformation; skeletal abnormalities (metaphyseal dysostosis type); caused by autosomal recessive mutation of the SBDS gene.
  • Biliary atresia
    • Similarities. Rarely, individuals with CF may present in infancy with symptoms of biliary obstruction, but without other clinically apparent GI or respiratory manifestations.
    • Differences. Serum levels of immunoreactive trypsinogen and stool levels of elastase should be normal in primary biliary atresia, whereas CF liver disease is invariably associated with evidence of pancreatic duct obstruction.

Recent investigations have shown that mutations at genetic loci other than CFTR can produce CF-like phenotypes that are clinically indistinguishable from non-classic CF caused by CFTR mutations [Groman et al 2002]. For example, mutations in the gene encoding the beta subunit of the epithelial sodium channel can mimic CFTR deficiency [Sheridan et al 2005].

Disorders in the differential diagnosis of CAVD. CAVD accounts for 1.2%-1.7% of male infertility. Approximately 80% of men with CAVD have at least one mutation in CFTR [Mak et al 1999].

CAVD may be part of a syndrome or may be an isolated finding.

CAVD is part of the differential diagnosis of obstructive azoospermia, caused by obstruction to sperm outflow from the testes or ductular system. Syndromes with obstructive azoospermia include the following:

  • Young syndrome, a progressive obstruction of the epididymis by inspissated secretions in males with chronic sinopulmonary infection. Males with Young syndrome do not have malformations of the vas deferens or epididymis. Genetic testing of individuals with Young syndrome indicates that this disorder is not associated with CFTR mutant alleles and thus is probably not an alternative presentation of CAVD [Friedman et al 1995].
  • Hereditary urogenital adysplasia, an autosomal dominant disorder of variable expressivity and reduced penetrance. Females have a range of uterine anomalies; males may have Wolffian duct anomalies including unilateral or bilateral absence of the vas deferens; males and females may have unilateral or bilateral renal agenesis.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with cystic fibrosis (CF), the following evaluations are recommended:

Pancreatic insufficiency

  • Fecal elastase (most helpful)
  • Fecal fat content based on 72-hour stool collection
  • Vitamin A, D, and E serum concentrations
  • Prothrombin time and international normalized ratio (INR)
  • Serum carotene concentration in children older than age six months
  • Esophago-gastro-duodenoscopy (EGD) with pancreatic duct cannulation, to measure stimulated enzyme secretion (available at some research centers)

Upper and lower respiratory tracts

  • Sinus CT to assess for pansinusitis in individuals with non-classic presentations or intermediate sweat tests
  • Pulmonary function testing (including infant PFTs at specialized centers)
  • Chest x-ray or possibly chest computed tomography (CT)
  • Sputum culture in patients who can expectorate a sputum sample, or culture of deep oropharyngeal swab in those who cannot
  • Bronchoscopy with bronchoalveolar lavage to evaluate lower airway microbiology and inflammation

Overall clinical status / extent of disease

  • CBC with differential cell count
  • Serum electrolytes, BUN, creatinine, random glucose
  • ALT, gamma-glutamyltransferase
  • Urinalysis

Treatment of Manifestations


  • Intervention to treat or prevent pulmonary complications may include oral, inhaled, or IV antibiotics, bronchodilators, anti-inflammatory agents, mucolytic agents, and chest physiotherapy (postural drainage with chest percussion) [Ramsey et al 1999, Gibson et al 2003a, Bradley et al 2006].
  • Lung or heart/lung transplantation is an option for selected individuals with severe disease.
  • Nasal/sinus symptoms may require topical steroids, antibiotics, and/or surgical intervention.


  • Nutritional therapy may include special formulas for infants to enhance weight gain through improved intestinal absorption, supplemental feeding to increase caloric intake, and additional fat-soluble vitamins and sometimes zinc to prevent the development of deficiencies. Among persons with CF age two to 20 years with body-mass index (BMI) less than 50th percentile followed at CF centers in the US, about 62% receive routine nutritional supplementation, often via an indwelling gastric feeding catheter; the comparable use of nutritional supplements among persons with CF age 20 years or older is 44.5% [Cystic Fibrosis Foundation 2006].
  • Pancreatic insufficiency is treated with oral pancreatic enzyme replacement with meals.
  • Biliary sludging or frank obstruction, and associated hepatic inflammation, are treated with oral ursodiol.


