CFTR-Related Disorders

[Includes: Cystic Fibrosis (CF, Mucoviscidosis) and Congenital Absence of the Vas Deferens (CAVD) ]

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
  and

• 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 the CFTR gene
    or

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

  • 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:

• Diagnosis in a newborn screening program (based on the presence of two disease-causing mutations in the CFTR gene or abnormal sweat chloride value). In 2002, 12.8% of newly diagnosed individuals were identified through newborn screening [Cystic Fibrosis Foundation 2003].

• In utero diagnosis by presence of two disease-causing mutations in the CFTR gene. In 2002, 4.0% of newly diagnosed individuals were identified by prenatal diagnosis [Cystic Fibrosis Foundation 2003].

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

Testing

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

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 profbe 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 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in CFTR-Related Disorders

Test Method	Mutations Detected	Mutation Detection Frequency by Population Group		Test Availability
Targeted mutation analysis	CFTR mutations using the original 25-mutation panel 1	Ashkenazi Jewish	97% 2	Clinical
		Non-Hispanic Caucasian	88.3% 3
		African American	69% 2
		Hispanic American	57% 2
		Asian American	Unknown
Deletion analysis	CFTR exonic and whole-gene deletions	All populations	Unknown
Sequence analysis	CFTR sequence variants	All populations	98.7% 4

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.

2. Grody et al [2001]

3. Palomaki et al [2002]

4. 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

• For issues to consider in interpretation of sequence analysis results, click here.

• 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 Method	Percentage of Individuals with CF for which a Given Number of Abnormal Alleles is Identified
	Two Abnormal Alleles	One Abnormal Allele	No Abnormal Allele
98%	96%	4%	0%
95%	90%	10%	0%
90%	81%	18%	1%
85%	72%	26%	2%
80%	64%	32%	4%
75%	56%	38%	6%
70%	49%	42%	9%
60%	36%	48%	16%
50%	25%	50%	25%
40%	16%	48%	36%
30%	9%	42%	49%

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 5T	5T
2	0	26%
0	2	2%
1	1	26%
1	0	17%
0	1	8%
0	0	22%

Based on pooled data from Dork et al [1997], Mak et al [1999], Casals et al [2000], Wang et al [2002]

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:

• 1

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

• 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.)

• 3

  Molecular genetic testing for CFTR mutations

Genetically Related (Allelic) Disorders

An increased prevalence of CFTR mutations has been noted in individuals with idiopathic pancreatitis, bronchiectasis, allergic bronchopulmonary aspergillosis, and chronic rhinosinusitis. The reader is referred to the following references for further information: Cohn et al [1998], Luisetti et al [1998], Mickle & Cutting [1998], Wang et al [2000], Cohn et al [2004], Cohn et al [2005], Nick & Rodman [2005], Weiss et al [2005].

At present, DNA testing is of unknown and unclear utility for these conditions.

Natural History

Genotype-Phenotype Correlations

Nomenclature

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.

Prevalence

CF is the most common life-limiting autosomal recessive disorder in the Caucasian population. The disease incidence is 1:3200 live births among Caucasians [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 the Caucasian population, the heterozygote frequency is one in 22-28 (see Table 5).

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

Respiratory

• 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.

Gastrointestinal

• 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.

Endocrine

• 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.

Pregnancy

• 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).

Immunization

• 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.

Surveillance

Respiratory

• 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.

Gastrointestinal/Endocrine

• 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

• 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)

Testing 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 ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

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.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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.

  • If the disease-causing CFTR alleles have been identified in the proband, it is most informative to test parents by molecular genetic testing.

• 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.

  • If the disease-causing CFTR alleles have been identified in the proband, it is most informative to test sibs by molecular genetic testing.

• 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).

• 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

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 Statements and Guidelines Regarding Genetic Testing). The ACMG Subcommittee on Cystic Fibrosis Screening recommends that CF carrier screening be offered to non-Jewish Caucasians 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.

DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

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 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing mutations of the CFTR gene 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 available for families in which the disease-causing mutations have been identified. This requires coordination between the genetic counselor, specialists in reproductive endocrinology and fertility (REI), and the molecular genetics laboratory. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Suggested Reading

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