  • CF-related diabetes mellitus (CFRD) may develop during teenage years or later. This form of diabetes mellitus is distinct from both juvenile-onset (type I) and adult-onset (type II) diabetes mellitus; however, some affected individuals do require routine insulin therapy for optimal management [Onady & Stolfi 2005].
  • Casual (random) glucose levels are measured annually in individuals with CF as part of routine management starting at age ten years [Allen et al 1998].
    • If this level is below 126 mg/dL (7.0 mM), it is unlikely that fasting hyperglycemia is present and no further work-up is necessary unless symptoms of CFRD are present.
    • Fasting glucose levels should be measured on all individuals with casual glucose levels ≥126 mg/dL (7.0 mM). A fasting glucose level ≥126 mg/dL (7.0 mM) is diagnostic for CFRD with fasting hyperglycemia when confirmed by a second fasting glucose test or if it occurs in association with a casual glucose level >200 mg/dL (11.1 mM).
    • In individuals with fasting glucose below 126 mg/dL but possible symptoms of diabetes mellitus, an oral glucose tolerance test (OGTT), in which plasma glucose is measured two hours after an oral glucose load of 1.75 g/kg, or 75 g maximum, should be strongly considered to distinguish among normal glucose tolerance (2-hr glucose level <140 mg/dL), impaired glucose tolerance (2-hr glucose level 140-199 mg/dL), and CFRD without fasting hyperglycemia (2-hr glucose level≥200 mg/dL) [Moran et al 1999].
  • Input from endocrinology consultants in the management of CFRD is recommended.


  • Ideally, a woman with CF of reproductive age should receive preconception counseling and take steps to optimize her health prior to pregnancy.
  • The management of pregnancy for a woman with CF requires a multidisciplinary team that includes a dietician, members of the CF team, and an obstetrician.
  • Maternal nutritional status and weight gain should be monitored and optimized aggressively and pulmonary exacerbations should be treated early.
  • The improved survival of women with CF has resulted in an increasing number of women with CFRD contemplating pregnancy. As in pregnancies of women with other forms of diabetes mellitus, fetal outcome is optimized when glycemic control is achieved prior to pregnancy.
  • Traditional screening paradigms for gestational diabetes mellitus are not useful in pregnancies of women with CF; therefore, screening at each trimester of pregnancy has been suggested to improve the detection of diabetes mellitus.
  • Only one pregnancy following lung transplantation in a woman with CF has been reported to date [Gyi et al 2006].

CAVD. The main issues relate to management of infertility that results from obstruction of sperm outflow through the ductal system. Assisted reproductive technologies (ART) to manage infertility include microscopic sperm aspiration from the epididymal remnant in conjunction with in vitro fertilization or artificial insemination using donor sperm.

Physical activity, exercise, and conditioning. A regular exercise program is important to all individuals in maintaining overall health. For persons with CF, regular exercise has the added benefits of maintaining bone health and improving airway clearance. Although exercise improves clearance of airway secretions, it should be used more as an adjunct rather than as a replacement for the individual's prescribed airway clearance regimen.

Prevention of Primary Manifestations

Pancreatic insufficiency and malnutrition. Historically (i.e., in the era prior to newborn screening), about half of all patients with CF presented with failure to thrive and/or steatorrhea during infancy. If untreated, this would typically progress to hypoproteinemia, edema, and severe cachexia. These primary nutritional manifestations of CF can be prevented through prompt institution of pancreatic enzyme replacement and supplementation of fat-soluble vitamins in CF patients with evidence of pancreatic insufficiency. In addition, some patients benefit from high-calorie, high-fat nutritional supplements, which may be recommended based on consultation with a nutritionist specializing in CF.

Biliary cirrhosis. Individuals with CF are also at risk for biliary sludging and obstruction, the first indications of which may be elevation of hepatic enzymes such as gamma-glutamyl transferase (GGT) and amino-acid transaminases (ALT and AST). Individuals with higher levels of endogenous ursodeoxycholic acid appear to be at lower risk for progression to CF liver disease [Smith et al 2004], and chronic oral administration of exogenous ursodiol can reverse focal biliary obstruction at least transiently [Nousia-Arvanitakis et al 2001]. However, whether chronic ursodiol therapy can prevent progression to biliary cirrhosis in the subset of CF patients who are at risk for this complication is uncertain [Brigman & Feranchak 2006].

Prevention of Secondary Complications

Airway clearance

  • Chest physiotherapy (CPT), which can be accomplished through a variety of airway clearance techniques (ACTs), is used to mobilize airway secretions, thereby minimizing the development of airway obstruction as well as the risk of acute exacerbations of airway infection. Several different ACTs are recognized as effective, including manual chest percussion with postural drainage, hand-held devices (e.g., flutter valve, or Acapella®), and inflatable vest therapy devices that vibrate the chest wall. These treatments are most effective when performed at least twice daily.
  • Additional therapies that are helpful in mobilizing airway secretions include once-daily inhalation of DNase (dornase alfa), a mucolytic that can increase cough productivity during CPT. In addition, inhalation of hypertonic saline (3%-7%) has recently been introduced as a maintenance "airway hydration" therapy in patients with CF [Donaldson et al 2006, Elkins et al 2006].
  • CPT is typically performed in conjunction with administration of any inhaled medications that have been prescribed, given in a standard sequence:

    Before CPT
    1. Bronchodilator
    2. Hypertonic saline
    3. DNase

    After CPT
    4. Inhaled corticosteroid and/or long-acting beta-agonist
    5. Inhaled antibiotics

    The rationale for this sequence is to open the airway, decrease sputum viscosity, promote expectoration of secretions, and then deliver anti-inflammatory treatments and/or antibiotics as widely and deeply as possible within the bronchial tree.

Eradication of initial airway infection and prevention of chronic airway infection. The clinical approach to initial CF airway infection has intensified over the past 20 years, with many CF care providers now advocating aggressive antibiotic treatment at the time of first isolation of Pseudomonas aeruginosa from cultured airway secretions. The goal of such treatment is eradication of the initial P. aeruginosa infection and prevention of chronic P. aeruginosa airway infection. Clinical trials of various regimens of inhaled and oral antibiotics have indicated that this organism may be rendered at least transiently undetectable in airway secretions in most cases of initial infection, although recrudescence or re-infection is a common occurrence [Littlewood et al 1985, Frederiksen et al 1997, Gibson et al 2003b, Gibson et al 2007] (see Therapies Under Investigation).


  • All routine immunizations should be given at the recommended times.
    • Especially important are vaccines that protect against microorganisms associated with pulmonary manifestations, including pertussis, measles, varicella, Haemophilus influenzae type B, and Streptococcus pneumoniae.
    • Influenza vaccine should be administered each year as well.

      Note: (1) Because the influenza vaccine may not be fully protective, some experts recommend immunizing a patient's entire family. (2) Some CF care providers prescribe anti-viral medications targeted toward influenza A and B for patients to keep on hand. Patients are instructed to take these medications promptly at the first sign of fever and cough during influenza season.
  • Most children now receive the heptavalent conjugated pneumococcal vaccine (Prevnar®); administration of the 23-valent polysaccharide pneumococcal vaccine (Pneumovax®) later in childhood or adulthood is more controversial because pneumococcal pneumonia is uncommon in CF. However, considering the risks/benefits of vaccine administration and the increased incidence of resistant organisms in CF, its use is reasonable.
  • Infection with respiratory syncytial virus (RSV) is an especially serious problem in younger patients with CF. Unfortunately, there is no safe and effective vaccine. Passive immunization with an anti-RSV monoclonal antibody (Synagis®) is available; however, this requires monthly subcutaneous injections for the duration of the local RSV season, and no convincing studies have been published to demonstrate efficacy (or lack thereof) in treating CF. Pending the availability of such data, passive immunization of young CF patients against RSV is considered by many CF care providers.



  • Patients should have regularly scheduled visits to their CF care providers to monitor for subtle changes in physical examination that are not yet manifest as symptoms.
  • Patients who are not yet chronically infected with P. aeruginosa should have cultures of respiratory tract secretions at least four times yearly. Some patients may benefit from more frequent visits and respiratory tract surveillance cultures (see Therapies Under Investigation).
  • Affected individuals are regularly followed with pulmonary function studies, chest radiographs, and specific blood and urine laboratory tests.


  • There are also increased risks of osteopenia related to vitamin D and calcium deficiencies that require screening of bone density starting in adolescence.
  • Casual (random) glucose levels are measured annually in individuals with CF as part of routine management starting at age ten years [Allen et al 1998]. Casual glucose levels ≥126 mg/dL (7.0 mM) require further evaluation (see Treatment of Manifestations).

Agents/Circumstances to Avoid

Avoid the following:

  • Respiratory irritants (smoke, dust)
  • Respiratory infectious agents (especially respiratory viruses)
  • Dehydration (need to add extra salt to diet in hot, dry climates because of perspiration-related salt losses)

Evaluation of Relatives at Risk

Sweat chloride testing of sibs and mothers of affected individuals to determine if they may have mild or not yet symptomatic forms of CF is appropriate.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Currently, studies are being performed in Europe and the United States to assess whether chronic respiratory tract infection can indeed be delayed, and if so, which antibiotic agents are most effective for this purpose.

  • Continuous prophylactic antibiotic treatment for Staphylococcus aureus has not been shown to reduce the deterioration in lung function.
  • One multicenter trial of continuous cephalexin administration demonstrated increased acquisition of P. aeruginosa in treated patients [Stutman et al 2002].
  • Large multicenter randomized controlled trials are now underway to determine optimal strategies and regimens for eradication of P. aeruginosa and prevention of chronic infection.

New therapies for the treatment of cystic fibrosis lung disease that span the pathophysiologic cascade of CF are being investigated. Additional research focuses on CFTR "bypass" therapy to augment alternative chloride channels (i.e., UTP), CFTR "protein assist" treatment to improve the trafficking and function of defective CFTR protein [Kerem 2005], use of small molecular modulators of CFTR [Verkman et al 2006], new anti-inflammatory agents, new IV and inhaled antibiotics, and antiproteases.

Gene therapy. Gene therapy is in a research phase only. Gene therapy is not able to control or treat the symptoms related to CF at this time [Anson et al 2006].

Search for access to information on clinical studies for a wide range of diseases and conditions.


There has been much interest in developing active and passive immunization strategies against Pseudomonas aeruginosa. However, an effective vaccine against P. aeruginosa has not yet been developed.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CFTR-related disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband with cystic fibrosis (CF)

  • The unaffected parents are obligate carriers (heterozygotes) and have an alteration in one copy of the CFTR gene.
  • Carriers are generally asymptomatic.
  • On rare occasions, a parent may be diagnosed as affected subsequent to the diagnosis of the child.

Sibs of a proband with CF

  • At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    • If the disease-causing CFTR alleles have been identified in the proband, it is most informative to test sibs by molecular genetic testing. Otherwise, sweat chloride testing should be performed.
  • For an at-risk sib who is known to be unaffected but has not yet undergone molecular genetic testing, the risk of being a carrier is 2/3.
  • Carriers are asymptomatic.

Offspring of a female proband with CF

  • Females with CF can be fertile.
  • A woman with CF transmits one disease-causing CFTR allele to each of her children.
  • The risk that her child will inherit a second disease-causing CFTR allele depends on her reproductive partner's carrier status. CFTR molecular genetic testing should be offered to her reproductive partner to determine his carrier status. The specific molecular genetic testing panel that is used should be based on the reproductive partner's ethnicity and family history.
    • If the reproductive partner is a carrier, the offspring will be at risk for CF or CAVD.

Offspring of a male proband with CF

  • Males with CF may conceive children through assisted reproductive technologies (ART).
    • An affected male will transmit one mutant CFTR allele to each of his offspring.
    • The risk that his child will inherit a second disease-causing CFTR allele depends on his reproductive partner's carrier status. CFTR molecular genetic testing should be offered to his reproductive partner to determine her CFTR carrier status. The specific molecular genetic testing panel that is used should be based on the reproductive partner's ethnicity and family history.
    • If the reproductive partner is a carrier, the offspring will be at risk for CF or CAVD

Parents, sibs, and offspring of a proband with CAVD

  • Males with CAVD may conceive children through assisted reproductive technologies (ART).
  • The risk to the relatives of a proband with CAVD depends on the parental genotypes and cannot readily be predicted without this information.
  • Molecular genetic testing is most informative when the CAVD-causing CFTR alleles have been identified in the proband. Men with CAVD sometimes have only one identifiable CFTR mutation, complicating the testing and interpretation of results in their family members.

Other family members. Each sib of a known CFTR mutation carrier is at a 50% risk of being a carrier. Even if the carrier has no known affected sibs, a residual risk remains that both parents could be carriers and thus could conceive an affected offspring.

Carrier Detection

The following situations may arise when carrier detection is pursued for at-risk relatives of individuals with CF or CAVD and their reproductive partners:

  • Both disease-causing alleles of a proband are known. If both disease-causing alleles have been identified in the proband, the at-risk maternal and paternal relatives can be tested for their family-specific mutation following genetic counseling.
  • Only one disease-causing allele of a proband is known. As mutation detection rates improve, one should consider performing additional molecular genetic testing for identifiable mutations in probands. Molecular genetic testing should be informative for relatives related through the parent with the identifiable mutation. Molecular genetic testing will not be informative for relatives related through the carrier parent who does not have an identifiable mutation if the relatives are only tested for mutations in the proband's test panel. Linkage analysis may be helpful for these relatives.
  • Neither disease-causing allele of a proband is known. As mutation detection rates improve, one should consider performing additional molecular genetic testing for identifiable mutations in probands. Molecular genetic testing of relatives will not be informative if the relatives are only tested for mutations in the proband's test panel. Linkage analysis may be helpful for these relatives.
  • The proband is deceased and no DNA testing was performed. Under such circumstances, it is appropriate to attempt to obtain any available tissue samples for the purpose of DNA extraction and CFTR molecular genetic testing. If DNA cannot be obtained, it is appropriate to test at-risk family members, following genetic counseling. Those family members who have a disease-causing CFTR mutation are carriers and follow-up genetic counseling regarding molecular genetic testing of partners and pregnancy risks is appropriate. Those family members who do not have a mutation detected using a panel of CFTR mutations can have their carrier risk reduced, though not eliminated, using Bayes Theorem (Table 6). (See also the National Society of Genetic Counselors statement on carrier testing for cystic fibrosis.)

Table 6.

Residual Risk (%) of a Relative Being a CFTR Mutation Carrier if Molecular Genetic Testing Does Not Detect a Mutation

Prior Risk of Being a CarrierMutation Detection Rate (%)
(66.7%) 1
(50.0%) 2
(25.0%) 3

1. Unaffected sib of a proband

2. Unaffected sib of a carrier

3. Unaffected cousin of a proband

See Table 6a (pdf) for residual risk of being a carrier for other values of prior risk.

  • Cis configuration and trans configuration of 5T variant with a disease-causing allele is not known. Additional family members may need molecular genetic testing to establish phase for informative interpretation of results.
  • A person has a reproductive partner who is a known carrier or is at risk based on family history. At-risk partners should be offered CFTR molecular genetic testing. It is appropriate to offer molecular genetic testing to the reproductive partners of those who are found to be carriers, with the understanding that failure to detect a mutation reduces but does not eliminate the risk of being a carrier (See Table 7).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

Population screening. Screening for CF carrier status is being offered to some couples as part of routine prenatal care in some centers [Grody 1999] (see Published Guidelines/Consensus Statements). The ACMG Subcommittee on Cystic Fibrosis Screening recommends that CF carrier screening be offered to non-Jewish whites and Ashkenazi Jews, and made available to other ethnic and racial groups through appropriate counseling regarding risks, testing options, detection rates, and informed consent. The Committee recommends use of a pan ethnic, 23-mutation panel that includes the majority of CF-causing mutations with an allele frequency of greater than 0.1% in the general US population (Table 8) [Watson et al 2004]. Screening panels may be supplemented with other mutations to improve sensitivity for specific ethnic groups. Implementation of population-based newborn screening programs for CF generally includes plans to address increased demands on genetic counseling resources.

Carrier testing at the time of newborn screening follow up. Lagoe et al [2005] found that providing genetic counseling and offering carrier testing to parents at the time their newborn was undergoing sweat testing for a positive newborn screening result led to greater use of these services than when parents were offered genetic counseling and carrier testing by phone at the time the sweat tests results were relayed.

5T/TG tract. The 5T/TG tract analysis should not be included in a routine carrier screen. It is an appropriate test in males with CAVD or suspected CAVD, individuals with non-classic CF, or adult carriers of 5T who wish to further define their reproductive risks. 5T/TG tract analysis can increase or decrease risk, but no specific risk figures are associated with test results.

Residual risk after carrier testing. Individuals with no family history of CF who test negative for a panel of CFTR mutations can have their carrier risk reduced (though not eliminated) based on their ethnicity. The residual risk of being a carrier depends on the carrier frequency and the mutation detection rate. Table 7 provides calculations of residual risk based on the mutation detection rate of the test method used and the individual's a priori risk of being a carrier. For example, an individual with no known family history of CF has a 1/30 a priori risk of being a carrier. If the individual does not have one of the mutations in a test panel with a mutation detection rate of 95%, his/her (residual) risk of being a carrier is 1/500.

Table 7.

Residual Risk (%) to an Individual with No Family History of a CFTR-Related Disorder of Being a CFTR Mutation Carrier if Molecular Genetic Testing Does Not Detect a Mutation

Prior Risk of Being a CarrierMutation Detection Rate

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies. Prenatal testing for pregnancies at increased risk is possible by molecular genetic testing of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The CFTR pathogenic allelic variants must be identified in both parents before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Indeterminate-risk pregnancies. When one parent is known to be a CFTR mutation carrier and the other parent has tested negative for a panel of CFTR alleles, no additional testing to clarify the status of the fetus is available. Although Girodon-Boulandet et al [2000] have suggested that assay of intestinal enzyme levels in amniotic fluid may be informative, these tests are not available in the United States and lack specificity and sensitivity.

Low-risk pregnancies. The finding of fetal echogenic bowel and/or dilated bowel on ultrasound examination is associated with an increased risk for CF in a pregnancy previously not known to be at increased risk for CF. The risk for CF may be 2%-3% with Grade 2 (moderate) echogenic bowel. For Grade 3 (severe) echogenic bowel, defined as echogenicity similar to or greater than that of surrounding fetal bone and/or intestinal dilation, the reported incidence of CF has been 5%-20% [Corteville et al 1996, Slotnick & Abuhamad 1996, Ghose et al 2000]. In this situation, genetic counseling of the parents regarding the risk for CF is appropriate, followed by CFTR molecular genetic testing of the parents and/or the fetus, depending on the gestational age of the pregnancy and the decision of the parents. Based on the mutation detection rate of the test method used, risk for CF when only one disease-causing allele is identified in the fetus can be calculated [Bosco et al 1999, Hodge et al 1999].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic allelic variants have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CFTR-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for CFTR-Related Disorders (View All in OMIM)


Gene structure. CFTR is 230 kb long and contains 27 coding exons. It produces a 6.5-kb mRNA product. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 1000 pathogenic variants are known; almost all are point mutations or small (1-84 bp) deletions. The most common mutation is ΔF508 (Phe508del), accounting for an estimated 30%-80% (depending on the ethnic group) of mutant alleles. Table 8 lists the panel of 23 alleles recommended by the American College of Medical Genetics for routine diagnostic and carrier testing [Watson et al 2004]. Table 9 lists ten of the most common CFTR mutations and shows their most typical phenotypic effect when present in affected individuals.

Table 8.

Recommended Core Mutation Panel for General Population CF Carrier Screening

3659delC ΔF508R347P 1898+1G>A3849+10kbC>T
ΔI507 N1303KR553*2184delA621+1G>T
G542* R1162*R560T 2789+5G>A711+1G>T

Table 9.

Ten Most Common CFTR Mutations in Persons of Northern European Heritage with Related Phenotypic Expression

Mutation Relative
Class 1
Phenotype 2
ΔF50866.0%IIClassic 3
R1162*0.3%Not clear 4 Classic

1. See Table 10.

2. At a recent European Cystic Fibrosis Society Consensus Conference (Interpretation of Genetic Analysis for CF, Garda Lake, Italy, March 23-24, 2007), it was decided that mutation class is useful from a molecular biology perspective but that it should not be used clinically. A manuscript summarizing the results of this consensus conference is in preparation [Garry R Cutting, personal communication].

3. There are numerous exceptions to the correlation between mutation effect and phenotype (e.g., A455E is Class II but associated with mild lung disease and pancreatic sufficiency).

4. Transcript is stable; truncated protein is probably misfolded; therefore, likely Class II.

Normal gene product. Cystic fibrosis transmembrane conductance regulator (CFTR) is a 1480-amino acid integral membrane protein that functions as a regulated chloride channel in epithelia.

Abnormal gene product. Mutations can affect the CFTR protein quantitatively, qualitatively, or both. Table 10 provides one classification scheme for the functional consequences of CFTR mutations.

Table 10.

Classification Scheme for CFTR Mutations

Mutation ClassEffect of Mutation on CFTR ProteinMechanisms
IReduced or absent synthesisNonsense, frameshift, or splice-junction mutations
IIBlock in protein processingMissense mutations, amino acid deletions
IIIBlock in regulation of CFTR chloride channelMissense mutations
IVAltered conductance of CFTR chloride channelMissense mutations


Published Guidelines/Consensus Statements

  1. American College of Medical Genetics. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics Mutation Panel. Available online. 2004. Accessed 3-6-14.
  2. National Institutes of Health. Genetic testing for cystic fibrosis: National Institutes of Health Consensus Development Conference Statement. Available online. 1997. Accessed 3-6-14.
  3. National Society of Genetic Counselors. Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors. Available online. 2014. Accessed 3-6-14. [PubMed: 24014130]
  4. Wilson RD, Davies G, Desilets V, Reid GJ, Shaw D, Summers A, Wyatt P, Young D, Crane J, Armson A, de la Ronde S, Farine D, Leduc L, Van Aerde J. Society of Obstetricians and Gynaecologists of Canada.; Cystic fibrosis carrier testing in pregnancy in Canada. J Obstet Gynaecol Can. 2002;24:644–51. [PubMed: 12196844]

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Suggested Reading

  1. Moskowitz SM, Gibson RL, Effmann EL. Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment. Pediatr Radiol. 2005;35:739–57. [PubMed: 15868140]
  2. Rubenstein RC. Novel, mechanism-based therapies for cystic fibrosis. Curr Opin Pediatr. 2005;17:385–92. [PubMed: 15891431]
  3. Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). 2015. New York, NY: McGraw-Hill. Chap 201.

Chapter Notes

Author History

Edith Cheng, MS, MD (2001-present)
James F Chmiel, MD (2008-present)
Garry R Cutting, MD (2001-present)
Ronald L Gibson, MD, PhD; University of Washington, Seattle (2001-2008)
Susan G Marshall, MD; University of Washington, Seattle (2001-2004)
Samuel M Moskowitz, MD (2004-present)
Darci Sternen, MS, CGC (2001-present)
Jonathan F Tait, MD, PhD; University of Washington, Seattle (2001-2004)

Revision History

  • 19 February 2008 (me) Comprehensive update posted to live Web site
  • 24 August 2005 (cd) Revision: changes to ACMG-recommended mutation panel
  • 24 August 2004 (me) Comprehensive update posted to live Web site
  • 26 March 2001 (me) Review posted to live Web site
  • 6 October 1998 (jt) Original submission
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